Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[BrH:11].BrBr.C(OCC)C>C(O)(=O)C>[BrH:11].[Br:11][CH2:9][C:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:10]
Reactant: CC(=O)c1cnccc1C
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1ccncc1C(=O)CBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
300 mg (2.22 mmol) of 1-(4-methylpyrid-3-yl)ethanone are dissolved in 20 mL of glacial acetic acid. 730 μl (4.44 mmol) of hydrobromic acid and 126 μl (2.44 mmol) of bromine are added to the medium. The reaction mixture is placed under magnetic stirring at room temperature for 2 hours. Ethyl ether is added to the solution until a precipitate appears. The precipitate corresponding to 2-bromo-1-(4-methylpyrid-3-yl)ethanone hydrobromide is filtered off, washed with ethyl ether and dried. The 550 mg of product obtained have the following characteristics:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)[OH:5].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)[O:5][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@H](O)c1cccc(Cl)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Yield: 99 %

Procedure:
A solution of (R)-(3-chloro-phenyl)-hydroxy-acetic acid methyl ester (21.0 g), imidazole (14.25 g), and tert-butyidimethylsilyl chloride (25.0 g) in N,N-dimethylformamide (250 ml) was stirred at room temperature for 18 h. The mixture was poured into water (2.5 l) and extracted with ethyl acetate. The combined extracts were washed with water and saturated brine, dried, and concentrated. The residue was purified by flash chromatography, eluting with cyclohexane:ethyl acetate (9:1) to give the title compound as a colourless oil (32.63 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[CH:8]([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:7]2.[CH3:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)CO>O>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[CH:8]([CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:7]3)=[CH:22][CH:21]=1
Reactant: O=C1c2c(Cl)cccc2CC1CC1CCCCC1
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: Cc1ccc(-c2cccc3c2C(=O)C(CC2CCCCC2)C3)cc1
Temperature: 125 °C

Procedure:
24.16 g (91.9 mmole) 7-Chloro-2-cyclohexylmethyl-indan-1-one, 15.0 g (1.2 eq.) 4-methylphenyl boronic acid, 19.49 g sodium carbonate, 303 ml ethylene glycol and 57 ml water were placed in a 1 l-roundbottom flask equipped with a mechanical stirrer and a reflux condenser. The mixture was degassed three times by slight evacuation and recharging with argon. A premixed catalyst solution consisting of 41 mg (0.2 mole %) palladium acetate, 1.2 ml NaTPPTS (2.6 M in water, 0.8 mole %) and 2 ml of water was added and the mixture was refluxed at 125° C. until complete conversion (approx. 8 h). 100 ml of water were added and the mixture was extracted three times with 100 ml of toluene each. The combined organic layers were washed twice with 100 ml water and once with 100 ml of a saturated sodium chloride solution. Drying over magnesium sulphate and evaporation of the solvent in vacuo yielded 30.57 g (quant.) of the desired product as a yellow sticky oil. 1H-NMR (400 MHz, CDCl3): δ=7.60-7.19 (m, 7H, aromatic), 3.31 (m, 1H, (C═O)CH), 2.91-2.61 (m, 2H, benzylic), 2.38 (s, 3H, Ph-CH3), 1.80-0.85 (m, 10H, aliphatic) ppm.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].Br[CH:16]1[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]1>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH:21]2[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: BrC1C=CCCC1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)n(C2C=CCCC2)c2ccccc12
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 39.2 %

