Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([P:8](=[O:13])([O:11]C)[O:9]C)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1.CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([P:8](=[O:9])([OH:13])[OH:11])=[O:7])=[CH:4][CH:3]=1
Reactant: COP(=O)(OC)C(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1ccc(Cl)cc1)P(=O)(O)O
Yield: 76 %

Procedure:
To a solution of dimethyl p-chlorobenzoylphosphonate (1 mmol) in dry dioxane (5 ml), BrMe3Si (3 mmol) was added dropwise under magnetic stirring, in nitrogen atmosphere at room temperature. After 5 hours the solvent was removed under vacuum and the brown residue was dissolved in MeOH at 0° C. The solvent was evaporated and a solution of NaOH (1 mmol) in MeOH (5 ml) was added in portions. The white solid was filtered and dried under vacuum. Yield: 76%. NMR, 1H, 7.54 (d, 2 H), 8.11 (d, 2 H); 31P, −1.48 ppm.
Reaction SMILES: [C:1]1([C:7]2[C:8]([O:10][C:11](=[O:13])[CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.S(Cl)([Cl:22])=O>>[Cl:22][C:12]1[C:11](=[O:13])[O:10][C:8](=[O:9])[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Solvent: c1ccncc1
Product: O=C1OC(=O)C(c2ccccc2)=C1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of phenylmaleic anhydride (5.74 mmol, 1.0 g) in thionyl chloride (6.0 mL) was added drop wise pyridine (11.4 mmol, 0.9 g). The reaction mixture was stirred for 60 min at 0° C., followed by heating to 75° C. for 20 min. The reaction mixture was cooled to room temperature and the thionyl chloride was removed in vacuo. The crude residue was suspended in toluene (10 mL), refluxed for 10 min., followed by filtration of the hot mixture. The filtrate was concentrated to give 1.15 g (96%) of the title. 1H NMR (400 MHz, CDCl3) δ 8.05-8.00 (m, 2H), 7.59-7.51 (m, 3H).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=O.[OH:13][C@H:14]1[CH2:18][NH:17][C@H:16](C(O)=O)[CH2:15]1>CS(C)=O>[OH:13][C@H:14]1[CH2:18][N:17]2[C@H:16]([C:5](=[O:12])[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=3[C:2]2=[O:4])[CH2:15]1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Solvent: CS(C)=O
Product: O=C1Nc2ccccc2C(=O)N2C[C@H](O)C[C@@H]12
Temperature: 120 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
Isatoic anhydride (3.5 g) and trans-4-hydroxy-L-proline (2.8 g) were suspended in 60 ml of dimethyl sulfoxide and the suspension was heated with stirring at 120° C. for 2 hours. After allowing the reaction liquid to cool, the solvent was distilled off under reduced pressure and the resulting residue was washed with ethyl acetate and dried. The crude crystals were recrystallized from ethanol to give 3.9 g (yield 78.5%) of the title compound.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Product: O=C(c1ccc(F)cc1)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1

