Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:26](=[O:27])[C:22]3([CH2:25][CH2:24][CH2:23]3)[N:21]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][C:37]([NH2:39])=O)=[CH:30][CH:29]=3)[C:20]2=[S:40])=[CH:15][C:14]=1[C:41]([F:44])([F:43])[F:42])#[N:12].C(N(CC)CC)C>ClCCl>[C:37]([CH2:36][CH2:35][CH2:34][C:31]1[CH:30]=[CH:29][C:28]([N:21]2[C:20](=[S:40])[N:19]([C:16]3[CH:17]=[CH:18][C:13]([C:11]#[N:12])=[C:14]([C:41]([F:44])([F:42])[F:43])[CH:15]=3)[C:26](=[O:27])[C:22]32[CH2:23][CH2:24][CH2:25]3)=[CH:33][CH:32]=1)#[N:39]
Reactant: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CCCC(N)=O)cc3)C2=S)cc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: N#CCCCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of DMSO (0.01 mL, 0.12 mmol) in dry dichloromethane (1 mL) was added to a stirred solution of oxalyl chloride (0.01 mL, 0.09 mmol) in dry dichloromethane (2 mL) at −78° C. After 15 min, a dichloromethane solution of 4-(4-(7-(4-Cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)butanamide, NC47 (Formula 52) (35 mg, 0.07 mmol) was added to the reaction mixture. Stirring was continued for 20 min at −78° C., and then triethylamine (0.03 mL, 0.22 mmol) was added. After 30 min at −78° C., the reaction mixture was warmed to room temperature and then reaction was quenched with saturated aq. NH4Cl solution. The reaction mixture was diluted with dichloromethane, and extracted with dichloromethane. The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane:acetone, 95:5) to yield 4-(5-(4-(3-Cyanopropyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-2-(trifluoromethyl)benzonitrile, NC57 (Formula 53) (29 mg, 87%) as a viscous oil. 1H NMR δ 7.98 (d, 1H, J=1.8 Hz), 7.98 (d, 1H, J=8.3 Hz), 7.86 (dd, 1H, J=8.3, 1.8 Hz), 7.43 (d, 2H, J=8.4 Hz), 7.27 (d, 2H, J=8.4 Hz), 2.90 (t, 2H, J=7.3 Hz), 2.63-2.73 (m, 2H), 2.52-2.62 (m, 2H), 2.42 (t, 2H, J=7.3 Hz), 2.18-2.30 (m, 1H), 2.07 (p, 2H, J=7.3 Hz), 1.63-1.73 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[CH3:15][CH:16]([CH3:25])[CH2:17][CH2:18][N:19]1[CH:23]=[N:22][NH:21][C:20]1=[O:24]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:21]1[C:20](=[O:24])[N:19]([CH2:18][CH2:17][CH:16]([CH3:25])[CH3:15])[CH:23]=[N:22]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: CC(C)CCn1cn[nH]c1=O
Product: CC(C)CCn1cnn([C@H](C)[C@@]2(c3ccc(F)cc3F)CO2)c1=O
Yield: 49.4 %

Procedure:
In the same menner as in Reference Example 5, starting from 1.38 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.21 g of 4-(3-methylbutyl)-3(2H,4H)-1,2,4-triazolone, 2-[(1R, 2S)-2-(2,4-Difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-(3-methylbutyl)-3 (2H, 4H)-1,2,4-triazolone (1.15 g) was obtained as a colorless oil.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=O.[OH-].[NH4+:12]>>[O:8]1[CH2:9][CH2:10][CH:5]([C:3]([NH2:12])=[O:2])[CH2:6][CH2:7]1
Reactant: COC(=O)C1CCOCC1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)C1CCOCC1

Procedure:
In a 5 L flask, charge methyltetrahydropyran-4-carboxylate (500 ml, 3.75 mol) and concentrated ammonium hydroxide (1.3 L) and stir the reaction at room temperature for 48 hours. Filter the reaction and dry the white solid in a vacuum oven at 60° C. overnight. to obtained 36.33 g white solid of the title compound.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[F:19][C:20]([F:30])([F:29])[O:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>>[F:30][C:20]([F:19])([F:29])[O:21][C:22]1[CH:23]=[CH:24][C:25]([S:28][CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:10][CH2:11]2)=[CH:26][CH:27]=1
Reactant: FC(F)(F)Oc1ccc(S)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccc(OC(F)(F)F)cc2)CC1
Yield: 41 %

