Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]1=[O:14].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[CH2:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.[C:37](=O)([O-:39])[OH:38].[Na+]>C(O)C>[C:6]([OH:14])(=[O:15])[C:37]([OH:39])=[O:38].[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[CH2:30][CH:31]1[CH2:32][CH2:33][N:34]([CH2:2][CH2:3][CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[NH:7][C:6]2=[O:14])[CH2:35][CH2:36]1
Reactant: c1coc(Cn2c(CC3CCNCC3)nc3ccccc32)c1
Reactant: O=C([O-])O
Reactant: O=c1[nH]c2ccccc2n1CCCCl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C(=O)O
Product: O=c1[nH]c2ccccc2n1CCCN1CCC(Cc2nc3ccccc3n2Cc2ccco2)CC1
Yield: 43 %

Procedure:
A mixture of 3.16 parts of 1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 4.4 parts of 1-(2-furanylmethyl)-2-(4-piperidinylmethyl)-1H-benzimidazole, 2 parts of sodium hydrogen carbonate and 80 parts of ethanol was stirred and refluxed for 32 hours. The reaction mixture was cooled and filtered over Hyflo. The filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the ethanedioate salt in methanol. The salt was filtered off and dried, yielding 4.2 parts (43%) of 1-[3-[4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]propyl]-1,3-dihydro-2H-benzimidazol-2-one ethanedioate (1:2); mp. 214.7°-218.4° C. (139).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][CH:4]=1)#[N:2].[C:20]([C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32]N[CH2:30][CH2:29]2)=[CH:24][CH:23]=1)#[CH:21].[CH3:34]CCCCCC.CCOC(C)=O>>[N:28]1([C:25]2[CH:26]=[CH:27][C:22]([C:20]#[C:21][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)=[CH:23][CH:24]=2)[CH2:33][CH2:32][CH2:34][CH2:30][CH2:29]1
Reactant: C#Cc1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C#N)cc2)cc1
Reactant: CCCCCCC
Solvent: CCOC(C)=O
Product: N#Cc1ccc(C#Cc2ccc(N3CCCCC3)cc2)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-cyano-phenyl ester and 1-(4-ethynyl-phenyl)-piperazine following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 9:1; yield (137 mg, 96%); 1H NMR δ (CDCl3): 7.61-7.51 (m, 4H), 7.4 (d, J=8.41 Hz, 2H), 6.85 (d, J=8.42 Hz, 2H), 3.25 (m, 4H), 1.73-153 (m, 6H); LCMS m/z 286.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]=[CH:15][C:16]([NH:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([O:23]C)=[O:22])=[O:17])[CH:5]=[CH:4][C:3]1=2.C1COCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1([CH3:29])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH:14]=[CH:15][C:16]([NH:18][C:19]3[CH:28]=[CH:27][CH:26]=[CH:25][C:20]=3[C:21]([OH:23])=[O:22])=[O:17])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccccc1NC(=O)C=Cc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C=CC(=O)Nc3ccccc3C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
540 mg (1.38 mmol) of methyl 2-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)acryloylamino]benzoate, 5 ml of THF and 5 ml of methanol are introduced into a round-bottomed flask. 5.5 ml of methanolic sodium hydroxide solution (2N) are added and the mixture is stirred at room temperature for four hours. The reaction medium is poured into water, acidified to pH 1 with hydrochloric acid and extracted with ethyl acetate, and the organic phase is separated out after settling has taken place, washed with water, dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (95/5). After evaporating the solvents, 400 mg (77%) of the expected acid, with a melting point of 185-6° C., are collected.
Reaction SMILES: [Br:1][C:2]1[C:6]2[S:7][CH:8]=[C:9]([C:10]3[N:11]=[C:12]([C@@H:15]4[CH2:19][CH2:18][CH2:17][NH:16]4)[NH:13][CH:14]=3)[C:5]=2[S:4][CH:3]=1.[CH3:20][O:21][C:22](=[O:79])[NH:23][C@H:24]([C:28](N1CCC[C@H]1C1NC(C2C=CC(C3SC4=NC(NC([C@@H]5CCCN5C(=O)[C@H](NC(OC(C)(C)C)=O)C5C=CC=CC=5)=O)=CN4C=3)=CC=2)=CN=1)=[O:29])[CH:25]([CH3:27])[CH3:26].C(OC(=O)N[C@@H](C1C=CC=CC=1)C(N1CCC[C@H]1C(=O)NC1N=C2N(C=1)C=C(Br)S2)=O)(C)(C)C>>[CH3:20][O:21][C:22](=[O:79])[NH:23][C@H:24]([C:28]([N:16]1[CH2:17][CH2:18][CH2:19][C@H:15]1[C:12]1[NH:13][CH:14]=[C:10]([C:9]2[C:5]3[S:4][CH:3]=[C:2]([Br:1])[C:6]=3[S:7][CH:8]=2)[N:11]=1)=[O:29])[CH:25]([CH3:27])[CH3:26]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3cn4cc(NC(=O)[C@@H]5CCCN5C(=O)[C@H](NC(=O)OC(C)(C)C)c5ccccc5)nc4s3)cc2)[nH]1)C(C)C
Reactant: Brc1csc2c(-c3c[nH]c([C@@H]4CCCN4)n3)csc12
Agent: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cn2cc(Br)sc2n1)c1ccccc1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2csc3c(Br)csc23)c[nH]1)C(C)C