Procedure:
To a solution of 2-chloro-1H-indole-3-carbaldehyde (2.00 g, 11.1 mmol) in DMF (15 ml) was added sodium hydride (468 mg, 11.7 mmol, 60% dispersion in mineral oil). Under an argon atmosphere, the suspension was stirred at 40° C. for 20 min and then allowed to cool to room temperature. After the addition of 3-bromocyclohexene (2.56 ml, 22.3 mmol) the reaction mixture was stirred at room temperature for 1 h. The mixture was then quenched with water and extracted with EA. The organic layer was separated, dried over sodium sulfate, filtered and evaporated. The residue was and purified by silica gel chromatography (EA/HEP 1:10). 1.13 g of the title compound were obtained.
Reaction SMILES: I[C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[Cl:21][C:22]1[C:27](B(O)O)=[CH:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Cl:21][C:22]1[C:27]([C:2]2[C:3](=[O:20])[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:7]=2)=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: O=c1c(I)cc(-c2ccccn2)cn1-c1ccccc1
Reactant: OB(O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(-c2cccnc2Cl)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
3-Iodo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one (200 mg) synthesized by the same method as mentioned in Referential Example 6, 130 mg of 2-chloro-3-pyridyl boronic acid and 250 mg of cesium carbonate were suspended in 10 ml of dimethylformamide, 40 mg of tetrakistriphenylphosphine palladium were added and the mixture was stirred at 100° C. in a nitrogen atmosphere for 3 hours. After allowing to cool, the reaction solution was poured into water, the mixture was extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo and the residue was purified by a silica gel column chromatography (hexane-ethyl acetate system) to give 143 mg of the title compound.
Reaction SMILES: [NH:1]([C:8]1[C:13]([CH2:14]OCC)=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([OH:32])[CH2:28][N:29]([CH3:31])[CH3:30])=[CH:21][CH:20]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]([NH2:36])=[O:35].Cl.C(OCC)C>O1CCOCC1>[NH:1]([C:8]1[C:13]([CH2:14][NH:33][C:34]([NH2:36])=[O:35])=[CH:12][N:11]=[C:10]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH:27]([OH:32])[CH2:28][N:29]([CH3:31])[CH3:30])=[CH:23][CH:24]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCc1cnc(Nc2ccc(OCC(O)CN(C)C)cc2)nc1Nc1ccccc1
Reactant: NC(N)=O
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN(C)CC(O)COc1ccc(Nc2ncc(CNC(N)=O)c(Nc3ccccc3)n2)cc1
Temperature: 100 °C
Yield: 27.7 %

Procedure:
4-Anilino-5-(ethoxymethyl)-2-{4-[2-hydroxy-3-(N,N-dimethylamino)propoxy]anilino}pyrimidine (Example 86, 70 mg, 0.16 mmol) was dissolved in 1,4-dioxane (2 ml). Urea (12 mg, 0.19 mmol) and ethereal hydrogen chloride (1.0M; 0.19 ml, 0.19 mmol) were added, and the suspension was heated at 100° C. for 20 hours. Diethyl ether (20 ml) was added, and the precipitated solid collected by filtration. The solid was dissolved in 10% methanol solution in DCM (3 ml), and loaded on a Varian Mega Bond Elut column. The column was eluted with 0-2.5% methanol solution in DCM containing 0.5% aqueous ammonia solution. Concentration of the appropriate fractions and trituration of the residue with diethyl ether gave the product as a white crystalline solid (20 mg, 28%). NMR: 2.18 (s, 6H), 2.2-2.45 (m, 2H), 3.75-3.9 (m, 3H), 4.07 (d, 2H), 4.74 (br d, 1H), 5.85 (s, 2H), 6.62 (t, 1H), 6.80 (d, 2H), 6.98 (t, 1H), 7.27 (dd, 2H), 7.54 (d, 2H), 7.77 (d, 2H), 7.88 (s, 1H), 8.88 (s, 1H), 9.88 (s, 1H); MS (MH+): 452.4.
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[CH:7][C:6](=[O:9])[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(O[CH:21]=[C:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>ClCCl.CC(C)=O>[CH2:26]([O:25][C:23](=[O:24])[C:22](=[CH:21][NH:1][C:2]1[CH:8]=[CH:7][C:6](=[O:9])[C:5]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][CH:3]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:27]
Reactant: Nc1ccc(OCc2ccccc2)c(=O)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCOC(=O)C(=CNc1ccc(OCc2ccccc2)c(=O)cc1)C(=O)OCC
Temperature: 140 °C