Procedure:
This compound is prepared by method C using compound 12e and 1-bromo-4-fluorobenzene
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:10]([CH:12]2[C:16](=O)[CH2:15][N:14]([CH3:18])[C:13]2=[O:19])[CH:11]=1.O.Cl>ClC1C=CC=CC=1Cl.CCCCCC>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:16]3[CH2:15][N:14]([CH3:18])[C:13](=[O:19])[C:12]=3[C:10]=2[CH:11]=1
Reactant: CN1CC(=O)C(c2cc(Cl)ccc2Oc2ccccc2)C1=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: O
Solvent: CCCCCC
Product: CN1CC2=C(C1=O)c1cc(Cl)ccc1Oc1ccccc12
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
Anhydrous aluminium chloride (5 g) was added to a reaction mixture containing 3-(5-chloro-2-phenoxyphenyl)-1-methylpyrrolidine-2,4-dione (1 g) in 1,2-dichlorobenzene (5 mL) at ambient temperature. The reaction mixture was stirred at about 85° C. for about 2 hours and 30 minutes, then cooled to ambient temperature. A mixture of water and concentrated hydrochloric acid (50 mL:5 mL) was added dropwise. The contents were stirred for about 30 minutes. Hexane (10 mL) was added. The contents were stirred for about 15 minutes, filtered, washed with hexane (10 mL) and dried in air at about 30° C. for about 15 hours followed by further drying at about 50° C. under reduced pressure to obtain 11-chloro-2-methyl-2,3-dihydro-1H-dibenzo [2,3:6,7]oxepino[4,5-c]pyrrol-1-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]=[O:13])=[N:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Si](C)(C)C)=[CH:17][C:16]=1[F:25].[Br:27]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:12]=[O:13])=[N:6][C:5]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:27])=[CH:17][C:16]=1[F:25]
Reactant: COC(=O)c1ccc(CNC=O)nc1Nc1ccc([Si](C)(C)C)cc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1ccc(CNC=O)nc1Nc1ccc(Br)cc1F
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
To a solution of 2-(2-fluoro-4-trimethylsilanylphenylamino)-6-formylamino methyl-nicotinic acid methyl ester (11.6 g, 30.9 mmol) in DCM (300 mL) at −30° C. was added N-bromo succinimide (5.56 g, 30.9 mmol) portionwise. The reaction mixture was stirred at −30° C. for 30 minutes. The reaction mixture was concentrated in vacuo and the residue partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organic layer was separated and washed with water, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as an orange gum (11.8 g, 100%). LCMS (Method B): RT=3.67 min, M+H+=382/384.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:6]2([CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]2)[O:5][C:4](=[O:18])[CH2:3]1.[ClH:20]>O1CCOCC1>[ClH:20].[CH3:1][C:2]1([CH3:19])[C:6]2([CH2:10][CH2:9][NH:8][CH2:7]2)[O:5][C:4](=[O:18])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)OC(=O)CC2(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)CC(=O)OC12CCNC2

Procedure:
tert-Butyl 4,4-dimethyl-2-oxo-1-oxa-7-azaspiro[4.4]nonane-7-carboxylate (0.20 g, 0.00074 mol) was treated with hydrogen chloride in 1,4-dioxane (4.00 M, 5.00 mL) at rt for 2 h. The volatiles were removed in-vacuo and the resultant HCl salt was used directly in the next step without further purification. LCMS (M+H) 170.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[N:18]([Si](C(C)C)(C(C)C)C(C)C)[C:17]1[CH2:16][CH2:15][CH:14]([N:32]([CH3:34])[CH3:33])[CH2:13][C:12]2=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B(O)(O)O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C(C(C(O)=O)O)O>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([N:32]([CH3:34])[CH3:33])[CH2:13][C:12]2=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1c2c(c3cc(NC(=O)OC(C)(C)C)ccc31)CC(N(C)C)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: OB(O)O
Solvent: C1CCOC1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)OC(C)(C)C)cc3c2C1
Yield: 82.1 %

Procedure:
To a solution of 0.44 gm (0.91 mMol) 6-(t-butoxycarbonyl)amino-3-(dimethyl)amino-9-triisopropylsilyl-1,2,3,4-tetrahydro-9H-carbazole in 10 mL tetrahydrofuran at 0° C. were added 0.30 gm boric acid followed by 1.5 mL 1M aqueous tetrabutylammonium fluoride. After 3 hours the reaction mixture was added to dilute aqueous tartaric acid and the resulting mixture extracted several times with dichloromethane. The remaining aqueous phase was made basic with dilute aqueous sodium hydroxide and extracted well with dichloromethane. This organic phase was dried over sodium sulfate and concentrated under reduced pressure. This residue was subjected to radial chromatography (2 mm silica gel), eluting with 96:4 chloroform:methanol containing 5% ammonium hydroxide. Fractions shown to contain product were combined and concentrated under reduced pressure to give 0.246 gm (83%) of the desired product.
Reaction SMILES: [C:1]([C:3]1[O:7][C:6]([C:8]2[CH:9]=[C:10]([N:14]3[CH2:23][C@H:22]4[N:18]([CH2:19][CH2:20][CH2:21]4)[C:17]4[N:24]=[C:25]([S:28][CH3:29])[N:26]=[CH:27][C:16]=4[C:15]3=[O:30])[CH:11]=[CH:12][CH:13]=2)=[N:5][CH:4]=1)#[N:2].[OH-:31].[Na+]>C(O)C.C(OCC)(=O)C>[CH3:29][S:28][C:25]1[N:26]=[CH:27][C:16]2[C:15](=[O:30])[N:14]([C:10]3[CH:9]=[C:8]([C:6]4[O:7][C:3]([C:1]([NH2:2])=[O:31])=[CH:4][N:5]=4)[CH:13]=[CH:12][CH:11]=3)[CH2:23][C@H:22]3[N:18]([CH2:19][CH2:20][CH2:21]3)[C:17]=2[N:24]=1
Reactant: [OH-]
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3ncc(C#N)o3)c1)C2=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3ncc(C(N)=O)o3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
(S)-5-[3-(5-Cyano-1,3-oxazol-2-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (140 mg, 0.334 mmol) obtained in Step 3 of Example 125 was dissolved in ethanol (5 mL), and the mixture was stirred at room temperature for 2 hours after adding a 2 mol/L aqueous sodium hydroxide solution (1.67 mL, 3.34 mmol). The mixture was diluted with ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give (S)-2-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3-oxazole-5-carboxamide (50.3 mg, 34%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([F:23])=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31][CH2:32][CH3:33])=[CH2:30])CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:32]([O:31][C:29]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([F:23])=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[N:7]=1)=[CH2:30])[CH3:33]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Fc1cc2ncccc2c(F)c1Cc1nnc2ccc(Cl)nn12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=C(OCC)c1ccc2nnc(Cc3c(F)cc4ncccc4c3F)n2n1
Temperature: 82.5 °C
Reaction time: 4 h