Procedure:
Compound 78 was synthesized from compound 77 (1.56 mmol) and compound 1 (1.64 mmol), following the procedure as described for compound 23 to give compound 78 in 82% yield. MS (ESI, EI+) m/z=513.2/515 (MH+).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:6]([O:21][CH2:22][CH3:23])[CH2:5]1)(=[O:3])[NH2:2].Br[CH:25]([CH2:35][CH3:36])[C:26](=O)[C:27]([O:29][CH2:30][CH2:31]CC)=[O:28].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:13]([O:12][C:11]([NH:10][C@H:7]1[CH2:8][CH2:9][N:4]([C:1]2[O:3][C:25]([CH2:35][CH3:36])=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:2]=2)[CH2:5][C@H:6]1[O:21][CH2:22][CH3:23])=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCCOC(=O)C(=O)C(Br)CC
Reactant: CCO[C@@H]1CN(C(N)=O)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OCC)C2)oc1CC
Yield: 90.5 %

Procedure:
The same operation as in Example (103c) was performed using cis(±)-benzyl (1-carbamoyl-3-ethoxypiperidin-4-yl)carbamate obtained in Example (112f) (0.95 g, 3 mmol), butyl 3-bromo-2-oxopentanoate obtained in Example (106a) (5 g, 19.9 mmol), sodium bicarbonate (0.72 g, 9 mmol) and THF (15 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/10, 1/2, 1/1, 2/1, 4/1) to obtain 1.21 g of the title compound as a light yellow oily substance (86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[CH2:14][CH2:15][C:16]([OH:18])=[O:17].S(=O)(=O)(O)O.[CH3:24]O>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[CH2:14][CH2:15][C:16]([O:18][CH3:24])=[O:17]
Reactant: O=C(O)CCc1cnoc1-c1ccc(F)cc1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(F)cc1F
Yield: 87 %

Procedure:
To a solution of 3-[5-(2,4-difluorophenyl)-4-isoxazolyl]propionic acid (1.25 g) in methanol (40 ml) was added conc. sulfuric acid (1 ml) and the mixture was heated under reflux for 1 hr. The reaction mixture was concentrated, and iced water was poured into the residue. The precipitated crystals were collected by filtration. The crystals were subjected to silica gel column chromatography, and the crystals obtained from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio) were recrystallized from ethyl acetate-hexane to give a colorless prism (1.15 g, yield 87%) of methyl 3-[5-(2,4-difluorophenyl)-4-isoxazolyl]propionate. melting point: 40–41° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:5])[CH2:3][OH:4].[C:6]1(=O)[O:11][C:9](=[O:10])[C:8]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:7]12>C(OCC)(=O)C>[OH:4][CH2:3][C@@H:2]([N:1]1[C:9](=[O:10])[C:8]2[C:7](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]1=[O:11])[CH3:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: C[C@H](N)CO
Solvent: CCOC(C)=O
Product: C[C@@H](CO)N1C(=O)c2ccccc2C1=O
Temperature: 140 °C
Yield: 99.9 %

