Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([I:18])=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20]([O:22]CC)=[O:21])=[CH:9]1)[CH2:5][O:6][CH3:7].[OH-].[Li+]>O1CCCC1.O>[CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([I:18])=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20]([OH:22])=[O:21])=[CH:9]1)[CH2:5][O:6][CH3:7]
Reactant: CCOC(=O)c1cn(C(COC)COC)c2ccc(I)cc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCC(COC)n1cc(C(=O)O)c(=O)c2cc(I)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.9 %

Procedure:
Ethyl 1-(1,3-dimethoxypropan-2-yl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (Intermediate 22, 270 mg, 0.60 mmol) was dissolved in tetrahydrofuran (20 mL) and water (5 mL). Lithium hydroxide (56 mg, 2.42 mmol) was added and the mixture was stirred for 10 min at room temperature. The reaction mixture was then refluxed at 80° C. for 1 h. The reaction mixture was concentrated under reduced pressure and water (10 mL) was added. The pH was adjusted to 2 with hydrochloric acid (2N) and the solid that precipitated was collected by filtration and dried to afford 185 mg (75%) of 1-(1,3-dimethoxypropan -2-yl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:10]([O:12][C@@H:13]1[CH2:29][C@@H:28]2[C@@:16]([CH3:39])([C@@H:17]3[C@@H:25]([CH2:26][CH2:27]2)[C@:24]2(O)[C@@:20]([CH3:38])([C@@H:21]([C:31]4[CH:32]=[CH:33][C:34](=[O:37])[O:35][CH:36]=4)[CH2:22][CH2:23]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:11])=O)(C)(C)C.Cl>CCOC(C)=O>[NH2:8][C@@H:9]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:10]([O:12][C@@H:13]1[CH2:29][C@@H:28]2[C@@:16]([CH3:39])([C@@H:17]3[C@@H:25]([CH2:26][CH2:27]2)[C:24]2[C@@:20]([CH3:38])([C@@H:21]([C:31]4[CH:32]=[CH:33][C:34](=[O:37])[O:35][CH:36]=4)[CH2:22][CH:23]=2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:11]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccc(=O)oc4)CC[C@]32O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](N)C(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@H]3C4=CC[C@H](c5ccc(=O)oc5)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
To a solution of (S)-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-(tert-butoxy carbonylamino)-4-methylpentanoate (18 mg, 0.03 mmol, 1 eq) in EtOAc (3 mL) was added HCl (4 M in EtOAc, 3 mL) in drops at 0° C. The resulting mixture was warmed to room temperature after 30 min and stirred for 2 h. The mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc (20 mL×3). The organic layer was washed with H2O (10 mL×4) and then dried over anhydrous Na2SO4, concentrated under reduced pressure. The crude product was then purified via Prep-TLC(CH2Cl2:MeOH=10:1) to afford the (S)-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-amino-4-methylpentanoate (7 mg, 48.5%). LCMS (M+H+) m/z 482.6.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:17][C@@H:6]2[CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9][C@@H:5]2[CH2:4]1.[ClH:18].C(OCC)(=O)C>>[ClH:18].[CH2:7]1[C@H:6]2[CH2:17][CH:3]([CH2:2][OH:1])[CH2:4][C@H:5]2[CH2:9][NH:8]1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CC(CO)C[C@H]2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: OCC1C[C@H]2CNC[C@H]2C1