Procedure:
A solution of 6-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-5,7-difluoro-quinoline (58 mg, 0.175 mmol) in dioxane (5 mL) was purged with argon for 1 min. Tributyl-(1-ethoxy-vinyl)stannane (0.2 mL, 0.53 mmol) was then added, followed by addition of PdCl2(PPh3)2 (14.4 mg, 0.021 mmol). The reaction mixture was purged with argon for another half min. The reaction mixture was stirred at 80-85° C. for 4 h; LC/MS showed the reaction was complete. The reaction mixture was diluted with EtOAc, and 15 mL of aqueous KF solution was added. The mixture was extracted with EtOAc, dried over anhydrous Na2SO4, concentrated to give the crude title compound, which was used without further purification. LCMS (method A): [MH]+=368, tR=5.39 min.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O.CCO>CC(C)=O.CCOCC.O>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH3:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccccc1-c1ccccc1
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCO
Product: COc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To a suspension of 2-phenylphenol (20.00 g, 0.117 mol) and K2CO3 (32.48 g, 0.235 mol) in 235 mL of anhydrous acetone was added a neat solution of dimethylsulfate (15.56 g, 0.123 mol) dropwise through a syringe over 5 minute at RT under argon. The resulting thick suspension was stirred over night at RT and 100 mL of EtOH was added. After 1 hour, the mixture was diluted with ether and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine and dried with MgSO4. After filtration, the solvents were removed and dried under high vacuum to give afford 2-phenylanisole (18.85 g, 87% yield). 1H NMR (300 MHz, CDCl3): δ 3.80 (s, 3H), 6.95–7.60 (m, 2H), 7.28–7.35 (m, 3H), 7.37–7.43 (m, 2H), 7.50–7.55 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[CH3:23][O:24][C:25]1[CH:56]=[CH:55][C:28]([CH2:29][N:30]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=2)[C:31]2[N:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][N:32]=2)=[CH:27][CH:26]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][N:30]([CH2:46][C:47]2[CH:48]=[CH:49][C:50]([O:53][CH3:54])=[CH:51][CH:52]=2)[C:31]2[N:36]=[CH:35][C:34]([C:2]3[C:3]4[CH2:16][CH2:15][N:14]([C:17]5[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=5)[C:4]=4[N:5]=[C:6]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[N:7]=3)=[CH:33][N:32]=2)=[CH:55][CH:56]=1
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccncc3)cn2)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 86.3 %

Procedure:
To 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (119 mg, 0.374 mmol) obtained from Step C, bis-(4-methoxybenzyl)-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-yl]amine (207 mg, 0.449 mmol), palladium acetate (4.2 mg, 0.0187 mmol), S-Phos (15 mg, 0.0374 mmol) and potassium phosphate (159 mg, 0.748 mmol), dimethylformamide (3 ml) was added, followed by being degassed under ultrasonic irradiation. This was stirred at 100° C. for 5 hours, followed by extraction with ethyl acetate with the addition of water, and the organic layer was washed with brine. After drying over anhydrous sodium sulfate, concentration was carried out under reduced pressure, followed by purification by silica gel column chromatography (dichloromethane/methanol=100/1 to 40/1), to obtain bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (199 mg, yield 87%).
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:27])=[C:5]([C@H:10]2[O:15][CH2:14][C@H:13]3[CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH2:19][N:12]3[CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[F:9][C:8]1[C:3]([C:1]#[N:2])=[C:4]([CH3:27])[C:5]([C@H:10]2[O:15][CH2:14][C@H:13]3[CH2:16][NH:17][CH2:18][CH2:19][N:12]3[CH2:11]2)=[CH:6][CH:7]=1
Reactant: Cc1c([C@@H]2CN3CCN(C(=O)OC(C)(C)C)C[C@@H]3CO2)ccc(F)c1C#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1c([C@@H]2CN3CCNC[C@@H]3CO2)ccc(F)c1C#N