Procedure:
A mixture of (2S)-2-aminopropan-1-ol (26 mL, 333 mmol) and phthalic anhydride (51.7 g, 349.4 mmol) is heated at 140° C. overnight. During this time the solid becomes an orange liquid. The reaction is cooled to RT and diluted with ethyl acetate (10 mL/g). The organic phase is washed with saturated NaHCO3 and 10% citric acid, dried over MgSO4, filtered, and concentrated to afford the title compound (68.3 g, 98%) as a white solid that is used without further purification. LC-ES/MS m/z 206 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([S:8][CH3:9])=[CH:6][CH:7]=1.[O:10]1[CH2:14][CH2:13][N:12]=[C:11]1[C:15]1[CH:30]=[CH:29][C:18]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[O:10]1[CH2:14][CH2:13][N:12]=[C:11]1[C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:24][CH2:25][N:26]([C:2]3[N:3]=[N:4][C:5]([S:8][CH3:9])=[CH:6][CH:7]=3)[CH2:27][CH2:28]2)=[CH:29][CH:30]=1
Reactant: c1cc(C2=NCCO2)ccc1OCCCN1CCNCC1
Reactant: CSc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CSc1ccc(N2CCN(CCCOc3ccc(C4=NCCO4)cc3)CC2)nn1
Reaction time: 120 h
Yield: 11.2 %

Procedure:
A mixture of 2.4 parts of 3-chloro-6-(methylthio)pyridazine, 4.5 parts of 1-[3-[4-(4,5-dihydro-2-oxazolyl)phenoxy]propyl]piperazine, 1.6 parts of sodium carbonate and 80 parts of 1-butanol was stirred for 5 days at reflux temperature. The reaction mixture was evaporated and the residue was dissolved in trichloromethane. The organic phase was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 0.7 parts (11.2%) of 3-[4-[3-[4-(4,5-dihydro-2-oxazolyl)phenoxy]-propyl]-1-piperazinyl]-6-(methylthio)pyridazine; mp. 163.1° C. (comp. 83).
Reaction SMILES: [CH3:1][C:2]([N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[N:19](COCC[Si](C)(C)C)[CH:20]=[CH:21][C:14]=23)[CH:10]=[N:9]1)([CH3:7])[CH2:3][CH2:4][C:5]#[N:6].[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>>[CH3:1][C:2]([N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[NH:19][CH:20]=[CH:21][C:14]=23)[CH:10]=[N:9]1)([CH3:7])[CH2:3][CH2:4][C:5]([NH2:6])=[O:31].[F:33][C:32]([F:35])([F:34])[C:30]([O-:36])=[O:31]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(CCC#N)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Product: CC(C)(CCC(N)=O)n1cc(-c2ccnc3[nH]ccc23)cn1
Product: O=C([O-])C(F)(F)F
Reaction time: 16 h
Yield: 58 %

