Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1.[ClH:38]>C(#N)C.CC(C)=O.C(OCC)C>[ClH:29].[ClH:38].[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][N:20]2[CH2:21][CH2:22][N:17]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:16]=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:8]=3)[CH2:18][CH2:19]2)=[CH:33][CH:32]=1
Reactant: c1ccc(-c2cc(N3CCNCC3)c3ccccc3c2)cc1
Reactant: Cc1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: CC#N
Product: Cc1ccc(CN2CCN(c3cc(-c4ccccc4)cc4ccccc34)CC2)cc1
Temperature: 5 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 3-phenyl-1-(1-piperazinyl)-naphthalene (17.9 g) in acetonitrile (280 cc), there is added potassium carbonate (8.6 g) and then, in the course of 20 minutes, a solution of α-chloro-p-xylene (8.7 g) in acetonitrile (50 cc), at a temperature in the region of 20° C., and stirring is continued for 16 hours. The insoluble material which is formed is separated by filtration. The solution obtained is evaporated under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue is dissolved in methylene chloride (35 cc) and the solution poured onto silica (1 kg) contained in a column 7.5 cm in diameter. Elution is performed with a mixture (3 liters) of methylene chloride and methanol (99:1 by volume) and the corresponding eluate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The residue obtained is dissolved in acetone (250 cc). The solution is cooled to a temperature in the region of 5° C., a 2.5N solution (52 cc) of anhydrous hydrochloric acid in ethyl ether is added and stirring is maintained for approximately 4 hours. The precipitates formed is separated by filtration and washed with ethyl ether ether (3×25 cc). 1-[4-(4-Methylbenzyl)-1-piperazinyl]-3-phenylnaphthalene dihydrochloride (19 g), m.p. 252° C., is thereby obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:27])([CH3:26])[CH2:9][NH:10][C:11]2[N:16]=[N:15][C:14]([C:17]3[N:18]=[C:19]([NH:22]C(=O)C)[NH:20][CH:21]=3)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Cl>CO>[NH2:22][C:19]1[NH:20][CH:21]=[C:17]([C:14]2[N:15]=[N:16][C:11]([NH:10][CH2:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)([CH3:27])[CH3:26])=[CH:12][CH:13]=2)[N:18]=1
Reactant: CC(=O)Nc1nc(-c2ccc(NCC(C)(C)c3ccc(F)cc3)nn2)c[nH]1
Agent: Cl
Solvent: CO
Product: CC(C)(CNc1ccc(-c2c[nH]c(N)n2)nn1)c1ccc(F)cc1
Yield: 41.5 %

Procedure:
To a 10 mL round bottom flask was added N-(4-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)-1H-imidazol-2-yl)acetamide (22 mg, 59 μmol), concentrated HCl (100 μL) and methanol (1 mL). The reaction was refluxed for 12 h and then concentrated, redissolved in EtOAc (10 mL), washed with saturated sodium carbonate (2×10 mL) and brine (1×10 mL), dried (Na2SO4) and concentrated to yield 8 mg (42%) of 6-(2-amino-1H-imidazol-4-yl)-N-(2-(4-fluorophenyl)-2-methylpropyl)pyridazin-3-amine as a pale yellow solid, m/z=327.2 [M+H].
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:25][CH3:26])=[CH:6][C:7]([O:23][CH3:24])=[C:8]([C:10]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:21]=[CH2:22])[CH:18]=3)[CH2:13]2)=[O:11])[CH:9]=1)([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:35])C=1>C(Cl)Cl.[OH-].[Na+]>[CH:1]([C:4]1[C:5]([O:25][CH3:26])=[CH:6][C:7]([O:23][CH3:24])=[C:8]([C:10]([N:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:21]4[CH2:22][O:35]4)[CH:18]=3)[CH2:13]2)=[O:11])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: C=Cc1ccc2c(c1)CN(C(=O)c1cc(C(C)C)c(OC)cc1OC)C2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cc(OC)c(C(C)C)cc1C(=O)N1Cc2ccc(C3CO3)cc2C1
Temperature: 25 °C

