Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[C:13]([OH:14])=[C:12]([Cl:15])[CH:11]=[C:10]([CH3:16])[CH:9]=1.[Br:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][CH2:23][CH2:24]OS(C)(=O)=O)=[CH:20][CH:19]=1>O.C(O)CC>[Br:17][C:18]1[CH:31]=[CH:30][C:21]([O:22][CH2:23][CH2:24][O:14][C:13]2[C:8]([Cl:7])=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=2[Cl:15])=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)OCCOc1ccc(Br)cc1
Reactant: Cc1cc(Cl)c(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCO
Solvent: O
Product: Cc1cc(Cl)c(OCCOc2ccc(Br)cc2)c(Cl)c1
Temperature: 85 °C
Reaction time: 6 h
Yield: 81.1 %

Procedure:
K2CO3 (29.3 g, 212 mmol) was dissolved in water (162 mL). 1-Propanol (150 mL) was added. A sol. of 2,6-dichloro-para-cresol (25 g, 141 mmol) in 1-propanol (150 mL) was added. Methanesulfonic acid 2-(4-bromo-phenoxy)-ethyl ester (41.6 g, 141 mmol) was added. The mixture was stirred at 85° C. for 6 h. The heating oil bath was removed, and water (330 mL) was added dropwise when the internal temperature had reached 78° C. The beige suspension was allowed to cool to rt. The mixture was filtered, and the precipitate was washed with water. Drying the precipitate under high vacuum at 30° C. for 48 h yielded the title compound (43 g, 81%). LC-MS: tR=1.15 min.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl.FC(F)(F)S(O[C:27]1[C:39]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][C:31]=2[CH:30]=[CH:29][CH:28]=1)(=O)=O>O1CCOCC1.O.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.Cl[Pd]Cl.[Fe+2]>[CH:30]1[C:31]2[NH:32][C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:39]=2[C:27]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[N:8][CH:7]=2)=[CH:28][CH:29]=1
Reactant: OCc1ccc(B(O)O)cn1
Reactant: O=S(=O)(Oc1cccc2[nH]c3ccccc3c12)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: OCc1ccc(-c2cccc3[nH]c4ccccc4c23)cn1
Temperature: 25 °C
Yield: 47.4 %

Procedure:
0.54 g of [6-(hydroxymethyl)pyridin-3-yl]boronic acid, 3.3 g of caesium carbonate and 93 mg of 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride as a complex with dichloromethane (1/1) [PdCl2(dppO'CH2Cl2] are successively added, under argon, to a solution of 0.8 g of 4-trifluoromethanesulphonyloxycarbazole, obtained in stage 1 of Example 1, in a mixture of 37 ml of dioxane and 12 ml of water. The reaction mixture is refluxed for 5 hours, cooled to ambient temperature and concentrated under reduced pressure. The residue is subsequently taken up with a mixture of dichloromethane and ethyl acetate, treated with carbon black, filtered through celite and concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a mixture of cyclohexane and ethyl acetate (55/45 by volume), so as to give 0.33 g of [5-(9H-carbazol-4-yl)pyridin-2-yl]methanol in the form of a colourless oil, the characteristics of which are the following:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[N:14]=[C:13]([C:15]([O:17]C)=O)[CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.[CH3:19][C:20]#[N:21]>>[O:17]=[C:15]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([O:8][CH2:7][CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[N:14]=1)[CH2:19][C:20]#[N:21]
Reactant: CC#N
Reactant: COC(=O)c1cccc(OCC2CCOCC2)n1
Product: N#CCC(=O)c1cccc(OCC2CCOCC2)n1

Procedure:
Reaction between methyl 6-((tetrahydro-2H-pyran-4-yl)methoxy)picolinate and CH3CN following the method used in Example 6 gives 3-oxo-3-(6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridin-2-yl)propanenitrile.
Reaction SMILES: ClC(Cl)(Cl)COC([N:7]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[C:8]([O:10]CC(Cl)(Cl)Cl)=O)=O.[C:24]1([C:30]2[N:31]=[C:32]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[S:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:24]1([C:30]2[N:31]=[C:32]([N:35]3[CH2:40][CH2:39][N:38]([C:8]([NH:7][C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)=[O:10])[CH2:37][CH2:36]3)[S:33][CH:34]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1cccnc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Yield: 27.7 %