Procedure:
A solution of tert-butyl(3aR,6aS)-5-(hydroxymethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (2.24 g) (WO 2006/14325 A2, 2006) in 4N hydrogen chloride/ethyl acetate (10 mL) was stirred at room temperature for 1 hr. The reaction mixture was concentrated to give the title compound (1.65 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][OH:16].CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][N:29]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:30]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>C1COCC1.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].CO>[OH:16][CH2:15][CH2:14][CH2:13][C:12]([N:7]1[C:8]2[C:3](=[C:2]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:30]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][CH2:6]1)=[O:17]
Reactant: O=C(CCCO)N1CCCc2c(Br)cccc21
Reactant: CCOC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)Cn1cc(-c2cccc3c2CCCN3C(=O)CCCO)cn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a degassed solution of 1-(5-bromo-3,4-dihydroquinolin-1(2H)-yl)-4-hydroxybutan-1-one (68 mg, 0.228 mmol), ethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate (80 mg, 0.285 mmol) and potassium phosphate (145 mg, 0.684 mmol) in THF (1 mL) was added PdCl2(dppf) (15 mg, 0.021 mmol). The vial was purged with argon, sealed, and stirred 80° C. overnight. After this time, the reaction mixture was partitioned between EtOAc and saturated NH4Cl solution, and the organic layer was separated. The aqueous phase was extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide the crude material. The crude material was purified by flash chromatography (0-100% ethyl acetate:hexanes then 10% ethyl acetate:MeOH) to afford the title compound (80 mg, 85% yield) as a yellow oil. LCMS, [M+H]+=372.1. 1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.53 (s, 1H), 7.23-7.12 (m, 3H), 4.94 (s, 2H), 4.25 (q, J=7.1 Hz, 2H), 3.78 (t, J=6.9 Hz, 2H), 3.68 (dd, J=11.1, 5.5 Hz, 2H), 2.73 (t, J=6.5 Hz, 2H), 2.64 (t, J=6.7 Hz, 2H), 1.97-1.83 (m, 4H), 1.29 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[CH:2]([C:4](=O)[CH2:5][CH3:6])[CH3:3].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([I:15])=[CH:11][N:10]=1>CCO>[CH2:5]([C:4]1[N:8]=[C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][N:10]2[C:2]=1[CH3:3])[CH3:6]
Reactant: CCC(=O)C(C)Br
Reactant: Nc1ccc(I)cn1
Solvent: CCO
Product: CCc1nc2ccc(I)cn2c1C
Yield: 30.8 %

Procedure:
To a stirred mixture of 2-bromopentan-3-one (2.0 g), 2-amino-5-iodopyridine (1.0 g) and EtOH (50 ml) was heated at reflux for 16 h. The reaction mixture was cooled and concentrated in vacuo. The residue was diluted with water (100 ml), and extracted with DCM. The DCM layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (400 mg) as a yellow solid.
Reaction SMILES: [Br-].[C:2]1([C:8]2[CH:25]=[CH:24][C:11]([C:12]([CH2:14][N+:15]3[CH:23]=[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][N:17]4[CH:16]=3)=[O:13])=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:32]([O:36][CH2:37][CH3:38])(=[O:35])[C:33]#[CH:34].Cl>>[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][N:15]1[C:14]([C:12](=[O:13])[C:11]2[CH:10]=[CH:9][C:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:25][CH:24]=2)=[CH:34][C:33]([C:32]([O:36][CH2:37][CH3:38])=[O:35])=[CH:16]1
Reactant: O=C(C[n+]1cc2ccccn2c1)c1ccc(-c2ccccc2)cc1
Reactant: C#CC(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Br-]
Product: CCOC(=O)c1cc(C(=O)c2ccc(-c3ccccc3)cc2)n(Cc2ccccn2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.3 %

Procedure:
2-(4-Phenylbenzoylmethyl)imidazo[3,4-a]pyridinium bromide (16 g., 40 mmoles), potassium carbonate (22 g., 160 mmoles) and ethyl propiolate (6.4 ml., 48 mmoles) were combined according to the procedure of Example 69, stirred for approximately 16 hours at room temperature, then isolated and converted to hydrochloride according to the procedure of Example 69, to yield ethyl 1-(2-pyridylmethyl)-5-(4-phenylbenzoyl)pyrrole-3-carboxylate (5.3 g., intermediate Rf on silica gel thin layer chromatography with ethyl acetate/5% acetic acid as eluant).
Reaction SMILES: [CH:1]([Cl:4])(Cl)Cl.[F:5][C:6]1[CH:36]=[CH:35][C:9]2[S:10][C:11]([S:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[S:25][CH:26]=[C:27](CO)[N:28]=4)=[CH:20][C:19]=3[S:31]([CH3:34])(=[O:33])=[O:32])(=[O:16])=[O:15])=[C:12]([CH3:13])[C:8]=2[CH:7]=1.S(Cl)(Cl)=O>C(N(CC)CC)C>[Cl:4][CH2:1][C:27]1[N:28]=[C:24]([C:21]2[CH:22]=[CH:23][C:18]([NH:17][S:14]([C:11]3[S:10][C:9]4[CH:35]=[CH:36][C:6]([F:5])=[CH:7][C:8]=4[C:12]=3[CH3:13])(=[O:15])=[O:16])=[C:19]([S:31]([CH3:34])(=[O:32])=[O:33])[CH:20]=2)[S:25][CH:26]=1
Reactant: Cc1c(S(=O)(=O)Nc2ccc(-c3nc(CO)cs3)cc2S(C)(=O)=O)sc2ccc(F)cc12
Reactant: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3nc(CCl)cs3)cc2S(C)(=O)=O)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 21 h