Procedure:
A mixture of 5-amino-2-benzyloxy-2,4,6-cycloheptatrien-1-one (10 g), described in example 1b, and diethyl ethoxymethylenemalonate (100 ml) was heated at 140° C. for 1.5 hr. The cooled reaction mixture was subjected to chromatography on silica gel using dichloromethane-acetone (9:1) as the eluant. The pure fractions were pooled to give 2-[(4-benzyloxy-5-oxo-1,3,6-cycloheptatrien-1-yl)aminomethylene]propanedioic acid diethyl ester (V; R7 =OCH2C6H5 and R8 =C2H5); nmr (CDCl3) δ1.3 (m 6H), 4.2 (m, 4H), 5.2 (s, 2H), 7.2 (m, 2H), 7.2 (m, 9H), 8.25 (d, 1H), 10.9 (d, 1H); ir (CHCl3) 3490, 3240, 1700, 1690, 1570; uv λmax (MeOH) 279 nm (ε10,410), 224 (27,380).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:13]2[C@@H:9]([O:10][C:11]([CH3:15])([CH3:14])[O:12]2)[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3Cl)[CH2:7]1)(=[O:3])[CH3:2].[Br-].[CH2:27]([Zn+])[CH:28]([CH3:30])[CH3:29]>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>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:13]2[C@@H:9]([O:10][C:11]([CH3:15])([CH3:14])[O:12]2)[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][CH:19]=[N:20][C:21]=3[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1C[C@@H](n2cnc3c(Cl)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Reactant: CC(C)C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1C[C@@H](n2cnc3c(CC(C)C)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Temperature: 60 °C
Yield: 45 %

Procedure:
To a solution of [(3aR,4R,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methyl acetate (250.0 mg, 0.68 mmol) in degassed THF (6 mL) under nitrogen was added Pd(PPh3)4 (44 mg, 0.038 mmol) followed by 0.5 M of isobutylzinc bromide in tetrahydrofuran (2.04 mL) dropwise over 15 min. The reaction was heated at 60° C. for 1 hour. The reaction was cooled then quenched with saturated aq NH4Cl, extracted with EtOAc and the organic phase was washed with saturated aq EDTA.Na2 solution then water. The organic phase was concentrated and the residue purified by flash chromatography (0 to 100% EtOAc/DCM) to provide the title compound (120 mg, 45%).
Reaction SMILES: [CH2:1]([O:17][C@H:18]([CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:19][OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].N1C=CC=CC=1.[O:45](S(C(F)(F)F)(=O)=O)[S:46]([C:49]([F:52])([F:51])[F:50])(=O)=[O:47]>C(Cl)Cl>[F:50][C:49]([F:52])([F:51])[S:46]([O:20][CH2:19][C@H:18]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:47])=[O:45]
Reactant: CCCCCCCCCCCCCCCCOC[C@H](CO)OCCCCCCCCCCCCCCCC
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOC[C@H](COS(=O)(=O)C(F)(F)F)OCCCCCCCCCCCCCCCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2,3-bis(hexadecyloxy)propan-1-ol (1 eq) and pyridine (4 eq) in DCM (0.1 M) at 0° C., was added Tf2O (2 eq). The reaction was stirred at 0° C. for 1 hour and quenched by H2O. The aqueous phase was extracted with DCM. The combined organic phases were washed with H2O, and the aqueous phase was back extracted with DCM. The combined organic phases were washed with saturated NaHCO3 and brine, dried over anhydrous Na2SO4 and concentrated en vaccuo. The resulting crude was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% EtOAc/Hex to give (R)-2,3-bis(hexadecyloxy)propyl trifluoromethanesulfonate as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:23])=[N:10][CH:11]=[C:12](B3OC(C)(C)C(C)(C)O3)[N:13]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:31]1[C:32]([F:44])=[C:33]([CH:41]=[CH:42][CH:43]=1)[O:34][CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.O>O1CCOCC1.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>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([NH2:23])=[N:10][CH:11]=[C:12]([C:31]3[CH:43]=[CH:42][CH:41]=[C:33]([O:34][CH:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[C:32]=3[F:44])[N:13]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2cnc(N)c(-c3ccc(N)cc3)n2)OC1(C)C
Reactant: Fc1c(Br)cccc1OC1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ccc(-c2nc(-c3cccc(OC4CCOCC4)c3F)cnc2N)cc1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 29.5 %