Procedure:
The title compound was prepared in 41% yield (0.66 g, colorless oil) from tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.20 g, 4.30 mmol) and 4-(trifluoromethoxy)benzenethiol (1.00 g, 5.15 mmol) by the similar manner in Step-1 of Intermediate-4.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.Br[C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27][C:22]=3[N:23]([CH3:26])[C:24]=2[CH:25]=1>>[CH3:26][N:23]1[C:24]2[CH:25]=[C:17]([N:4]3[CH:5]=[CH:6][C:7]([C:9]4[N:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=4)=[CH:8][C:3]3=[O:2])[CH:18]=[CH:19][C:20]=2[C:21]2[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27][C:22]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: COc1cc(-c2ccc(C)nn2)ccn1
Product: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCN(C(=O)OC(C)(C)C)C5)c(=O)c2)nn1
Yield: 59.7 %

Procedure:
3-(2-Methoxypyridin-4-yl)-6-methylpyridazine (133 mg, 0.710 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (259 mg, 0.71 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (200 mg, 59%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.83 (d, J=8.7 Hz, 1H), 7.60 (d, J=7.2 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.39 (d, J=1.6 Hz, 1H), 7.29 (overlapping ddd, J=7.3, 1.8 Hz, 1H), 7.17 (d, J=1.8 Hz, 1H), 7.11 (d, J=7.6 Hz, 1H), 4.67 (br s, 2H), 3.91-3.83 (br m, 2H), 3.67 (s, 3H), 2.89-2.83 (br m, 2H), 2.53 (s, 3H), 1.52 (s, 9H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C@@H:13]1[O:25][C@H:24]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:14]1[O:15][C:16](=[O:18])[CH3:17])(=O)C.O>C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[C:16]([O:15][C@@H:14]1[C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@@H:24]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[O:25][C@H:13]1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: OCc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](OCc2ccccc2)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Yield: 85.2 %

Procedure:
Benzyl alcohol (0.57 mL, 5.5 mmol) was added to a solution of β-D-ribofuranose-1,2,3,5-tetraacetate (1.59 g, 5 mmol) and zinc chloride (681.4 mg, 5 mmol) in ethyl acetate (8 mL), and the mixture was stirred with heating to 60° C. for 2 hours. After cooling the mixture to ambient temperature, water (2 mL) was added to the resulting solution, for layer separation. The resulting organic layer was washed twice with aqueous 7% sodium hydrogen carbonate solution (2 mL) and subsequently concentrated under reduced pressure. The resulting oil was purified by silica gel column chromatography, to recover the desired 1-O-benzyl-β-D-ribofuranose-2,3,5-triacetate (1.56 g; yield of 85.1%) as a colorless solid. Melting point: 65° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[CH3:1][C:2]1([CH3:11])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CC1(C)Cc2ccccc2N1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CN1c2ccccc2CC1(C)C)C(=O)OCC
Temperature: 105 °C