Procedure:
A mixed solution of bis(2,2,2-trichloroethyl)pyridin-3-ylimidodicarbonate (359 mg, 0.810 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (396 mg, 1.62 mmol) and diisopropylethylamine (0.281 ml, 1.62 mmol) in dimethyl sulfoxide (2.7 ml) was stirred at 70° C. for 3 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (100% ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 82.0 mg (27.8%) of the desired product as a solid. mp 74-75° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:18][N:6]2[CH2:7][CH2:8][N:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=3)[CH2:10][C@@H:5]2[CH2:4]1.[F:19][C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([O:1][CH2:2][C@@H:3]2[CH2:18][N:6]3[CH2:7][CH2:8][N:9]([C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=4)[CH2:10][C@@H:5]3[CH2:4]2)=[CH:22][CH:21]=1
Reactant: OC[C@H]1C[C@H]2CN(c3ccc(Cl)cn3)CCN2C1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(OC[C@H]2C[C@H]3CN(c4ccc(Cl)cn4)CCN3C2)cc1
Yield: 71.3 %

Procedure:
A solution of 0.25 g (0.93 mmol) of (7S,8aS)-7-hydroxymethyl-2-(5-chloropyridin-2-yl)-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 14), 0.157 g (1.40 mmol) of 4-fluorophenol, 0.29 g (1.12 mmol) of triphenylphosphine and 0.18 mL (1.1 mmol) of diethyl azodicarboxylate (DEAD) in 10 mL of dry THF was stirred at ambient temperature for 16 hours. The solvent was evaporated, the residue was dissolved in chloroform and washed with 1M sodium hydroxide. The organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 1:1 hexane:ethyl acetate gave 0.24 g (71%) of the title compound. Mp (.HCl) 221-224° C. HRMS calc'd for C19H22ClFN3O (MH+): 362.1435, found: 362.1415.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[C:7]([N:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)=[O:8])([O-:3])=[O:2].CO.[BH4-].[Na+]>C1COCC1.O>[OH:15][CH:12]1[CH2:13][CH2:14][N:9]([C:7]([C:6]2[CH:16]=[CH:17][CH:18]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:8])[CH2:10][CH2:11]1
Reactant: O=C1CCN(C(=O)c2cccc([N+](=O)[O-])c2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(3-nitrobenzoyl)piperidin-4-one (1.5 g, 6.04 mmol) in THF: Methanol (20 mL, 1:1), was added sodium borohydride (0.229 g, 6.04 mmol) at room temp. Reaction mixture was stirred at room temperature for 30 min. and diluted with water (20.0 ml), extracted with ethyl acetate (3×30.0 ml). Combined organic layer was dried over sodium sulphate and the solvents were removed under vacuum to obtain the title compound. (1 gm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18](I)[N:17]=[CH:16]3)[CH:9]=2)=[CH:4][CH:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][N:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18]([C:25]4[CH:26]=[CH:27][C:22]([NH2:21])=[N:23][CH:24]=4)[N:17]=[CH:16]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)cc(-n2cnc(I)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(Cl)cc2)cc(-n2cnc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-methyl-pyridine (example E.30) (0.200 g, 0.51 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.122 g, 0.62 mmol) according to the general procedure VI. Obtained as a white solid (0.035 g, 19%). MS (ISP) 362.3 [(M+H)+] and 364 [(M+2+H)+]; mp 230-233° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[O:15][CH3:16])=[CH:12][C:11]([I:17])=[CH:10][CH:9]=2)=O.[OH-].[NH4+:19]>>[I:17][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[CH:6][C:5]([C:3]([NH2:19])=[O:2])=[C:14]2[O:15][CH3:16]
Reactant: [NH4+]
Reactant: COC(=O)c1cnc2ccc(I)cc2c1OC
Agent: [OH-]
Product: COc1c(C(N)=O)cnc2ccc(I)cc12
Temperature: 150 °C
Yield: 88 %