Procedure:
The crude 4-methyl-4-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]pentanenitrile (36 mg, 0.000088 mol, see preparation in Example 59), was stirred in TFA (2 mL) for 1 hour. The mixture was concentrated to remove excess TFA, and the resulting residue was stirred in 2 mL methanol containing 0.5 mL NH4OH for 16 hours. The product was purified by preparative-HPLC (C18 eluting with a gradient of ACN/H2O containing 0.1% TFA) to afford 4-methyl-4-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]pentanamide as the trifluoro-acetate salt (21 mg, 58%). 1H NMR (400 MHz, d6-DMSO): 12.18 (s, 1H), 8.60 (s, 1H), 8.33-8.21 (m, 2H), 7.62 (br s, 1H), 7.53 (d, 1H), 7.22 (br s, 1H), 7.04 (br s, 1H), 6.71 (br s, 1H), 2.14-2.07 (m, 2H), 1.86-1.79 (m, 2H), 1.58 (s, 6H); MS (ES): 298 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2/[C:13](=N/[S@](C(C)(C)C)=O)/[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[O:24]1CCCC1>>[CH2:1]([N:8]1[CH2:12][C@H:11]2[C:13](=[O:24])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: CC(C)(C)[S@](=O)/N=C1\CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Agent: Cl
Product: O=C1CC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S,E)-N-((3aS,6aR)-2-Benzylhexahydrocyclopenta[c]pyrrol-4(5H)-ylidene)-2-methylpropane-2-sulfinamide (2.67 g, 8.38 mmol) from Example 14 Step A and 2.0 N aqueous HCl (18.86 mL, 37.7 mmol) were combined in tetrahydrofuran (25 mL). The reaction was stirred at room temperature for 2 hours and the tetrahydrofuran was removed in vacuo and the remaining aqueous portion was made slightly basic with aqueous sodium bicarbonate solution. The aqueous layer was extracted with 3×200 mL of dichloromethane. The combined organic layers were separated, and the solvent was removed in vacuo. The crude material was purified on a silica gel cartridge (Analogix®, Burlington, Wis., RS25-25) eluting with 5-50% ethyl acetate/hexanes to give (3aS,6aR)-2-benzylhexahydrocyclopenta[c]pyrrol-4(5H)-one: 1H NMR (300 MHz, CDCl3) δ ppm 7.35-7.16 (m, 5H), 3.61 (d, J=13.1, 1H), 3.48 (d, J=13.1, 1H), 3.02 (dd, J=1.8, 9.1, 1H), 2.96-2.82 (m, 1H), 2.71-2.56 (m, 2H), 2.43 (dt, J=8.2, 17.4, 3H), 2.34-2.21 (m, 1H), 2.12 (ddd, J=8.3, 13.0, 16.9, 1H), 1.79 (dddd, J=4.2, 6.4, 9.2, 13.2, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:28]=[CH:27][C:14]([CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][C:18]=2[O:25][CH3:26])=[CH:13][CH:12]=1.[CH3:29]O.[OH-].[K+]>C(OCC)(=O)C.O>[Cl:10][C:11]1[CH:28]=[CH:27][C:14]([CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]([O:22][CH3:29])[C:3]3[C:4]4[C:9](=[N:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)=[CH:19][C:18]=2[O:25][CH3:26])=[CH:13][CH:12]=1
Reactant: COc1cc(C=O)ccc1OCc1ccc(Cl)cc1
Reactant: CO
Reactant: c1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(C(OC)c2c[nH]c3ncccc23)ccc1OCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 432 h
Yield: 74 %

Procedure:
To 1H-Pyrrolo[2,3-b]pyridine (94, 0.235 g, 1.99 mmol) and 4-(4-chlorobenzyloxy)-3-methoxybenzaldehyde (106, 0.500 g, 1.81 mmol) was added 5 mL of methanol followed by the addition of solid potassium hydroxide (0.203 g, 3.61 mmol). The reaction was allowed to stir at ambient temperature for 18 days. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated and volatiles removed to give a solid which was suspended in hot ethyl acetate. The suspension was allowed to cool and the solid collected by vacuum filtration to provide 107 (548 mg, 74%). MS(ESI) [M+H+]+=409.4.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH:9]([C:13]([OH:15])=O)[CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl.[C:20]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[C:20]1([CH:26]2[CH2:27][CH2:28][N:29]([C:13]([CH:9]3[CH2:8][CH2:7][C:6]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[C:11](=[O:12])[CH2:10]3)=[O:15])[CH2:30][CH2:31]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C1CC(C(=O)O)CCc2ccccc21
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1CC(C(=O)N2CCC(c3ccccc3)CC2)CCc2ccccc21
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of 0.3 g (1.47 mmol) of (±)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one-7-carboxylic acid in 5 mL of CH2Cl2 were added, at 0° C., 0.27 mL (3.69 mmol) of SOCl2 and the solution was warmed at 50° C. for 20 min. The solvent and the excess SOCl2 were removed in vacuo and the resulting residue was redissolved in 5 mL of CH2Cl2. 0.24 g (1.47 mmol) of 4-phenylpiperidine and 0.2 mL (1.47 mmol) of triethylamine dissolved in 5 mL of CH2Cl2 were added at room temperature to this solution; the stirring was continued overnight, then the solvent was removed in vacuo and the residue was taken up in AcOEt; the organic phase was washed successively with 10% NaOH, 10% HCl and water, the solvent was removed in vacuo yielding 0.49 g of the title compound as an oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[C:35](=[O:36])[N:34]([CH2:37][CH3:38])[C:15]2[N:16]=[C:17]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]4)=[CH:23][CH:22]=3)[N:18]=[CH:19][C:14]=2[CH:13]=1)[C:5]([NH:7][NH2:8])=[O:6].F[C:40](F)(F)C(O)=O>C(OCC)(OCC)OCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH:40]=[N:8][N:7]=2)[CH:9]=[CH:10][C:11]=1[C:12]1[C:35](=[O:36])[N:34]([CH2:37][CH3:38])[C:15]2[N:16]=[C:17]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([N:27]4[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]4)=[CH:25][CH:26]=3)[N:18]=[CH:19][C:14]=2[CH:13]=1
Reactant: CCn1c(=O)c(-c2ccc(C(=O)NN)cc2Cl)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Reactant: O=C(O)C(F)(F)F
Solvent: CCOC(OCC)OCC
Product: CCn1c(=O)c(-c2ccc(-c3nnco3)cc2Cl)cc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Temperature: 130 °C
Yield: 50 %