Procedure:
Into 20 mL of chloroform was suspended 159 mg of Compound 63, and 47 μL of thionyl chloride was added at 0° C., followed by 21 hours of stirring at room temperature. Further, 1 mL of thionyl chloride was added, followed by 1 hour of heating under refluxing. After 2 mL of triethylamine was added at 0° C. and the mixture was stirred for 3 hours, the reaction was terminated with 1 mol/L hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, successively and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform) to obtain 104 mg of the title compound as light brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19]([OH:21])=O)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.[NH2:22][N:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([C:19]([NH:22][N:23]3[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]3)=[O:21])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:17][CH2:18]2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Reactant: NN1CCC(O)CC1
Product: O=C(NN1CCC(O)CC1)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chlorophenyl)-6-(cyclopropylmethoxy)-3-pyridinecarboxylic acid (CAN 1018782-76-7) and 1-amino-4-piperidinol (CAN 79414-82-7) as starting materials; MS (EI) 402.4 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](Br)=[CH:24][CH:23]=[C:22]([Cl:27])[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:33]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O.CCO.C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:33]4[CH:34]=[C:35]([N+:38]([O-:40])=[O:39])[CH:36]=[CH:37][C:32]=4[F:31])=[CH:24][CH:23]=[C:22]([Cl:27])[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Reactant: O=[N+]([O-])c1ccc(F)c(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1-c1cc([N+](=O)[O-])ccc1F

Procedure:
A mixture of INTERMEDIATE 9 (1.0 g, 1.93 mmol), 2-fluoro-5-nitro phenyl boronic acid (0.51 g, 2.74 mmol), tetrakis(triphenylphosphine) palladium (223 mg, 10% mol) and Na2CO3 (410 mg, 3.86 mmol) in 14 mL of water/EtOH/toluene (1:2:4) was heated at reflux for 2 h. The solvents were removed. Water (20 mL) was added. The organic was extracted with CH2Cl2 (3×10 mL). The combined CH2Cl2 layers were washed with brine, and dried (Na2SO4). The title compound was obtained after flash chromatography using CH2Cl2/hexane (8:2) as the eluant. LCMS M+H 578.30.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][C:6](=[O:8])[N:5]([CH3:9])[CH:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[K+].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[CH3:9][N:5]1[C:6](=[O:8])[CH2:7][CH:3]([CH2:2][O:1][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[CH:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CN1C(=O)CC(CO)C1c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)OCC2CC(=O)N(C)C2c2ccccc2)cc1
Temperature: 15 °C
Reaction time: 4 h

Procedure:
To 27.8 g. of 3-hydroxymethyl-1-methyl-2-phenyl-pyrrolidin-5-one in 40 ml. of potassium hydroxide dried pyridine was added in portions at 0°-5° 29.4 g. of p-toluenesulfonyl chloride. The orange solution was then stirred at 15° C. for 4 hours and then decanted into 180 ml. of ice cold 10% hydrochloric acid. The resulting solid was collected by filtration and washed with water and air dried. Washing with ether provided 37 g. of crude product.
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[CH3:53][C:54]1[CH:59]=[C:58]([CH3:60])[CH:57]=[CH:56][C:55]=1[NH:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C.O>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([N:65]2[CH2:66][CH2:67][CH:62]([NH:61][C:55]3[CH:56]=[CH:57][C:58]([CH3:60])=[CH:59][C:54]=3[CH3:53])[CH2:63][CH2:64]2)=[O:12])=[CH:5][CH:6]=1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: Cc1ccc(NC2CCNCC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC2CCN(C(=O)CC(=O)Nc3ccc(-c4ccccc4)cc3)CC2)c(C)c1
Reaction time: 8 h
Yield: 44 %