Procedure:
To (5-isopropyl-2,4-dimethoxy-phenyl)-(5-vinyl-1,3-dihydro-isoindol-2-yl)-methanone (0.80 g, 2.28 mmol) in DCM (22 ml) was added mCPBA (0.61 g, 2.73 mmol) at 0° C. The reaction was stirred at room temperature for an hour. The reaction was diluted with NaOH (1M, aq.) and extracted the product with EtOAc. The EtOAc layer was washed with NaOH again. The organic layer was washed with brine and dried over MgSO4. The product was filtered and evaporated to dryness to yield crude (5-isopropyl-2,4-dimethoxy-phenyl)-(5-oxiranyl-1,3-dihydro-isoindol-2-yl)-methanone as a very pale yellow oil. MS: [M+H]+ 368.
Reaction SMILES: Br[C:2]1[S:3][C:4]([Cl:7])=[CH:5][CH:6]=1.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:7][C:4]1[S:3][C:2]([C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: Clc1ccc(Br)s1
Reactant: OB(O)c1cccs1
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: COCCOC
Product: Clc1ccc(-c2cccs2)s1
Yield: 80.7 %

Procedure:
To a solution of 2-bromo-5-chlorothiophene (4.11 g), thiophene-2-boronic acid (4.00 g), tetrakis(triphenylphosphine)palladium (0) (1.20 g) and 2M aqueous sodium carbonate solution (31.3 ml) in dimethoxyethane (100 ml) was heated under reflux under argon atmosphere for 2.5 hours. The reaction mixture was cooled, and extracted with ethyl acetate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give 2-(5-chloro-2-thienyl) thiophene (3.37 g) as pale yellow oil. (2) The above 2-(5-chloro-2-thienyl)thiophene and 5-bromo-2-methylbenzoic acid obtained in Reference Example 4-(1) were used and treated in a manner similar to Reference Example 5 to give 5-bromo-1-(5-(5-chloro-2-thienyl)-2-thienylmethyl)-2-methylbenzene as a colorless solid. APCI-Mass m/Z 383/385 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:23]=[CH:22][C:18]2[S:19][CH:20]=[CH:21][C:17]=2[CH:16]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:19]1[CH:20]=[CH:21][C:17]2[CH:16]=[C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])[CH:23]=[CH:22][C:18]1=2
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Brc1ccc2sccc2c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3sccc3c2)C1=O
Yield: 10.7 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.847 mmol) was reacted with 5-bromo-benzo[b]thiophene (180.5 mg, 0.847 mmol), 1,4-dioxane (15 mL), copper iodide (16.13 mg, 0.0847 mmol), trans-1,2-diamino cyclohexane (0.03 mL, 0.254 mmol) and potassium carbonate (233.97 mg, 1.694 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in chloroform) afforded 28 mg of the product in (10.69% yield).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@H:7]([C:8]2[C:9]([O:30]C)=[CH:10][C:11]([O:28]C)=[C:12]3[C:17]=2[O:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)=[CH:14][C:13]3=[O:27])[CH2:6][CH2:5][N:4]1[CH3:32].Cl.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[OH:28][C:11]1[CH:10]=[C:9]([OH:30])[C:8]([C@@H:7]2[CH2:6][CH2:5][N:4]([CH3:32])[C@H:3]2[CH2:2][OH:1])=[C:17]2[C:12]=1[C:13](=[O:27])[CH:14]=[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1)[O:16]2
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc([N+](=O)[O-])c3)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cccc([N+](=O)[O-])c4)oc23)[C@@H]1CO
Temperature: 180 °C

Procedure:
A mixture of compound of example 24 (0.5 g, 1.13 mmol) and pyridine hydrochloride (1.2 g, 10.38 mmol) was heated at 180° C. for a period of 2.5 hours. The reaction mixture was diluted with methanol (60 mL) and basified with solid Na2CO3 to pH 10. The reaction mixture was filtered, and washed with methanol. The organic layer was concentrated and the residue purified by column chromatography using 0.01% ammonia and 4.5% methanol in chloroform as eluent to afford the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH2:15][C@H:16]([NH2:18])[CH3:17])=[CH:11][NH:12]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C@H:25]1[O:27][CH2:26]1>C(#N)C>[CH2:19]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH2:15][C@H:16]([NH:18][CH2:26][C@@H:25]([C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([Cl:21])[CH:23]=3)[OH:27])[CH3:17])=[CH:11][NH:12]2)=[CH:8][CH:7]=1)=[O:5])[CH3:20]
Reactant: Clc1cccc([C@@H]2CO2)c1
Reactant: CCN(CC)C(=O)c1ccc2c(C[C@@H](C)N)c[nH]c2c1
Solvent: CC#N
Product: CCN(CC)C(=O)c1ccc2c(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)c[nH]c2c1
Yield: 63.2 %

