Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[C:4]=1[O:5][CH2:6][C@H:7]([O:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:8][O:9][S:10]([CH3:13])(=[O:12])=[O:11].B(Br)(Br)Br.O>ClCCl>[OH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:3]([OH:2])[C:4]=1[O:5][CH2:6][C@H:7]([O:14][S:15]([CH3:18])(=[O:16])=[O:17])[CH2:8][O:9][S:10]([CH3:13])(=[O:11])=[O:12]
Reactant: COc1cccc(OC)c1OC[C@@H](COS(C)(=O)=O)OS(C)(=O)=O
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H](COc1c(O)cccc1O)OS(C)(=O)=O
Temperature: 0 °C
Yield: 88.7 %

Procedure:
Methanesulfonic acid (S)-3-(2,6-dimethoxy-phenoxy)-2-methanesulfonyloxy-propyl ester (3.08 g, 8.00 mmol) in) in dichloromethane (40 ml) was cooled to 0° C. and stirred under nitrogen atmosphere. Boron tribromide (1 M solution in dichloromethane, 18 ml, 18 mmol) was added in 15 min. The mixture was stirred at +25° C. for 4 h, and poured on mixture of ice (10 g) and water (15 ml), and the layers were separated. Organic phase was recovered and water layer was extracted twice with dichloromethane (15 ml). Organic phase and dichloromethane extracts were combined and washed with water (15 ml) and saturated sodium chloride solution (15 ml). The combined organic phase was dried (Na2SO4), filtered and evaporated to dryness to give 2.53 g of the title compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:12]=[CH:13][CH:14]=2)O1.Br[C:23]1[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>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].O>[CH3:28][N:27]1[C:23]([C:9]2[CH:10]=[C:11]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:24][CH:25]=[N:26]1
Reactant: CCOC(=O)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cn1nccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cc1cccc(-c2ccnn2C)c1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
A mixture of ethyl 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (500 mg, 1.72 mmol), 5-bromo-1-methyl-1H-pyrazole (252 mg, 1.57 mmol), K2CO3 (651 mg, 4.71 mmol) and Pd(dppf)Cl2 (20 mg) in a solution of dioxane (10 mL) and H2O (2.5 mL) was stirred at 120° C. for 30 min under microwave. The catalyst was filtered through a pad of celite and the filtrate concentrated. The residue was purified by column chromatography to give the desired product (270 mg, Yield 70%) and used directly in the next step. LCMS (m/z): 245.1 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[CH:15]([N:18]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O)[CH3:19])([CH3:17])[CH3:16].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[CH:15]([N:18]([C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1)[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(C)N(C)c1ccccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N(C)c1ccccc1CN1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl piperidin-4-ylcarbamate (262 mg, 1.31 mmol) (Aldrich) and 2-(N-isopropyl-N-methylamino)benzaldehyde (150 mg, 0.85 mmol) in CH2Cl2 (6 mL) was added Na(OAc)3BH (288 mg, 1.36 mmol) followed by AcOH (0.1 mL). This mixture was stirred for 3 h at RT. The reaction was quenched by adding 2M NaOH—H2O (5 mL) and stirred for 5 min. The mixture was then extracted with CH2Cl2 (2×25 mL), and the organic layer was washed with brine, and dried, and the solvent was removed. The crude material was purified by silica gel column chromatography eluting with 5% NH3-MeOH in CH2Cl2 gave Compound 221.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[OH:7][C:8]1([CH2:14][CH2:15][N:16]2[C:20](=[O:21])[CH2:19][S:18][CH:17]2[CH2:22][CH2:23][CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>CO.O>[OH:7][C:8]1([CH2:14][CH2:15][N:16]2[C:20](=[O:21])[CH2:19][S:18](=[O:2])[CH:17]2[CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:32][CH:33]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C(O)c1ccc(CCCC2SCC(=O)N2CCC2(O)CCCCC2)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(CCCC2N(CCC3(O)CCCCC3)C(=O)CS2=O)cc1