Procedure:
To a stirred solution of N-biphenyl-4-yl-malonamic acid (0.101 g, 0.00039 mole) in DMF (3 mL) was added DIPEA (0.233 g, 0.0018 mole), HOBt (0.053 g, 0.00039 mole) and EDCI.HCl (0.138 g, 0.000721 mole). After 2 minutes (2,4-dimethyl-phenyl)-piperidin-4-yl-amine dihydrochloride (0.1 g, 0.00036 mole was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using silica gel 60-120 mesh (1% methanol in chloroform) afforded 0.07 g (44%) of N-biphenyl-4-yl-3-[4-(2,4-dimethyl-phenylamino)-piperidin-1-yl]-3-oxo-propionamide. LC-MS purity: 442.24 (M+1)+, 98.89%, 1H NMR (DMSO-d6): δ 10.2 (s, 1H), 7.8-7.6 (m, 6H), 7.5 (t, 2H), 7.4 (t, 3H), 6.8 (d, 2H), 6.6 (d, 1H), 4.3 (dd, 2H), 3.9 (d, 1H), 3.7 (s, 2H), 3.5 (bs, 1H), 3.2 (t, 1H), 2.7 (m, 1H), 2.2 (s, 3H), 2.1 (s, 3H), 1.9 (t, 2H), 1.5 (t, 1H), 1.3 (d, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](=[O:37])[C:20]4[C:21]([O:29][C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:22]3[C:26](=[CH:27][CH:28]=4)[NH:25][N:24]=[CH:23]3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:41]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19](=[O:37])[C:20]4[CH:28]=[CH:27][C:26]5[C:22](=[CH:23][N:24]([CH3:41])[N:25]=5)[C:21]=4[O:29][C:30]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]ncc54)c3=O)cc2)CCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc2c(ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc32)n1
Reaction time: 0.08 h
Yield: 32.4 %

Procedure:
To a solution of {1-[4-(4-oxo-2-phenyl-4,7-dihydro-pyrano[2,3-e]indazol-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (65 mg, 0.13 mmol) in DMF (3 mL) at 0° C. under an atmosphere of N2 was added sodium hydride (60% in mineral oil, 6 mg, 0.15 mmol). After 5 min, methyl iodide (10 μL, 0.16 mmol) was added. After a further 2 hours, the reaction was quenched with H2O, partitioned between EtOAc and H2O and the phases were separated. The organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 50 to 70% ethyl acetate in cyclohexane) to afford the title compound as a white solid (22 mg, 32%). LCMS (Method B): RT=4.26 min, [M+H]+=522. Also obtained was {1-[4-(7-methyl-4-oxo-2-phenyl-4,7-dihydro-pyrano[2,3-e]indazol-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester as an oil (41 mg, 60%). LCMS (Method B): RT=4.42 min, [M+H]+=522.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH2:8][NH:9][C:10](=[O:40])[CH2:11][CH2:12][NH:13][C:14](=[O:39])[CH2:15][NH:16][C:17](=[O:38])[CH2:18][C:19]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:3]1.[Na]>O1CCCC1.CC(CC)C=O.C(OCC)(=O)C>[CH3:3][CH:4]([CH2:5][CH3:6])[CH2:8][N:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([CH2:8][NH:9][C:10](=[O:40])[CH2:11][CH2:12][NH:13][C:14](=[O:39])[CH2:15][NH:16][C:17](=[O:38])[CH2:18][C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:3]1
Reactant: O=C(CCNC(=O)CNC(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1)NC[C@H]1CCCNC1
Agent: CCC(C)C=O
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(C)CN1CCC[C@H](CNC(=O)CCNC(=O)CNC(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reaction time: 2 h
Yield: 149.1 %

Procedure:
To a solution of 200 mg of N-(2-{3-((3S)-3-piperidylmethyl)amino-3-oxopropyl}amino-2-oxoethyl)-3,3,3-triphenylpropanamide monohydrochloride in 10 ml of tetrahydrofuran, 0.10 ml of 2-methylbutanal and 230 mg of sodium triacetoxyborohydrate were successively added at room temperature, followed by 2 hours' stirring at the same temperature. The reaction liquid was diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate solution and saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resultant residue was purified by means of silica gel column chromatography (eluting solvent: chloroform/methanol=19/1-4/1), to provide 158 mg of the title compound as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=O.[C:15]1([CH2:21][CH2:22][NH2:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([NH:23][CH2:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(F)c1
Reactant: NCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCCc1ccccc1)c1ccc(C(F)(F)F)c(F)c1
Reaction time: 28 h