Procedure:
(3R,9aR)-tert-Butyl 3-(3-cyano-4-fluoro-2-methylphenyl)hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (1.09 g, 2.90 mmol) was stirred in trifluoroacetic acid (10 mL) for 1 h then concentrated and azeotroped with dichloroethane (3×) to yield the title compound. LC-MS (IE, m/z): 276 [M+1]+; 1H-NMR (500 MHz, DMSO) δ ppm 7.989 (t, J=6.4 Hz, 1H), 7.416 (t, J=8.85 Hz, 1H), 4.959 (dd, J=7.75, 2.35 Hz, 1H), 3.855 (d, J=11.9 Hz, 1H), 3.755 (b, 1H), 3.236-3.54 (m, 8H), 3.066 (d, J=11.5 Hz, 1H), 2.50 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(c2ncccc2O)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ncccc3O)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(3-hydroxy-pyridin-2-yl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=O)[CH:5]=[N:6][CH:7]=1.[CH2:10]([S:12]([NH2:15])(=[O:14])=[O:13])[CH3:11].C(O)(=O)C.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:15][S:12]([CH2:10][CH3:11])(=[O:14])=[O:13])[CH:5]=[N:6][CH:7]=1
Reactant: CCS(N)(=O)=O
Reactant: O=Cc1cncc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCS(=O)(=O)NCc1cncc(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-3-pyridinecarboxaldehyde (CAS#113118-81-3, 450 mg, 2.4 mmol) in dichloroethane (15 mL) was added ethanesulfonamide (CAS#1520-70-3, 175 mg, 1.6 mmol), acetic acid (0.18 mL 3.2 mmol), triethylamine (0.45 mL, 3.2 mmol) and sodium triacetoxyborohydride (1.0 g, 4.8 mmol). The reaction was stirred at room temperature for 3 hours, at which time it was diluted with dichloromethane and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted two additional times with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 10 to 100%) to provide ethanesulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide; MS: (ES+) m/z 278.9 (M+H)+.
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[Si:18]([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:1]1([O:9][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=C1CCCCCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)OC1=CCCCCCC1
Reaction time: 15 h
Yield: 92.7 %

Procedure:
To a solution of cyclooctanone (40.0 g, 316 mmol) in 200 mL of anhydrous DMF were added triethylamine (TEA, 93.0 mL, 666 mmol) and chlorotrimethylsilane (84.0 mL, 666 mmol). The reaction was heated to reflux. After 15 h, the reaction was quenched with 20 mL of H2O and the DMF was removed on a rotary evaporator. The residue was diluted with hexanes (300 mL), washed with H2O (3×100 mL) and brine (1×50 mL), and dried over MgSO4. Distillation under reduced pressure (20 torr) yielded 58.1 g (93%) of the desired product as a colorless oil, bp 108° C. (20 torr) (lit. 106° C. at 25 torr). Nakamura, et al. J. Am. Chem. Soc. (1976) 98, 2346-2348. IR: 2926, 2851, 1661 cm−1. 1H NMR (CDCl3, 300 MHz): δ 0.20 (s, 9H), 1.39-1.58 (m, 8H), 2.02 (m, 2H), 2.19 (m, 2H), 4.75 (t, 1H, J=9.0 Hz). (Lit: 1H NMR (CDCl3, 600 MHz): δ 0.16 (s, 9H), 1.46 (m, 4H), 1.49 (m, 2H), 1.55 (m, 2H), 1.97 (m, 2H), 2.14 (m, 2H), 4.70 (t, 1H, J=8.0 Hz) (Frimer et al. J. Org. Chem. (2000) 65, 1807-1817.) 13C NMR (CDCl3, 75 MHz): δ 0.4, 25.5, 26.3, 26.4, 27.8, 30.9, 31.0, 105.41, 152.99. (Lit: 13C NMR (CDCl3, 150 MHz): δ 0.45, 25.52, 26.36, 26.40, 27.83, 30.98, 31.05, 105.45, 153.05) Frimer et al. (2000) supra) FAB—HRMS: Calcd. for C11H23OSi+[M+H]+: 199.1518, found 199.1520.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](O)=[CH:4][CH:3]=1.[NH3:19]>>[NH2:19][C:5]1[C:6]2[C:7](=[O:17])[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14](=[O:16])[C:15]=2[C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: N
Reactant: O=C1c2ccccc2C(=O)c2c(O)ccc(O)c21
Product: Nc1ccc(O)c2c1C(=O)c1ccccc1C2=O