Procedure:
To a 80 mL microwave vessel containing the compound prepared in Example 15 (263.9 mg) was added Na2CO3 (181.7 mg) and Pd(PPh3)4 (48.8 mg). The 4-(3-bromo-2-fluorophenoxy)tetrahydro-2H-pyran (253.6 mg) was added by dissolving in 3:1 1,4-dioxane:H2O then adding via pipet and using the remainder of the solvent to wash over any remaining material (total volume: 8.5 mL). The mixture was stirred and sparged with argon for 5 minutes. The vial was placed in the microwave then heated to 150° C. After 15 minutes at 150° C., the mixture was allowed to cool. The dark brown mixture was diluted with EtOAc and washed with H2O two times. The aqueous layers were back extracted with EtOAc. The combined organic layers were washed with brine then dried over Na2SO4, filtered and solvent was removed in vacuo. The material was absorbed onto silica and purified on the Isolera (50 g silica column; 0-15% MeOH in EtOAc) followed by purification via reverse phase on the Isolera (60 g C18 column; 5-95% ACN with 0.1% trifluoroacetic acid (TFA) in H2O with 0.1% TFA). Fractions containing product were combined and solvent was removed in vacuo. The material was taken up in MeOH and desalted by passing through a StratoSphere 200 mg PL-HCO3 MP SPE cartridge. Resin was washed with MeOH and 20% MeOH in DCM. Solvent was removed in vacuo to give the title compound (94.9 mg) having the following data as a dark amber solid/film solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17]([CH3:19])=O)[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]([C:24]1[CH:33]=[C:32]([C:34]([NH:36][NH2:37])=[O:35])[CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27])[C:21]([CH3:23])=[O:22].O.S(C1C=CC(C)=CC=1)(O)(=O)=O>C(O)(C)C>[NH:20]([C:24]1[CH:33]=[C:32]([C:34]([NH:36][N:37]=[C:17]([C:14]2[C:15]([OH:16])=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[S:12][CH:13]=2)[CH3:19])=[O:35])[CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27])[C:21]([CH3:23])=[O:22]
Reactant: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)cc1NC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(C(C)(C)C)cc3)c2O)cc1NC(C)=O
Yield: 82.7 %

Procedure:
To a suspension of 2-(4-t-butylphenyl)-3-hydroxy-4-methylcarbonylthiophene (54.8 mg, 0.2 mmol) and methyl 2-acetamino-4-hydrazinocarbonylbenzoate (50.2 mg, 0.2 mmol) in isopropyl alcohol (2 mL), tosylic acid monohydrate (11.4 mg, 0.06 mmol) was added, and the mixture was heated with reflux for 12 hours. The precipitated solid was filtered to obtain 84 mg of the desired product as a pale yellow solid (yield 83%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[O:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][NH2:28])[CH2:22][CH2:21]1>>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:28][CH2:27][CH2:26][CH:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Reactant: NCCC1CCOCC1
Product: NC(=O)c1ccc(Oc2ccc(CNCCC3CCOCC3)cc2F)cn1
Yield: 44.3 %

Procedure:
Using a method similar to Example 405, a reaction of 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.0294 g, 0.113 mmol) and 2-(tetrahydropyran-4-yl)ethylamine (0.016 g, 0.124 mmol) gives the title compound (0.0187 g, 44.2%): TOF MS ES+ 374.2 (M+H)+, HRMS calcd for C20H25N3O3F 374.1880 (M+H)+, found 374.1863, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 30-99% over 19 min], tR=5.2 min, 95.2% purity.
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:8][C:7](=[O:9])[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][N:4]=1.O1CCCC1.Cl.[CH3:24][NH:25][CH3:26].[OH-].[Na+]>O>[CH2:11]([O:10][C:6]1[C:7](=[O:9])[CH2:8][C:3]([CH2:2][N:25]([CH3:26])[CH3:24])=[N:4][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CC(CCl)=NC=C1OCc1ccccc1
Reactant: CNC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CC1=NC=C(OCc2ccccc2)C(=O)C1
Reaction time: 1.5 h
Yield: 96.7 %