Procedure:
To a 100-mL round-bottomed flask, 3-fluoro-4-(trifluoromethyl)benzoic acid (1.036 g, 4.98 mmol) and 2-phenylethanamine (0.700 mL, 5.53 mmol) were dissolved into 25 mL of DMF. Triethylamine (0.840 mL, 6.03 mmol) was added followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.955 g, 4.98 mmol) and 1-hydroxybenzotriazole (0.915 g, 5.97 mmol). The mixture was stirred for 28 h. The reaction mixture was poured into 80 mL of saturated aqueous sodium bicarbonate. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford a yellowish solid. DCM was added to the crude product and the resulting solid was collected via filtration to afford the title compound as a white solid. The filtrate was concentrated and purified by silica gel chromatography (100% EtOAc) to afford another batch of the title compound as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.66 (t, J=7.45 Hz, 1H) 7.46-7.59 (m, 2H) 7.28-7.41 (m, 3H) 7.20-7.26 (m, 2H) 6.14 (br. s., 1H) 3.69-3.81 (m, 2H) 2.96 (t, J=6.87 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:56][CH2:57][CH:58]([OH:64])[CH2:59][NH:60][CH:61]1[CH2:63][CH2:62]1>CN(C=O)C>[CH:61]1([NH:60][CH2:59][CH:58]([OH:64])[CH2:57][NH:56][C:31](=[O:32])[CH2:30][C:26]2[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])[CH2:63][CH2:62]1
Reactant: NCC(O)CNC1CC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCC(O)CNC1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (208 mg, 0.4 mmol), HOBt (54 mg, 1 eq.) and EDAC (153 mg, 2 eq.) in DMF (1.5 mL) was stirred at rt for 30 mins. To the mixture was added 1-amino-3-cyclopropylamino-propan-2-ol (104 mg, 2 eq.) in DMF (1.5 mL). After stirring at rt for overnight, the reaction was concentrated and purified on a silica gel column to give 115 mg (45%) of the titled compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6](Cl)[C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)=[CH:2]1.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH:21]([CH3:33])[CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N+:30]([O-:32])=[O:31])[CH2:16][CH2:15]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[O:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH:21]([CH3:33])[CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N+:30]([O-:32])=[O:31])[CH2:18][CH2:19]2)=[CH:2]1
Reactant: CC(COc1ccccc1[N+](=O)[O-])CN1CCC(O)CC1
Reactant: ClC(c1ccsc1)c1ccsc1
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: CC(COc1ccccc1[N+](=O)[O-])CN1CCC(OC(c2ccsc2)c2ccsc2)CC1

Procedure:
The procedure of Example 36 (a) was repeated except for using di(3-thienyl)methyl chloride and 4-hydroxy-1-[2-methyl-3-(2-nitrophenoxy)propyl]piperidine instead of phenyl-2-thienylmethyl chloride and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-di(3-thienyl)methoxy-1-[2-methyl-3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [C:1]1(=[CH:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:12]1[C:14]([CH3:16])([CH3:15])[CH2:13]1.[I-].[Sm+2].[I-]>O1CCCC1>[CH2:8]([CH:7]1[C:1]2([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:12][C:14]([CH3:16])([CH3:15])[CH2:13]1)[CH2:9][CH2:10][NH2:11]
Reactant: CC1(C)CO1
Reactant: NCCCC=C1CCCCC1
Agent: [I-]
Agent: [Sm+2]
Solvent: C1CCOC1
Product: CC1(C)CC(CCCN)C2(CCCCC2)O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
A mixture of 1 mmol of N-cyclohexylidenebutylamine, 2 mmol of 1,2-epoxy-2-methylpropane, 0.05 mmol of samarium(II) iodide (SmI2), and 1 ml of tetrahydrofuran was stirred at room temperature for 5 hours. Products in the reaction mixture was isolated through column chromatography to yield 4-aza-4-butyl-2,2-dimethyl-1-oxaspiro[4.5]decane of the following formula in yield of 85%.