Procedure:
Sodium metaperiodate (0.75 g., 3.5 mmoles) is added to a cold (0°-5° C.) solution of 4-{3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]propyl}benzoic acid (1.33 g., 3.4 mmoles) in methanol (20 ml.) and water (5 ml.). The resulting mixture is stirred without further cooling for 16 hours. The precipitated solid is then removed by filtration. The filtrate is diluted with water and extracted with chloroform. The organic extract is washed with brine, dried over sodium sulfate, and evaporated in vacuo to leave an oily residue which is chromatographed on silica gel (25 g.). Elution with 4% acetic acid in chloroform affords the title compound as a viscous, yellowish oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:24][C:25](=[O:33])[CH:26]([NH:31][CH3:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[C:17](=[O:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:35]1[CH2:40][CH2:39][CH2:38][CH:37]=[CH:36]1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:24][C:25](=[O:33])[CH:26]([N:31]([CH:40]2[CH2:39][CH2:38][CH2:37][CH:36]=[CH:35]2)[CH3:32])[CH2:27][CH:28]([CH3:29])[CH3:30])[C:17](=[O:23])[NH:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrC1C=CCCC1
Reactant: CNC(CC(C)C)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)CC(C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C)N(C)C1C=CCCC1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
4-Methyl-2-methylamino-pentanoic acid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide (Example 35) (1.0 mmol) was dissolved in THF (10 mL) and treated with 3-bromocyclohexene (1.5 mmol) and diisopropylethylamine (3 mmol). The reaction was stirred at 50° C. for 18 hours. Then the reaction mixture was allowed to cool to room temperature and concentrated to dryness. The residue was chromatographed on silica gel eluting with a gradient of 10-30% acetone/CH2Cl2 to give the title compound with the yields of 50%.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]3[CH2:17][C:16]([CH:19]([CH3:21])[CH3:20])([OH:18])[CH2:15]3)[N:8]2[CH3:11])=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:3]=1.[CH2:28]([C:30]1[NH:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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]>[CH2:28]([C:30]1[N:31]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:14]4[CH2:17][C:16]([CH:19]([CH3:21])[CH3:20])([OH:18])[CH2:15]4)[N:8]3[CH3:11])=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[N:3]=2)[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1)[CH3:29]
Reactant: CC(C)C1(O)CN(CCc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)C1
Reactant: CCc1nc2ccccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CCN3CC(O)(C(C)C)C3)n(C)c2n1
Temperature: 120 °C
Yield: 44.6 %

Procedure:
A mixture of 1-[2-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)ethyl]-3-isopropyl-azetidin-3-ol (33 mg, 0.08 mmol), 2-ethylbenzimidazole (14 mg, 0.09 mmol), Pd2(dba)3 (1.9 mg, 2.5 mol %), Xphos (4.0 mg, 10 mol %) and Cs2CO3 (41 mg, 0.13 mmol) in dioxane (1.0 mL) was purged with argon gas then heated at 120° C., for 18 h, in a sealed tube. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by flash chromatography (Si—PCC, 0-10% 2 M NH3/MeOH in DCM) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient of acetonitrile 20-98%) to give 466 (18 mg, 42%) as an off white solid. LCMS: (Method I): RT 2.62 min; [M+H]+ 505.3. 1H NMR (400 MHz, CHCl3-d): δ 8.01-7.96 (m, 1 H), 7.76-7.72 (m, 1 H), 7.28-7.22 (m, 2 H), 4.45-4.33 (m, 4 H), 3.86 (t, J=4.7 Hz, 4 H), 3.77 (s, 3 H), 3.41 (d, J=8.1 Hz, 2 H), 3.34 (q, J=7.5 Hz, 2 H), 3.18 (d, J=8.1 Hz, 2 H), 3.04 (t, J=7.2 Hz, 2 H), 2.93 (t, J=7.2 Hz, 2 H), 2.01-1.89 (m, 1 H), 1.44 (t, J=7.5 Hz, 3 H), 0.94 (d, J=6.8 Hz, 6 H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[N:6][CH:7]=1.C[Si](C)(C)[C:13]([F:16])([F:15])[F:14].Cl.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])([CH3:9])[C:13]([F:16])([F:15])[F:14])[CH:5]=[N:6][CH:7]=1
Reactant: CC(=O)c1cncc(Br)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC(O)(c1cncc(Br)c1)C(F)(F)F
Reaction time: 3 h
Yield: 82.9 %