Procedure:
3-Chloro-4-{8-ethyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl}benzoic acid hydrazide (7, 30 mg, 0.06 mmol) was suspended in triethyl orthoformate (5 mL) to which was added trifluoroacetic acid (1 mL). The resulting reaction mixture was heated at 130° C. for 2 h. The volatiles were removed and the residue was taken up in dichloromethane (1×20 mL) and washed with 10% sodium hydroxide solution (2×10 mL). The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography using dichloromethane:methanol (95:5). The title compound (18 mg, 0.03 mmol, 50%) was obtained as a yellow solid. ESMS m/z 543 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.57 (s, 1H) 8.50 (s, 1H) 8.21 (d, J=1.5 Hz, 1H) 8.04 (dd, J=8.0, 1.5 Hz, 1H) 7.62 (s, 1H) 7.52-7.60 (m, 3H) 7.29 (br. s., 1H) 6.98 (d, J=9.0 Hz, 2H) 4.50 (q, J=6.8 Hz, 2H) 3.16-3.27 (m, 4H) 2.56-2.65 (m, 4H) 2.37 (s, 3H) 1.39 (d, J=6.8 Hz, 3H).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH3:16][O-:17].[Na+].O([Si](C)(C)C)[K].Cl>CS(C)=O.O>[CH3:16][O:17][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: O=c1[nH]cnc2cc(F)c([N+](=O)[O-])cc12
Reactant: C[O-]
Agent: C[Si](C)(C)O[K]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nc[nH]c(=O)c2cc1[N+](=O)[O-]
Yield: 75.6 %

Procedure:
7-fluoro-6-nitroquinazolin-4(3H)-one (60 g, 287 mmol) in <Step 3> of Example 3 was dissolved in DMSO (600 mL) and sodium methoxide (46.5 g, 861 mmol) was added dropwise thereto in an ice water bath. Thirty minutes later, KOTMS (147 g, 1150 mmol) was added slowly to the water bath, and the mixture was subjected to a reaction for one day. Then, the mixture was neutralized with a 2N HCl solution. Subsequently, the solid thus obtained was filtered and dried to obtain the title compound (48 g, 76%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[C:4]([CH3:16])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][C:25]2[CH:37]=[CH:36][C:28]3[C:29]([CH2:32][C:33]([OH:35])=[O:34])=[CH:30][O:31][C:27]=3[CH:26]=2)[CH:18]=1.C(O)C>C(N(CC)CC)C>[CH3:16][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][O:24][C:25]2[CH:37]=[CH:36][C:28]3[C@H:29]([CH2:32][C:33]([OH:35])=[O:34])[CH2:30][O:31][C:27]=3[CH:26]=2)[CH:18]=1
Reactant: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(COc2ccc3c(CC(=O)O)coc3c2)c1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(OCCCS(C)(=O)=O)cc(C)c1-c1cccc(COc2ccc3c(c2)OC[C@H]3CC(=O)O)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 99.8 %