Procedure:
To a solution of (R)-3-(2-aminopropyl)-1H-indole-6-carboxylic acid diethylamide (960 mg, 3.51 mmol) in acetonitrile (10 ml) is added (R)-(+)-3-chlorostyrene oxide (1.09 g, 7.02 mmol), and the mixture is refluxed for 5 hours. The reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (chloroform/methanol=20/1→(a saturated ammonia solution in chloroform)/methanol=20/1) to give 3-{(2R)-2-[2-(3-chloro-phenyl)-(2R)-2-hydroxyethylamino]propyl}-1H-indole-6-carboxylic acid diethylamide (950 mg, 2.22 mmol, 63%).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([CH:22]2[CH2:24][CH2:23]2)[CH:19]=[CH:18][C:17]=1[CH2:25]O>>[Cl:15][C:16]1[CH:21]=[C:20]([CH:22]2[CH2:24][CH2:23]2)[CH:19]=[CH:18][C:17]=1[CH2:25][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(C2CC2)cc1Cl
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(C3CC3)cc2Cl)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2-chloro-4-cyclopropylphenyl)methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C19H15ClN4O, 351. Found, 351.
Reaction SMILES: [CH2:1]([Li])[CH3:2].[Li].C(Br)C.[F:8][C:9]1[CH:23]=[CH:22][C:12]([C:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[O:14])=[CH:11][CH:10]=1.[Cl-].[NH4+]>O1CCCC1.CCOCC>[F:8][C:9]1[CH:23]=[CH:22][C:12]([C:13]([CH2:1][CH3:2])([OH:14])[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(F)cc1
Reactant: [Li]CC
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CCBr
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)(c1ccc(O)cc1)c1ccc(F)cc1
Temperature: 0 °C

Procedure:
To a solution of ethyl lithium prepared from 2.8 g. of lithium metal and 21.8 g. of ethyl bromide in 265 ml. of dry ether a solution of 10.8 g. of 4-fluoro-4'-hydroxy-benzophenone in 50 ml. of dry tetrahydrofurane is added dropwise, with stirring in argon atmosphere, at a temperature between -40° C. and -30° C. When the addition is complete, the mixture is allowed to warm up to 0° C., and is then stirred at this temperature for further 30 minutes. The mixture is decomposed with a 20% aqueous ammonium chloride solution under cooling. The aqueous phase is extracted with ether, the ethereal phases are combined, washed to neutral with water, and dried over anhydrous magnesium sulfate. The solution is evaporated under reduced pressure, and the solid residue is crystallized from a mixture of n-hexane and ethyl acetate to yield 8.2 g. of the named product, melting at 125° to 126° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.CCN(CC)CC.[S:20](Cl)([CH3:23])(=[O:22])=[O:21]>C(Cl)Cl>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][NH:1][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:5]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCCc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A round bottom flask charged with tryptamine (2.0 g, 12.5 mmol) in DCM (20 mL) was added Et3N (3.5 mL, 25 mmol) under an atmosphere of Ar and cooled to 0° C. The solution was then added mesyl chloride (1.5 mL, 18.7 mmol) and the resulting reaction mixture was stir to RT for 2 h. The reaction was quenched with water (20 mL) and extracted with DCM (3×20 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The desired product was purified via automated column chromatography method 2 (2.1 g, 70%) and isolated as a brown oil. 1H NMR (400 MHz, MeOD) δ 7.55 (d, J=7.6 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.08 (m, 2H), 7.01 (td, J=8.0, 0.8 Hz, 1H), 3.35 (t, J=7.2 Hz, 2H), 2.99 (t, J=7.2 Hz, 2H), 2.76 (s, 3H). 13C NMR (100 MHz, MeOD) δ 138.28, 128.77, 123.91, 122.54, 119.85, 119.34, 112.93, 112.43, 45.09, 40.02, 27.60.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]=[CH:11][N:12]([CH3:14])[CH3:13])=[N:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=Nc1ccc(Br)cn1
Temperature: 130 °C