Procedure:
A suspension of 6-iodo-4-methoxy-quinoline-3-carboxylic acid methyl ester (example 1d) (1.7 g, 5 mmol) in ammonium hydroxide (28%, 75 mL) was heated at 150° C. for 4 days under pressure tube. After cooling, the solvent was removed by rotary evaporator. The solid was collected by filtration, washed with water and dried to obtain 6-iodo-4-methoxy-quinoline-3-carboxylic acid amide (1.4 g, 88%) as a black solid. LC-MS m/e 329 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:20][OH:21]>CCO>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:7]=[CH:6][C:3]=1[CH:4]=[N:20][OH:21]
Reactant: CCCCCCCCOc1ccc(C=O)c(O)c1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CCCCCCCCOc1ccc(C=NO)c(O)c1
Reaction time: 2 h

Procedure:
To a solution of 2-hydroxy-4-octyloxy-benzaldehyde (3.64 g; 14.5 mmol) in abs. EtOH (30 mL) was added hydroxylamine hydrochloride [50% H2O (w/w)] and the slurry was stirred for 2 hours. The reaction mixture was evaporated to dryness and the resulting solid triturated in H2O (20 mL) and EtOAc/diethylether (20 mL+10 mL) to give 1.8 g (47%) as a white solid. MS (direct; EI): 265 (M).
Reaction SMILES: [CH2:1]([N:8](CCC)[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][C:13]([N:18]3[CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:14][CH:15]=2)[CH2:10]1)[C:2]1C=CC=C[CH:3]=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH2:1]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][C:13]([N:18]3[CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:14][CH:15]=2)[CH2:10]1)[CH2:2][CH3:3]
Reactant: CCCN(Cc1ccccc1)C1Cc2ccc(-n3cccc3)cc2C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCCNC1Cc2ccc(-n3cccc3)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
A mixture of benzyl-propyl-(6-pyrrol-1-yl-indan-2-yl)-amine (540 mg, 1.64 mmol), ammonium formate (0.8 g, 12.6 mmol) and 10% Pd/C (0.3 g) in 99% ethanol (50 mL) was stirred for at ambient temperature for 1 h. The mixture was filtered on a Celite pad and the solution concentrated in vacuo. The residue was redissolved in 10% sodium carbonate/diethyl ether. After 2 additional ether extractions of the aqueous phase, the combined ethereal phases were dried (magnesium sulfate) filtered and evaporated to yield 320 mg of a residue containing both the pyrrolo and the pyrrolidino derivative. The two compounds were separated on a silica column using methanol as eluant, yielding 230 mg (58%) of the pyrrolo derivative and 40 mg (10%) of the pyrrolidino derivative.: 1H NMR (300 MHz, CDCl3) δ 0.93 (t, 3H), 1.52 (m, 2H), 2.61 (t, 2H), 2.77 (m, 2H), 3.18 (m, 2H), 3.67 (m, 1H), 6.31 (m, 2H), 7.03 (m, 2H), 7.1-7.3 (m, 3H); MS m/e 240 (M+, 72), 211 (100), 182 (72), 171 (65), 115 (25).
Reaction SMILES: [F:1][C:2]1([F:14])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]#[N:13])=[CH:10][C:4]=2[O:3]1.Br[CH2:16][CH2:17]Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:14][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:12]#[N:13])[CH2:17][CH2:16]3)=[CH:10][C:4]=2[O:3]1
Reactant: N#CCc1ccc2c(c1)OC(F)(F)O2
Reactant: ClCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: N#CC1(c2ccc3c(c2)OC(F)(F)O3)CC1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
A stock solution of 50% w/w NaOH was degassed via nitrogen sparge for no less than 16 h. An appropriate amount of MTBE was similarly degassed for several hours. To a reactor purged with nitrogen was charged degassed MTBE (143 mL) followed by (2,2-difluoro-1,3-benzodioxol-5-yl)-acetonitrile (40.95 g, 207.7 mmol) and tetrabutylammonium bromide (2.25 g, 10.38 mmol). The volume of the mixture was noted and the mixture was degassed via nitrogen sparge for 30 min. Enough degassed MTBE is charged to return the mixture to the original volume prior to degassing. To the stirring mixture at 23.0° C. was charged degassed 50% w/w NaOH (143 mL) over 10 min followed by 1-bromo-2-chloroethane (44.7 g, 311.6 mmol) over 30 min. The reaction was analyzed by HPLC in 1 h intervals for % conversion. Before sampling, stirring was stopped and the phases allowed to separate. The top organic phase was sampled for analysis. When a % conversion >99% was observed (typically after 2.5-3 h), the reaction mixture was cooled to 10° C. and was charged with water (461 mL) at such a rate as to maintain a temperature <25° C. The temperature was adjusted to 20-25° C. and the phases separated. Note: sufficient time should be allowed for complete phase separation. The aqueous phase was extracted with MTBE (123 mL), and the combined organic phase was washed with 1 N HCl (163 mL) and 5% NaCl (163 mL). The solution of (2,2-difluoro-1,3-benzodioxol-5-yl)-cyclopropanecarbonitrile in MTBE was concentrated to 164 mL under vacuum at 40-50° C. The solution was charged with ethanol (256 mL) and again concentrated to 164 mL under vacuum at 50-60° C. Ethanol (256 mL) was charged and the mixture concentrated to 164 mL under vacuum at 50-60° C. The resulting mixture was cooled to 20-25° C. and diluted with ethanol to 266 mL in preparation for the next step. 1H NMR (500 MHz, DMSO) δ 7.43 (d, J=8.4 Hz, 1H), 7.40 (d, J=1.9 Hz, 1H), 7.30 (dd, J=8.4, 1.9 Hz, 1H), 1.75 (m, 2H), 1.53 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([Br:16])=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Li]CCCC.CN([CH:25]=[O:26])C.C(Cl)Cl.CCCCCC>C1COCC1>[Br:16][C:9]1[C:10]2[C:15]([C:2]([CH:25]=[O:26])=[C:3]3[C:8]=1[CH:7]=[CH:6][CH:5]=[CH:4]3)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1c2ccccc2c(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 68 %