Procedure:
Under an argon atmosphere, to [6-({2′,6′-dimethyl-4′-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-1-benzofuran-3-yl]acetic acid (522 mg), dichloro[(+)-1,2-bis((2R,5R)-2,5-diisopropylphosphorano)benzene]ruthenium (II)-N,N-dimethylformamide complex (7.4 mg) in an autoclave container was added a solution of dehydrated ethanol (6 mL) containing triethylamine (0.139 mL), and the mixture was stirred at 50° C. for 24 hr under a hydrogen atmosphere (1 MPa). The reaction mixture was concentrated, 10% aqueous citric acid solution (25 mL) and ethyl acetate (25 mL) were added, and an extraction operation was performed. The aqueous layer was extracted with ethyl acetate (25 mL), and the combined organic layer was washed with water (25 mL), dried over sodium sulfate and concentrated. The crude product was washed with diisopropyl ether. After filtration, the obtained solid was dried at 50° C. under reduced pressure to give the title compound (523 mg) as white crystals. 80.0% ee.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](=[NH:14])([NH2:13])=[O:12])(=[O:4])=[O:3].C1([O:21][C:22](=O)[NH:23][C:24]2[N:29]=[C:28]([O:30][CH3:31])[CH:27]=[C:26]([O:32][CH3:33])[N:25]=2)C=CC=CC=1.N12CCCN=C1CCCCC2.Cl>C(#N)C.O>[CH3:31][O:30][C:28]1[CH:27]=[C:26]([O:32][CH3:33])[N:25]=[C:24]([NH:23][C:22]([NH:14][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:2]([CH3:1])(=[O:4])=[O:3])(=[NH:13])=[O:12])=[O:21])[N:29]=1
Reactant: CS(=O)(=O)c1ccccc1S(=N)(N)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(OC)nc(NC(=O)NS(=N)(=O)c2ccccc2S(C)(=O)=O)n1
Reaction time: 0.75 h
Yield: 68.8 %

Procedure:
To a solution of 62.6 mg (0.267 mmol) of 2-(methylsulfonyl)benzenesulfonimidamide and 73.5 mg (0.21 mmol) of phenyl(4,6-dimethoxypyrimidin-2-yl)carbamate in 1.3 mL of dry acetonitrile was added 0.04 mL (0.27 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene. After 45 minutes at room temperature, 1.3 mL of water and 0.65 mL of 5% HCl were added. A solid precipitated out of solution. This material was isolated by filtration, washed with ether to give 60 mg of a white solid; m.p. 135° to 145° C. (d).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]([C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:22]1[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[CH:24][N:23]=1>CN(C=O)C.[Cu]>[O:7]([C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[O:20][C:22]1[C:27]([C:28]#[N:29])=[CH:26][CH:25]=[CH:24][N:23]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Oc1cccc(Oc2ccccc2)c1
Reactant: N#Cc1cccnc1Cl
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cccnc1Oc1cccc(Oc2ccccc2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 157 %

Procedure:
A mixture of potassium carbonate (5.53 g, 0.04 mol) and 3-phenoxyphenol (15 g, 0.08 mol) in DMF (60 ml) was heated at 80° C. with stirring for 30 minutes. 2-Chloro-3-cyanopyridine (11.08 g, 0.08 mol) and copper bronze (0.8 g) were added and the resulting mixture heated at reflux for 90 minutes. GC analysis indicated the formation of a single product (96%). The reaction mixture was cooled and filtered, and then poured into water (300 ml) and allowed to sand over the weekend. The yellow-brown oily precipitate was extracted into dichloromethane and dried. The dichloromethane solution was then filtered and evaporated to yield crude 2-(3-phenoxyphenoxy)-3-cyano-pyridine (36.2 g, contaminated with DMF) which was used in the next stage without further purification.