Procedure:
To a mixture of 2-chloromethyl-5-benzyloxy-4-pyridone (1.0 g), tetrahydrofuran (10 ml) and water (10 ml) were added dimethylamine hydrochloride (1.31 g) and sodium hydroxide (0.64 g). After being stirred for 1.5 hours, the mixture was concentrated under reduced pressure to dryness. The residue was dissolved in methanol and the insoluble material was filtered off. The filtrate was evaporated in vacuo to give 5-benzyloxy-2-(N,N-dimethylamino)methyl-4-pyridone (1.0 g) as a powder.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11]([OH:22])=[N:10][C:8]=2[N:9]=1.I[CH2:24][CH2:25][CH3:26]>CN(C)C=O>[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[N:10]([CH2:24][CH2:25][CH3:26])[C:8]=2[N:9]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(O)nc2n1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
To a suspension of NaH (60% in mineral oil, 31 mg) in 6 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one from Example 11 (205 mg, 0.67 mmol). The mixture was heated at 50° C. for 1 hour resulting in a clear solution. 1-Iodopropane (100 μL, 1.03 mmol) was added, and the solution was stirred at 50° C. for 10 minutes, then cooled to room temperature and poured onto 40 mL of ice water. The resulting precipitate was removed by filtration and washed with water. The residue was dried and purified by flash chromatography, eluting with 1:1 hexane:ethyl acetate to provide 159 mg (68%) of 2-amino-6-(2,6-dichlorophenyl)-8-propyl-8H-pyrido[2,3-d]pyrimidin-7-one; mp 196°-197° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]3[CH2:18][CH2:19][N:20](C([O-])=O)[CH:16]3[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.[ClH:24]>[Pd].C(O)C.CO>[ClH:1].[ClH:24].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:17]3[CH2:18][CH2:19][NH:20][C@H:16]3[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])N1CCC2C(c3ccc(Cl)cc3)Nc3ccccc3C21
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: Clc1ccc([C@@H]2Nc3ccccc3[C@@H]3NCC[C@H]23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of benzyl(3aR*,4R*,9bR*)-4-(4-chlorophenyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (730 mg, 1.75 mmol) and 10% palladium on carbon (50% aqueous, 0.3 g) in ethanol (10 ml) was added a hydrogen chloride in methanol solution (1 ml) and the mixture was stirred at room temperature under hydrogen atmosphere for 3 hrs. The reaction mixture was filtered, washed with aqueous methanol, and the filtrate was concentrated. The residue was dried under reduced pressure to give the crude title compound as an oil. (350 mg, ca. 100%)
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:18][CH2:17][C:16]([OH:15])([C:22]4[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: OC1(c2ccc(Br)cc2)CCNCC1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2ccc(Br)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-(4-bromophenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 80% overall yield. FDMS m/e=444, 446 (M+ of free base). α[D]589 =-7.52 (c=0.45, methanol).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([CH:8]([CH3:10])[CH3:9])=[N:5][CH:4]=1.BrCC1CCCCO1.[F:19][C:20]([F:43])([F:42])[C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:29]=1[NH:28][C:27](=[O:30])[C:26]12[C:34]2=[CH:35][C:36]3[O:40][CH2:39][O:38][C:37]=3[CH:41]=[C:33]2[O:32][CH2:31]1>>[CH:8]([C:6]1[S:7][C:3]([CH2:2][N:28]2[C:29]3[C:25](=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]([F:42])([F:19])[F:43])[C:26]3([C:34]4=[CH:35][C:36]5[O:40][CH2:39][O:38][C:37]=5[CH:41]=[C:33]4[O:32][CH2:31]3)[C:27]2=[O:30])=[CH:4][N:5]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1ncc(CCl)s1
Reactant: O=C1Nc2c(C(F)(F)F)cccc2C12COc1cc3c(cc12)OCO3
Agent: BrCC1CCCCO1
Product: CC(C)c1ncc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3cccc(C(F)(F)F)c32)s1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-chloromethyl-2-(isopropyl)thiazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 7′-(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[(2-isopropyl-1,3-thiazol-5-yl)methyl]-7′-(trifluoromethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (51%) as a colorless solid: mp 101-103° C.; 1H NMR (300 MHz, DMSO-d6) δ7.61 (d, J=8.1 Hz, 1H), 7.48 (d, J=6.8 Hz, 1H), 7.23 (dd J=7.8, 7.8 Hz, 1H), 7.18 (s, 1H), 6.69 (s, 1H), 6.48 (s, 1H), 5.91 (s, 2H), 5.08 (ABq, 2H), 4.77 (ABq, 2H), 3.21-3.16 (m, 1H), 1.22 (d, J=6.9 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ178.7, 177.4, 156.0, 150.7, 149.0, 142.3, 140.7, 135.6, 128.7, 125.7, 124.5 (d), 123.6, 119.8, 113.3, 111.5 (m), 103.9, 101.9, 93.8, 80.8, 56.6, 43.3, 32.8, 23.3; MS (ES+) m/z 489.4 (M+1).