Procedure:
To the yellow suspension of 9,10-Dibromoanthracene (2 g, 5.95 mmol) in THF (20 mL) at −90° C., n-BuLi (2.88 mL, 7.18 mmol, 2.5 M in hexane) was added dropwise. Orange solution was observed after 45 min additional stirring. Anhydrous DMF (0.92 mL, 11.9 mmol) was added to the orange solution. The reaction mixture was slowly warmed to room temp and stirred overnight. The reaction mixture was quenched with H2O and extracted with CH2Cl2. The organic layer was washed with 10% aq. Na2CO3 solution (3×50 mL). The CH2Cl2 layer was separated, dried over anhydrous Na2SO4, filtered and removed in vacuo to give yellow solid. The crude product was purified by column chromatography using 30% CH2Cl2/hexane to give 6 in 68% yield. Rf=0.3 (30% CH2Cl2/hexane; 1H NMR (CDCl3) d 11.39 (s, 1H), 8.77-8.82 (d, 2H), 8.55-8.60 (d, 2H), 7.56-7.67 (m, 4H). (Ref. de Montigny, Frederic; Argouarch, Gilles; Lapinte, Claude. New route to unsymmetrical 9,10-disubstituted ethynylanthracene derivatives. Synthesis, 2006, 2, 293-298.)
Reaction SMILES: Cl[C:2](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([CH3:24])=[CH2:23])=[CH:20][CH:19]=1>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[C:22]([C:21]3[CH:25]=[CH:26][C:18]([Cl:17])=[CH:19][CH:20]=3)([CH3:24])[CH2:23][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8]2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(Cl)=NNc1ccc(Cl)cc1
Reactant: C=C(C)c1ccc(Cl)cc1
Product: CCOC(=O)C1=NN(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)C1