Procedure:
To a stirred solution of 5-bromo-2-aminopyridine (3.0 g, 17.3 mmol) in N,N-dimethylformamide (6 mL) was added N,N-dimethylformamide dimethyl acetal (5.37 g, 45.0 mmol). The reaction mixture was heated to 130° C. overnight. After cooling to room temperature, the volatiles were removed under reduced pressure to afford the desired product as a brown oil. LC/MS 227.8 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([CH:9]3[CH2:11][CH2:10]3)[N:6]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=3[F:21])[N:5]=2)[CH2:3][CH2:2]1.[Cl:22]N1C(=O)CCC1=O>CN(C=O)C>[Cl:22][C:8]1[C:4]([CH:1]2[CH2:2][CH2:3]2)=[N:5][N:6]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[F:21])[C:7]=1[CH:9]1[CH2:11][CH2:10]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=[N+]([O-])c1ccc(-n2nc(C3CC3)cc2C2CC2)c(F)c1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2nc(C3CC3)c(Cl)c2C2CC2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
Intermediate 10 (1.15 g, 3.40 mmol) was dissolved in DMF and to this N-Chlorosuccinimide (0.64 g, 4.8 mmol) was added at 0° C. Then reaction was allowed to stir at rt for 2 h. After completion of the reaction, work up (EtOAc) and purification afforded the title compound (0.575 g). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.18-8.09 (m, 2H), 7.64 (t, J 8.3, 1H), 1.98-1.90 (m, 1H), 1.82-1.72 (m, 1H), 0.90-0.80 (m, 4H), 0.68-0.60 (m, 4H).
Reaction SMILES: [N:1]12[CH2:24][CH2:23][CH2:22][C@@H:21]1[C:20](=[O:25])[O:19][CH2:18][CH:17]=[CH:16][CH2:15][O:14][C:13](=[O:26])[C@@H:12]1[N:8]([CH2:9][CH2:10][CH2:11]1)[C:7](=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[O:28]>C(OC(=O)C)C.[Pd]>[N:1]12[CH2:24][CH2:23][CH2:22][C@@H:21]1[C:20](=[O:25])[O:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:13](=[O:26])[C@@H:12]1[N:8]([CH2:9][CH2:10][CH2:11]1)[C:7](=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[O:28]
Reactant: O=C1OCC=CCOC(=O)[C@H]2CCCN2C(=O)CCCCC(=O)N2CCC[C@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1OCCCCOC(=O)[C@H]2CCCN2C(=O)CCCCC(=O)N2CCC[C@H]12
Yield: 97.9 %

Procedure:
A mixture of 260 mg (0.66 mmol) (12R,21R)-14,19-dioxa-1,8-diaza-tricyclo[19.3.0.0 8,12]tetracos-16-ene-2,7,13,20-tetraone and 30 mg 10% palladium/carbon in 10 ml ethylacetate was hydrogenated over night. Filtration and removal of the solvent yielded 255 mg (98%) (12R,21R)-14,19-dioxa-1,8-diaza-tricyclo[19.3.0.0 8,12]tetracosane-2,7,13,20-tetraone as a light yellow oil, MS m/e (%): 395 (M+H+, 100).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[C:11](=[O:17])[CH2:10][CH2:9]2.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>COCCOC>[CH3:16][O:15][C:14]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][C:11]2=[O:17])=[CH:7][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1cc2c(cc1OCCCBr)CCC2=O
Reactant: C1CCNC1
Solvent: COCCOC
Product: COc1cc2c(cc1OCCCN1CCCC1)CCC2=O