Procedure:
A mixture of 2,2-dimethylindoline (1.47 g) and diethyl ethoxymethylenemalonate (2.0 ml) is heated to 105° C. for 17 hours to afford the title compound as a pale yellow oil. Physical characteristics: 1H NMR (CDCl3) δ7.76, 7.18, 7.12, 6.97, 6.74, 4.24, 3.16, 1.50, 1.34.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([OH:28])=O)[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:74][C:75]([CH3:79])([CH3:78])[CH2:76][NH2:77]>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:77][CH2:76][C:75]([CH3:79])([CH3:78])[CH3:74])=[O:28])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: CC(C)(C)CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CNC(=O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 μL, 0.14 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added 2,2-dimethylpropan-1-amine (7.9 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of 2,2-dimethylpropan-1-amine were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (25-50_90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-neopentylacetamide. (40 mg, 0.083 mmol, 59%).
Reaction SMILES: [OH-].[Na+].[NH2:3][N:4]1[C:13]2[CH:12]=[C:11]3[O:14][CH2:15][O:16][C:10]3=[CH:9][C:8]=2[C:7](=[O:17])[C:6]([C:18]([O:20]CC)=[O:19])=[CH:5]1.C(O)(=O)C>O>[NH2:3][N:4]1[C:13]2[CH:12]=[C:11]3[O:14][CH2:15][O:16][C:10]3=[CH:9][C:8]=2[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]1
Reactant: CCOC(=O)c1cn(N)c2cc3c(cc2c1=O)OCO3
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Nn1cc(C(=O)O)c(=O)c2cc3c(cc21)OCO3
Temperature: 90 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
To a solution of 4.4 g (0.11 mole) of sodium hydroxide in 350 ml of water was added 3.0 g (0.047 mole) of ethyl 5-amino-5,8-dihydro-8-oxo-1,3-dioxolo[4,5-g]quinoline-7-carboxylate (Example 1). The resulting slurry was stirred at about 90° C. for three hours, then cooled to room temperature and neutralized with 9.3 ml of acetic acid. The solid product was collected by filtration and recrystallized from dimethylformamide to give 10.3 g of 5-amino-5,8-dihydro-8-oxo-1,3-dioxolo[4,5-g]quinoline-7-carboxylic acid, colorless crystals, m.p. 309°-313° C. (decompn.).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]([O:13][CH2:14][CH3:15])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH:23]1(B(O)O)[CH2:25][CH2:24]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[CH:23]1([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:4][C:5]([O:13][CH2:14][CH3:15])=[C:6]([CH:12]=2)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:25][CH2:24]1
Reactant: CCOC(=O)c1cc(Br)c(-c2ccc(F)cc2)nc1OCC
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cc(C2CC2)c(-c2ccc(F)cc2)nc1OCC
Temperature: 25 °C
Yield: 96 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (418 mg) was added to a mixture of ethyl 5-bromo-2-ethoxy-6-(4-fluorophenyl)nicotinate (2.40 g), cyclopropylboronic acid (1.68 g), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (401 mg), a 2 M aqueous sodium carbonate solution (9.78 mL), and toluene (25 mL), and the resultant mixture was stirred at 100° C. for 2 hours in an argon atmosphere. The reaction mixture was allowed to cool to room temperature and poured to water, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.06 g).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:8]([C:20]2[S:21][CH:22]=[C:23]([CH2:25][C:26](O)=[O:27])[N:24]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[O:29]1[CH2:34][CH2:33][CH:32]([CH2:35][NH2:36])[CH2:31][CH2:30]1>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[C:8]([C:20]2[S:21][CH:22]=[C:23]([CH2:25][C:26]([NH:36][CH2:35][CH:32]3[CH2:33][CH2:34][O:29][CH2:30][CH2:31]3)=[O:27])[N:24]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NCC1CCOCC1
Reactant: COc1ccc(CCc2c(-c3nc(CC(=O)O)cs3)cnn2C(C)(C)C)cc1
Product: COc1ccc(CCc2c(-c3nc(CC(=O)NCC4CCOCC4)cs3)cnn2C(C)(C)C)cc1

Procedure:
Using the compound obtained in step 5 and (tetrahydro-2H-pyran-4-yl)methanamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10](=[O:13])[CH:11]=[CH2:12].C(N(CC)CC)C>C(#N)C>[C:10]([O:9][CH3:8])(=[O:13])/[CH:11]=[CH:12]/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: C=CC(=O)OC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
To a solution of iodobenzene (102 mg), methylacrylate (1.25 eq.) and triethylamine (1.25 eq.) in acetonitrile (3.00 ml) was added the catalyst substrate (5×5) obtained in Example 2. The mixture was stirred at 100° C. for 12 h under an argon atmosphere. The organic layers were then washed with brine and dried over sodium sulfate. The solvents were removed under reduced pressure and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1). The intended product, trans-methyl cinnamate was obtained with yield of 35%. The recycled substrate was subjected to the above reaction conditions in a 2nd run and the intended product methyl cinnamate was obtained with yield of 13%. Further conducted the 3rd run and the intended methyl cinnamate was obtained with yield of 9%.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:3]=1/[CH:4]=[C:5]1/[C:6](=[O:22])[C:7]2[C:12]([CH2:13]/1)=[CH:11][C:10]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[C:9]([O:20][CH3:21])[CH:8]=2>CO.[Pd]>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][C:3]=1[CH2:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:20][CH3:21])=[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH:11]=2)[C:6]1=[O:22]
Reactant: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1cc(C(F)(F)F)ccc1Cl)C2=O
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N1CCOCC1)CC(Cc1cc(C(F)(F)F)ccc1Cl)C2=O
Reaction time: 6 h