Procedure:
The compound of Example 6 (1.0 gm) was converted to the title compound (0.6 gm) by adaptation of the procedure of Example 9 to 4-chloro-α-methyl styrene (2.5 ml). The product was a yellow oil. NMR (CDCl3) 7.3-6.8 (m, ArH, 8H), 4.3 (q, 2H, CH2), 3.3 (m, 2H, CH2), 1.8 (s, 3H, CH3), 1.3 (t, 3H, CH3).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[O:1]([CH2:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCCOc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCCOc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Phenoxypropan-1-ol (3.17 g, 20.86 mmol) was dissolved dichloromethane (25 mL) and pyridinium chlorochromate (6.76 g, 31.28 mmol) was added. The slurry was stirred at room temperature for 1 hour and then filtered through silica gel eluting with an ethyl acetate/hexanes gradient. The desired compound was isolated as a yellow oil (1.1 g).
Reaction SMILES: C(O)=[O:2].OO.[C:6]12(C)[C:12](C)(C)[CH:9]([CH:10]=[CH:11]1)[CH2:8][CH:7]2[S:15]([O-:18])(=[O:17])=[O:16].CC1C=CC=C[NH+]=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>>[OH:2][CH:10]1[CH:11]2[CH:6]3[CH:7]([CH2:8][CH:9]1[CH2:12]3)[S:15](=[O:18])(=[O:17])[O:16]2
Reactant: O=CO
Reactant: CC1(C)C2C=CC1(C)C(S(=O)(=O)[O-])C2
Agent: Cc1cccc[nH+]1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Product: O=S1(=O)OC2C(O)C3CC2C1C3
Temperature: 10 °C
Reaction time: 21 h

Procedure:
Into a three-necked flask having an inner volume of 300 mL equipped with a stirrer, a thermometer and a dropping funnel, the whole amount of “Aqueous Solution C” obtained above was charged, and cooled down to 10° C. 99% Formic acid (10.8 g, 0.232 mol) was weighed into a dropping funnel, and added dropwise to the reaction system so that the inner temperature of the reaction system was maintained in a range of 11 to 15° C. After that, the inner temperature was raised up to 50 to 52° C. by heating, and then 30% hydrogen peroxide aqueous solution (18.69 g, 0.165 mol) weighed and contained in another dropping funnel was added dropwise to the reaction system over 3 hours. After completion of the dropping, the inner temperature of the reaction system was also maintained at around 50° C. After 21 hours from completion of the dropping, the reaction liquid was analyzed by HPLC to confirm that conversion ratio of 2-methylpyridinium 5-bornene-2-sulfonate was 98.1%. After cooling down the reaction liquid to 15° C., sodium sulfite was added slowly to the reaction system so that the inner temperature of the reaction system was maintained in a range of 15 to 18° C. until a starch paper did not detect hydrogen peroxide. Subsequently, sodium hydrogen carbonate was added slowly to adjust pH of the reaction liquid at 7.0 so that the inner temperature of the reaction system was maintained in a range of 17 to 20° C. The reaction liquid was extracted with ethyl acetate (100 g) twice, the resultant organic layers were combined, washed with water (25 g), and then concentrated under the reduced pressure until the amount of the liquid became 35.1 g. Isopropyl ether (21.0 g) was added to the resultant concentrated liquid in a heated state at 50° C., then the mixture was cooled down to 5° C. at a rate of about 10° C./hour, to precipitate crystal of the product. After filtering the precipitated crystal, the filtered out crystal was washed with isopropyl ether (6.0 g) at 5° C., and dried at 40° C. for hours under the reduced pressure, to obtain 2-hydroxy-4-oxa-5-thiatricyclo[4.2.1.03,7]nonane 5,5-dioxide (8.74 g, purity: 98.6%, 0.045 mol). It should be noted that, yield of the product from 5-norbornene-2-sulfonyl chloride was 52.3%.
Reaction SMILES: [F:1][C:2]([CH3:9])([CH3:8])[C:3](=[O:7])[CH2:4][C:5]#[N:6].[CH3:10][Si](C=[N+]=[N-])(C)C>C(OCC)C>[F:1][C:2]([CH3:9])([CH3:8])[C:3]([O:7][CH3:10])=[CH:4][C:5]#[N:6]
Reactant: CC(C)(F)C(=O)CC#N
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=CC#N)C(C)(C)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 91 %