Procedure:
To a solution of 1-(5-bromo-pyridin-3-yl)-ethanone (1.0 g, 5.0 mmol) in THF (dry, 25 ml) at room temperature is added tetrabutyl-ammonium fluoride (0.35 ml, 1M in THF, 0.35 mmol). Then trimethyl-trifluoromethyl-silane (3.25 ml, 2.0M in THF, 6.5 mmol) is added to the reaction mixture dropwise. The reaction mixture is stirred for 3 h. Then HCl (4N, 6.6 ml, 26.5 mmol) is added to the mixture. The reaction mixture is stirred for 4 h at room temperature and then is neutralized by adding Na2CO3 powder slowly. The resulting mixture is partitioned between water and EtOAc, and the aqueous phase is extracted with EtOAc. The combined organic phases are concentrated in vacuo. The crude mixture is separated by flash silica gel column (EtOAc/Heptane 0 to 30% gradient, then 30%) to obtain 1.12 g 2-(5-bromo-3-pyridyl)-1,1,1-trifluoro-propan-2-ol.
Reaction SMILES: COC1C=CC(C[O:8][CH2:9][C:10]([O:12][CH2:13][NH:14][C:15]([C:17]2[CH:22]=[C:21]([CH3:23])[C:20]([CH:24]([C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=3[F:42])[S:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])=[CH:19][N:18]=2)=[O:16])=[O:11])=CC=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O>ClCCl.O>[OH:8][CH2:9][C:10]([O:12][CH2:13][NH:14][C:15]([C:17]1[CH:22]=[C:21]([CH3:23])[C:20]([CH:24]([C:35]2[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=2[F:42])[S:25]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)(=[O:26])=[O:27])=[CH:19][N:18]=1)=[O:16])=[O:11]
Reactant: COc1ccc(COCC(=O)OCNC(=O)c2cc(C)c(C(c3cc(F)ccc3F)S(=O)(=O)c3ccc(F)cc3)cn2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C(=O)NCOC(=O)CO)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
To a mixed solution of [[[5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridin-2-yl]carbonyl]amino]methyl (4-methoxybenzyloxy)acetate (150 mg, 0.24 mmol) in dichloromethane-water (1:1, 10 ml), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (65 mg, 0.29 mmol) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, subsequently the solvent was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. The fraction obtained from an elution with dichloromethane:methanol=50:3 was concentrated under reduced pressure, washed with diethyl ether, and collected by filtration, to obtain the title compound (26 mg, 0.05 mmol, 21%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>C(O)(C)(C)C.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>[N:9]1([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: Nc1ccc(Br)cn1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: Nc1ccc(N2CCOCC2)cn1

Procedure:
A solution of 2-amino-5-bromopyridine (2.0 g, 0.011 mol) in t-butanol (5 ml) is degassed with nitrogen for 5 min. Morpholine (1.4 g, 0.016 mol), Davephos (0.4 g, 0.001 mol) and tris(dibenzylideneacetone)dipalladium(0) (0.25 g, 0.027 mmol) is added. A 1.6M solution of lithium bis(trimethylsilyl)amide in THF (5.51 g, 0.033 mol) is then added dropwise. The reaction mixture is irradiated in the microwave at 150° C. for 2 h. Water is added (30 ml), and the mixture is extracted with ethyl acetate (2×100 ml). The organic phases are washed with water (1×100 ml) and dried over sodium sulfate. The crude material is employed in the next step without purification. 5-Morpholin-4-ylpyridin-2-ylamine is employed in the synthesis of “A7”.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([NH2:12])=[C:7]([Cl:13])[CH:6]=[CH:5][C:4]=2[N:3]=1.[CH:14]1([CH2:20][CH2:21][C:22](O)=[O:23])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[C:8]=2[NH:12][C:22](=[O:23])[CH2:21][CH2:20][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[N:3]=1
Reactant: Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: O=C(O)CCC1CCCCC1
Product: O=C(CCC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12

Procedure:
Prepared according to the method of example 62(a), using 2,6-dichloroquinolin-5-amine (example 1(d)) (0.5 g) and cyclohexanepropionic acid (1.2 mL). The resulting precipitate was filtered and washed with acetone. The precipitate was further washed with water and then ether to give the sub-title compound as a solid (0.248 g)
Reaction SMILES: [CH2:1]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1[O:13]C)[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].I[C:22]1[CH:31]=[CH:30][CH:29]=C[C:23]=1[C:24]([O:26][CH3:27])=[O:25]>N1C=CC=CC=1.O.[Cu]I>[CH3:27][O:26][C:24](=[O:25])[C:23]1[CH:22]=[CH:31][CH:30]=[CH:29][C:12]=1[O:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:13])[C:5]=1[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1ccccc1I
Reactant: CCCCc1c(OC)cccc1OC
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: CCCCc1c(O)cccc1Oc1ccccc1C(=O)OC
Temperature: 25 °C
Yield: 13 %