Procedure:
The 157 (100 mg, 0.228 mmol) was dissolved in methanol and Pd/C (40 mg) added, the reaction stirred under hydrogen balloon for 6 h, filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude compound 158 which was purified by flash chromatography using 100-200 mesh silica gel. The compound was eluted at 10% ethyl acetate in hexane as half white coloured solid 2-(2-chloro-5-(trifluoromethyl)benzyl)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 158. 1HNMR (400 MHz, CDCl3) δ ppm 7.43 (m, 3H), 7.20 (s, 1H), 6.84 (s, 1H), 3.89 (m, 7H), 3.54 (dd, 1H), 3.14 (m, 4H), 3.07 (m, 2H), 2.75 (m, 2H); MS (ESI) m/z 440.0 (M+H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[C:12]([CH3:13])=[CH:11][N:10]=[C:9]([NH:14][CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][NH:19][C:18]3=[O:22])[N:8]=2)=[CH:4][CH:3]=1.[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].COC>ClCCl.CO.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>[CH3:13][C:12]1[C:7]([C:5]2[S:6][C:2]([C:24]3[S:23][CH:27]=[CH:26][CH:25]=3)=[CH:3][CH:4]=2)=[N:8][C:9]([NH:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][NH:19][C:18]2=[O:22])=[N:10][CH:11]=1
Reactant: OB(O)c1cccs1
Reactant: Cc1cnc(NCCN2CCNC2=O)nc1-c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc(NCCN2CCNC2=O)nc1-c1ccc(-c2cccs2)s1
Temperature: 145 °C

Procedure:
1-(2-(4-(5-Bromothiophen-2-yl)-5-methylpyrimidin-2-ylamino)ethyl)imidazolidin-2-one (0.1 g, 0.26 mmol), thiophen-2-ylboronic acid (0.066 g, 0.52 mmol), and sodium carbonate (0.26 mL of 2 M solution, 0.52 mmol) were added to a microwave tube containing dimethyl ether (2 mL). The tube was flushed with nitrogen and tetrakis(triphenylphosphine)palladium (0.06 g, 0.054 mmol) was added. The tube was capped and heated to 145° C. for 20 min in a Personal Chemistry microwave. The reaction was diluted with a mixture of 2:1 dichloromethane and methanol (9 mL), filtered through a pad of celite, washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried with sodium sulfate, concentrated in vacuo and purified by flash chromatography on silica gel using a gradient 2 to 10% of methanol in dichloromethane to afford a yellow solid. Yield=0.036 g. MS (M+H)+ 386.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:20]=[C:19]3[NH:21][C:22]([C:24]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([C:32]5[C:41]6[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=6)[CH:35]=[N:34][CH:33]=5)[CH:27]=4)=[O:25])=[N:23][C:18]3=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CCOCC>[N:11]1([C:15]2[N:20]=[C:19]3[NH:21][C:22]([C:24]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([C:32]5[C:41]6[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=6)[CH:35]=[N:34][CH:33]=5)[CH:27]=4)=[O:25])=[N:23][C:18]3=[CH:17][CH:16]=2)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc3nc(C(=O)c4ccnc(-c5cncc6ccccc56)c4)[nH]c3n2)CC1
Agent: Cl
Solvent: CCOCC
Product: O=C(c1ccnc(-c2cncc3ccccc23)c1)c1nc2ccc(N3CCCNCC3)nc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
The mixture of 4-[2-(2-Isoquinolin-4-yl-pyridine-4-carbonyl)-3H-imidazo[4.5-b]pyridine-5-yl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (15 mg, 0.03 mmole) and 2 molar HCl in ether (1 ml) was stirred at room temperature for 2 hours. Solvent was removed. Residue was washed with ethyl ether a few times to afford (5-[1,4]diazepan-1-yl-3H-imidazo[4,5-b]pyridine-2-yl)-(2-isoquinolin-4-yl-pyridin-4-yl)-methanone (6 mg, 49%) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 2.26 (m, 2H), 3.34 (m, 2H), 3.48 (m, 2H), 3.89 (m, 2H), 4.15 (m, 2H), 7.16 (m, 1H), 7.95 (m, 1H), 8.20 (m, 3H), 8.41-9.16 (m, 5H), 9.93 (d, J=6.53 Hz, 1H). HR-MS m/z 450.2033 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:28][CH3:29])[C:25](=[O:27])[CH3:26]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:28][CH3:29])[C:25](=[O:27])[CH3:26])=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Reactant: CCN(CCCCN)C(C)=O
Product: CCN(CCCCNc1c2ccc(Cl)cc2nc2ccc(OC)cc12)C(C)=O