Procedure:
CH-A-640 873 describes the reaction of 1,4-dihydroxyanthraquinone with ammonia in aqueous phase to form 1-amino-4-hydroxyanthraquinone.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:29][CH2:30]C)[CH2:5][N:6]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]2[O:24][CH2:25][O:26][C:20]=2[C:19]=1[O:27][CH3:28])S(C1C=CC(C)=CC=1)(=O)=O)C.O.[OH-].[Na+].[CH2:35](Cl)Cl>>[CH3:30][O:29][CH:4]([O:3][CH3:1])[CH2:5][N:6]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]2[O:24][CH2:25][O:26][C:20]=2[C:19]=1[O:27][CH3:28])[CH3:35]
Reactant: CCOC(CN(Cc1ccc2c(c1OC)OCO2)S(=O)(=O)c1ccc(C)cc1)OCC
Reactant: ClCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(CN(C)CC(OC)OC)ccc2c1OCO2
Yield: 99.7 %

Procedure:
17.8 g (74.3 mmol) of the compound (2) thus obtained was added to 50 ml of water, to which 100 ml of methylene chloride was added. This solution was made basic with 25% aqueous solution of sodium hydroxide under water-cooling. The solution was separated and the aqueous layer was extracted with 20 ml of methylene chloride. The obtained methylene chloride layers were combined, washed with 30 ml of water, dried over anhydrous magnesium sulfate and then concentrated under vacuum to obtain 15.06 g of 8-methoxy-6,7-methylenedioxyisoquinoline (3) (yield 99.7%). The product thus obtained was recrystallized from ethylacetate-n-hexane, m.p. 144°-5° C. IR and NMR spectra of the resultant product are listed below. ##STR48##
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:19]3[O:18][CH2:17]1)[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH:13]1[CH2:15][CH2:14]1.BrC1C=CC=[C:34]2[C:30]=1[C:31]1([C:47]3=[CH:48][C:49]4OCO[C:50]=4[CH:54]=[C:46]3OC1)C(=O)[N:33]2CCCCC.N1C2C(=CC=CC=2)C=C(B(O)O)C=1.CN(C)C1N=CC(B(O)O)=CC=1>>[CH:13]1([CH2:12][CH2:11][N:6]2[C:7]3[C:3](=[C:2]([C:30]4[CH:34]=[N:33][C:48]5[C:47]([CH:31]=4)=[CH:46][CH:54]=[CH:50][CH:49]=5)[CH:10]=[CH:9][CH:8]=3)[C:4]3([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:19]4[O:18][CH2:17]3)[C:5]2=[O:16])[CH2:14][CH2:15]1
Reactant: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Reactant: O=C1N(CCC2CC2)c2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Agent: CN(C)c1ccc(B(O)O)cn1
Agent: OB(O)c1cnc2ccccc2c1
Product: O=C1N(CCC2CC2)c2cccc(-c3cnc4ccccc4c3)c2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 4′-bromo-1′-(2-cyclopropylethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and quinolin-3-ylboronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained: MS (ES+) m/z 477.5 (M+1)
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][C@@H:21]([CH3:25])[NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[CH2:27][CH:28]1[CH2:30][CH2:29]1.[H-].[Na+]>>[CH:28]1([CH2:27][N:22]2[C@H:21]([CH3:25])[CH2:20][N:16]3[C:17]4[CH:18]=[CH:19][C:11]([O:10][CH:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)=[CH:12][C:13]=4[CH:14]=[C:15]3[C:23]2=[O:24])[CH2:30][CH2:29]1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3C[C@@H](C)NC2=O)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3C[C@@H](C)N(CC3CC3)C2=O)CC1

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-3-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 14), 1-(bromomethyl)cyclopropane and sodium hydride, to give the compound as a colorless oil (77%).