Procedure:
2-Butyl-1,3-dimethoxybenzene (14.98 g, 77.6 mmol) was de-methylated as described above for the preparation of Example 10(B) to provide 19 g crude product as a brown oil. A solution of 15 g of this material and potassium tert-butoxide (9.70 g, 86.5 mmol) in pyridine (150 mL) was added to a second solution of methyl 2-iodobenzoate (11.9 g, 180 mmol) and copper(I) iodide (17.3 g, 91.0 mmol) in pyridine (150 mL). The resulting mixture was refluxed for 36 hours. The mixture was cooled to room temperature, diluted with water, and extracted three times with diethyl ether. The combined ether fractions were filtered through a mat of Celite®, washed once with 5N aqueous hydrochloric acid, once with 2N aqueous sodium hydroxide, and filtered again through a mat of Celite®. The resulting solution was dried over magnesium sulfate, filtered, and evaporated in vacuo. Silica gel chromatography (ethyl acetate/hexane) provided 3.02 g (11%) of the title intermediate product as an orange oil: NMR (CDCl3) 7.91 (d, J=8 Hz, 1H), 7.41 (t, J=8 Hz, 1H), 7.14 (t, J=8 Hz, 1H), 6.97 (t, J=9 Hz, 1H), 6.83 (d, J=8 Hz, 1H), 6.59 (d, J=8 Hz, 1H), 6.39 (d, J=8 Hz, 1H), 5.04 (bs, 1H, —OH), 3.83 (s, 3H), 2.66 (t, J=9 Hz, 2H), 1.54 (quintet, J=5 Hz, 2H), 1.35 (hextet, J=5 Hz, 2H), 0.91 (t, J=8 Hz, 3H); MS-EI m/e 300 (p, 34), 225 (100), 213 (42), 197 (53), 107 (38); IR (mull, cm−1) 3410, 2926, 1709, 1600, 1463, 1234, 1107, 1090, 992.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[CH:7]=[C:8]([C:12]([OH:14])=O)[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]=1[O:17][CH3:18].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25]>>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[CH:7]=[C:8]([C:12]([N:29]3[CH2:30][CH2:31][N:26]([C:24](=[O:25])[C:23]4[CH:32]=[C:33]([O:37][CH3:38])[C:34]([O:35][CH3:36])=[C:21]([O:20][CH3:19])[CH:22]=4)[CH2:27][CH2:28]3)=[O:14])[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]=1[O:17][CH3:18]
Reactant: COc1ccc2c(c1OC)CCCC(C(=O)O)=C2
Reactant: COc1cc(C(=O)N2CCNCC2)cc(OC)c1OC
Product: COc1cc(C(=O)N2CCN(C(=O)C3=Cc4ccc(OC)c(OC)c4CCC3)CC2)cc(OC)c1OC

Procedure:
In a manner as that described in Example 62, 3,4-dimethoxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid and 1-(3,4,5-trimethoxy-benzoyl)piperazine are subjected to amidation to give 1-(3,4-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl)-4-(3,4,5-trimethoxybenzoyl)piperazine. This product is recrystallized from ethyl acetate to give colorless prisms, m.p. 133°-134° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10](=O)[C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CS(C)=O.O.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2Cc1ccccc1
Agent: NN
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc2c(c1)CC(=O)N2Cc1ccccc1
Reaction time: 3 h
Yield: 85.8 %