Procedure:
Following the general procedure of Example 1, and making non-critical variations but using 6,9-dichloro-2-methoxyacridine and N-(4-aminobutyl)-N-ethylacetamide (Step 1), the title compound was obtained; MS (Found M+1=400).
Reaction SMILES: [OH:1][CH:2]([C:30]1[O:31][C:32]2[C:33]([N:38]=1)=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:3]([NH:6][C:7](=[O:29])[CH:8]([CH2:18][S:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:21])=[O:20])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11])[CH2:4][CH3:5].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>>[N:12]1([C:10](=[O:11])[CH2:9][CH:8]([CH2:18][S:19]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)(=[O:20])=[O:21])[C:7]([NH:6][CH:3]([C:2]([C:30]2[O:31][C:32]3[C:33]([N:38]=2)=[N:34][CH:35]=[CH:36][CH:37]=3)=[O:1])[CH2:4][CH3:5])=[O:29])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CCC(NC(=O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1)C(O)c1nc2ncccc2o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Product: CCC(NC(=O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1)C(=O)c1nc2ncccc2o1
Reaction time: 1 h

Procedure:
This amide was treated with Dess-Martin periodinane (371 mg 0.75 mmol) at room temperature. After stirring for 1 hour, 5 mls of saturated Na2S2O3—NaHCO3 were added. After a further 0.5 hours, the reaction mixture was extracted with ethyl acetate, washed with brine, dried with MgSO4 and concentrated. The residue was purified with silica gel column chromatography to yield 224 mg of 4-morpholin-4-yl-N-[1-(oxazolo[4,5-b]pyridine-2-carbonyl)-propyl]-4-oxo-2-benzylsulfonylmethyl-butyramide; H1 NMR (DMSO-d): 8.96, 8.85(1H, d,d, NH, diastereomeric), 8.75–8.7(1H, m), 8.42–8.3(1H, m), 7.7–7.6(1H, m), 7.4–7.3(5H, m), 5.15–5.04(1H, m), 4.5–4.3(2H, m), 3.6–3.2(11H, m), 3.15–3.0(1H, m), 2.7–2.5(1H, m), 2.1–1.9(1H, m), 1.8–1.7(1H, m), 0.98(3H, t); MS: 541.2(M−1), 543.2(M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.[H-].[Na+].Cl[CH2:12][C:13]1[N:18]=[C:17]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:16]2=[CH:15][C:14]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25].O>C1COCC1.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][CH2:12][C:13]2[N:18]=[C:17]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:16]3=[CH:15][C:14]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:2]=1
Reactant: CCOC(=O)c1cc2c(nc1CCl)CCCCC2
Reactant: OCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc2c(nc1COCc1cccnc1)CCCCC2
Reaction time: 1 h
Yield: 21.2 %

Procedure:
In an atmosphere of argon, 3-pyridinemethanol (0.41 ml, 4.20 mmol) was dissolved in anhydrous THF (4.0 ml), and the solution was mixed with sodium hydride (173.6 mg, 4.34 mmol) at 0° C. and stirred at the same temperature for 1 hour. To this was added dropwise THF solution (4.0 ml) of ethyl 2-chloromethyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate (1.07 g, 3.98 mmol) at 0° C., and the mixture was stirred at from 0° C. to room temperature for 20 hours. The reaction solution was diluted with ethyl acetate, mixed with water and then extracted with ethyl acetate. Thethus obtainedorganiclayer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (ethyl acetate:hexane=1:3—chloroform:methanol=40:1) to obtain the title compound (287.8 mg, 20.1%) as yellow oil.