Procedure:
To a stirred solution of 4-fluoro-4-methyl-3-oxopentanenitrile (1 g, 7.75 mmol) in dry diethyl ether (150 mL) at 0° C., was added dropwise (trimethylsilyl)diazomethane (4.65 mL of a 2.0 M solution in diethyl ether, 9.30 mmol). After warming to room temperature the reaction mixture was stirred for a further 15 h. The reaction mixture was concentrated under reduced pressure to afford 4-fluoro-3-methoxy-4-methylpent-2-enenitrile as a yellow oil (1 g, 91%) which was taken on to the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 4.89 (s, 1H), 4.23 (s, 3H), 1.47 (d, J=21 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:31][C:11]3[C:12](=[O:30])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]5)=[C:18]([O:28][CH3:29])[CH:17]=4)[CH:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:31][C:11]3[C:12](=[O:30])[N:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:26][CH2:25][C@@H:24]([O:27][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:23]5)=[C:18]([O:28][CH3:29])[CH:17]=4)[CH:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1N1CC[C@@H](O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(-n2ccc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1N1CC[C@@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-6-[4-((R)-3-hydroxy-pyrrolidin-1-yl)-3-methoxy-phenyl]-6H-thieno[2,3-c]pyridin-7-one (2.407 g, 5.34 mmol) in CH2Cl2 (50 mL) and add MsCl (0.46 mL, 5.87 mmol) and Et3N (1.0 mL, 7.32 mmol). Stir the mixture at RT for one hour. Dilute the mixture with CH2Cl2 (50 mL) and wash with water (30 mL). Dry the solution with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 10% EtOAc/CH2Cl2 to give 1.05 g (37%) of the title compound. LC-MS/ES m/z (35Cl) 531.8 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][CH2:12][NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1>CC(O)C>[CH3:28][O:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:29][CH3:30])[N:20]=[CH:19][N:18]=[C:17]2[N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:15]=2)[CH2:11][CH2:12]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: c1ccc(-c2ccc3c(c2)NCC3)cc1
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4ccc(-c5ccccc5)cc43)c2cc1OC
Yield: 61 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 61% yield from 6-phenyl-indoline (1.1 eq.), and 4-chloro-6,7- dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 175°-177° C.; GC-MS: 383 (M+); anal. RP18-HPLC RT: 6.03min.).
Reaction SMILES: Cl[C:2]1[N:10]2[CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]3=[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[C:20]2[C:21]([CH3:26])=[N:22][O:23][C:24]=2[CH3:25])[N:3]=1.Br[Zn]CCC>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:26][C:21]1[C:20]([C:7]2[C:8]3[O:13][CH2:12][CH:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:10]4[CH:2]=[N:3][C:4]([C:9]=34)=[CH:5][CH:6]=2)=[C:24]([CH3:25])[O:23][N:22]=1
Reactant: Cc1noc(C)c1-c1ccc2nc(Cl)n3c2c1OCC3c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCC[Zn]Br
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc2ncn3c2c1OCC3c1ccccc1
Temperature: 150 °C

Procedure:
A reaction mixture of 2-chloro-7-(3,5-dimethylisoxazol-4-yl)-4-phenyl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (15 mg, 0.041 mmol), 0.5 M bromo(propyl)zinc in THF (0.5 mL) and tetrakis(triphenylphosphine)palladium(0) (2 mg, 0.002 mmol) in THF (0.4 mL) under nitrogen was heated in a microwave at 150° C. for 5 min. Purification of the product by preparative LCMS using pH 10 buffer gave the title compound. LCMS calc. for C20H17N3O2 (M+H)+: m/z=332.1. found: 332.2.