Procedure:
A stirred solution of 5-methoxyisatin (5.0 g, 28 mmol) in dry DMF (40 mL) was cooled in an ice bath before addition of sodium hydride (60 wt % in mineral oil, 1.7 g, 42 mmol) slowly, the dark red solution turning quickly black. After stirring for 20 min, BnBr (3.7 mL, 31 mmol) was added to the reaction mixture by syringe and the resulting mixture was stirred for 1 h. Water (150 mL) was added with stirring, and the resulting dark red precipitate collected by filtration and washed with water to give 1-benzyl-5-methoxyindoline-2,3-dione as a dark red solid (6.1 g, 81%). 1H NMR (400 MHz, CDCl3) δ 7.39-7.31 (m, 5H), 7.17 (s, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.68 (d, J=8.6 Hz, 1H), 4.92 (s, 2H), 3.79 (s, 3H). MS ESI 268.1 [M+H]+, calcd for [C16H13NO3+H]+ 268.09. A solution of 1-benzyl-5-methoxyindoline-2,3-dione (6.1 g, 23 mmol) and hydrazine hydrate (50-60% grade, 2.9 mL, ca. 2 eq) in DMSO (15 mL) is heated to 140° C. in an oil bath. After 3 h, the mixture was cooled, diluted with water and EtOAc, the layers separated and the aqueous extracted with EtOAc three times (30 mL). The combined organic portions were washed with 2M H2SO4, brine, and dried over MgSO4, filtered and concentrated to afford the crude product as a viscous brown oil. The crude product was purified by silica gel chromatography (20-50% EtOAc in hexane) to yield the title compound as a brown oil (5.0 g, 85%). 1H NMR (400 MHz, CDCl3) δ 7.34-7.23 (m, 5H), 6.89 (s, 1H), 6.69 (d, J=8.3 Hz, 1H), 6.61 (d, J=8.5 Hz, 1H), 4.91 (s, 2H), 3.76 (s, 3H), 3.62 (s, 2H). MS ESI 254.0 [M+H]+, calcd for [C16H15NO2+H]+ 254.1.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH3:11]>C1C=CC=CC=1>[C:1]1([N:12]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCCCNCCCC
Reactant: O=C1CCCCC1
Solvent: c1ccccc1
Product: CCCCN(CCCC)C1=CCCCC1

Procedure:
This example shows a typical preparation of an enamine of this invention using a ketone. A half mole of both cyclohexanone and di-n-butylamine in 100 ml. of benzene were refluxed for 2-3 days using a Dean Stark trap to collect the water as it formed. After about 61/2 ml. of water was collected, the benzene was stripped off, and the enamine was collected as the fraction distilling between 121°-124° C. at 7.5 mm. Hg.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:8](=O)[CH2:7][CH:6]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[CH2:5][C:4]=2[N:3]=1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].[ClH:26].Cl.O>C(O)C>[ClH:26].[NH:24]([N:25]=[C:8]1[CH2:7][CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[CH2:5][C:4]2[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]([CH3:12])[C:9]1=2)[C:21]([NH2:23])=[NH:22]
Reactant: Cc1cc(C)c2c(n1)CC(c1ccccc1C)CC2=O
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2c(n1)CC(c1ccccc1C)CC2=NNC(=N)N
Yield: 89.6 %

Procedure:
A mixture of 2,4-dimethyl-7-(2-methylphenyl)-5,6,7,8-tetrahydroquinolin-5-one (0.48 g), aminoguanidine hydrochloride (0.21 g), concentrated hydrochloric acid (0.19 ml), water (0.19 ml) and ethanol (50 ml) was refluxed for 4 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with diethylether, and to the solution was added sodium hydrogen carbonate solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated. The residue was dissolved in ethanol, and to the solution was added 1N hydrochloric acid. Under reduced pressure, the solvent was evaporated to give 5-guanidinoimino-2,4-dimethyl-7-(2-methylphenyl)-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 84) (0.58 g) as amorphous.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:40]1[CH2:45][CH2:44][C:43]2([O:50][C:49]3[CH:51]=[CH:52][CH:53]=[CH:54][C:48]=3[N:47]3[CH:55]=[CH:56][CH:57]=[C:46]23)[CH2:42][CH2:41]1.CCN(CC)CC>CN(C=O)C>[N:40]1([C:9]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:1])([F:15])[F:14])=[CH:13][CH:12]=2)=[O:11])[CH2:41][CH2:42][C:43]2([O:50][C:49]3[CH:51]=[CH:52][CH:53]=[CH:54][C:48]=3[N:47]3[CH:55]=[CH:56][CH:57]=[C:46]23)[CH2:44][CH2:45]1
Reactant: c1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Reactant: O=C(O)c1ccc(OCC(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccc(OCC(F)(F)F)cc1)N1CCC2(CC1)Oc1ccccc1-n1cccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(2,2,2-Trifluoroethoxy)benzoic acid (22 mg, 0.10 mmol), HATU (42 mg, 0.11 mmol), and DMF (0.8 mL) were combined and allowed to sit at room temperature for 10 minutes. The activated acid was then added to spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] (28 mg, 0.10 mmol) followed by the addition of Et3N (84 μL, 0.60 mmol). The reaction mixture was stirred at room temperature for 17 h before it was filtered and purified by prep-HPLC (5 mM HCl/H2O and MeOH) to provide spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl(4-(2,2,2-trifluoroethoxy)phenyl)methanone. ESI-MS m/z calc. 442.2. found 443.4 (M+1)+. Retention time: 2.05 minutes (4 min run).