Procedure:
A mixture of 5-(3-bromo-propoxy)-6-methoxy-indan-1-one (Intermediate J) (2.0 g, 0.0066 mole) and pyrrolidine (1.7 mL, 0.02 mole) was stirred in 50 mL of DME (1,2-Dimethoxyethane) at room temperature overnight under Argon. The reaction was quenched with water (150 mL) and made acidic with 1N HCl (50 mL). The water solution was washed with ethyl acetate, made basic with 3N NaOH (25 mL) and extracted with ethyl acetate. After washing with brine and drying over sodium sulfate, the solvent was removed in vacuo to yield the title compound. MS m/z 290 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N=C2CCCCC2=O)=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.OS(O)(=O)=O.[C:26]([O-:29])(O)=O.[Na+]>CC#N>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([C:17]([F:18])([F:19])[F:20])[CH:3]=1)[NH:8][C:7]1[C:26](=[O:29])[CH2:5][CH2:4][CH2:3][C:2]2=1
Reactant: O=C1CCCCC1=NNc1ccc(Br)cc1C(F)(F)F
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Product: O=C1CCCc2c1[nH]c1c(C(F)(F)F)cc(Br)cc21
Temperature: 80 °C
Yield: 39 %

Procedure:
2-(2-(4-Bromo-2-(trifluoromethyl)phenyl)hydrazono)cyclohexanone (2 g, 5.73 mmol) was dissolved in MeCN (18 mL) and H2SO4 (1.68 g, 17.19 mmol) was added. The reaction mixture was heated to 80° C. for 32 h, cooled to room temperature, basified with saturated aqueous NaHCO3 (pH-8) and extracted with EtOAc (2×30 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude compound which was purified by silica gel chromatography [EtOAc-hexane (19:1) as eluant] to provide the title compound as a pale green solid (750 mg, 39%). 1H NMR (200 MHz, CDCl3, δ in ppm) 9.0 (bs, 1H), 7.9 (s, 1H), 7.72 (d, 1H, J=0.8 Hz), 2.96 (t, J=12.0 Hz, 2H), 2.66 (t, J=12.8 Hz, 2H), 2.33-2.27 (m, 2H).
Reaction SMILES: [BrH:1].C([CH:9]1[NH:17][CH2:16][CH2:15][C:14]2[CH2:13][NH:12][CH2:11][C:10]1=2)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[BrH:1].[BrH:1].[C:10]12[CH2:11][NH:12][CH2:13][C:14]=1[CH2:15][CH2:16][NH:17][CH2:9]2
Reactant: [H][H]
Reactant: c1ccc(CC2NCCC3=C2CNC3)cc1
Agent: [Pd]
Agent: Br
Solvent: CC(=O)O
Product: C1CC2=C(CN1)CNC2
Reaction time: 7 h
Yield: 73 %

Procedure:
0.7 g of N3 -(benzyl)-3,8-diazabicyclo[4.3.0]non-1(6)-ene hydrobromide, prepared in Preparation 10, was dissolved in 20 ml of 5% aqueous acetic acid solution. 0.5 g of 10% palladium charcoal in this solution was suspended and the reaction mixture was refluxed under the hydrogen stream for 7 hours. The solid was filtered off. The filtrate was concentrated under reduced pressure and dissolved in 10 ml of 48% bromic acid. By concentrating the solution under reduced pressure again, 0.5 g of the title compound was obtained (yield 73%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(Cl)Cl.CN.[C:17]([BH3-])#[N:18].[Na+]>C(O)(=O)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:18][CH3:17])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: [BH3-]C#N
Agent: CN
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNC1CCC2(CC1)OCCO2
Reaction time: 8 h
Yield: 43.8 %

Procedure:
A solution of 1,4-dioxa-spiro[4.5]decan-8-one (3.1 g, 20 mmol) and CH2Cl2 (50 mL) was stirred with methylamine (15 mL, 30 mmol, 2.0M solution in THF), sodium cyanoborohydride (1.3 g, 20 mmol), and acetic acid (0.1 mL) at room temperature. After 8 hours, the reaction mixture was washed with water (50 mL) and concentrated. The residue was purified by flash chromatography to afford 1.5 g of (1,4-dioxa-spiro[4.5]dec-8-yl)-methyl-amine as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:29])[C:8]2[O:14][C:13]3[C:15]([Cl:25])=[CH:16][C:17]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[CH:18][C:12]=3[CH2:11][S:10](=[O:27])(=[O:26])[C:9]=2[CH:28]=1)=[O:4].[CH3:30][C:31]1[O:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1.C([BH3-])#N.[Na+]>CO.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH3:29])[C:8]2[O:14][C:13]3[C:15]([Cl:25])=[CH:16][C:17]([N:19]4[CH2:20][CH2:21][N:22]([CH2:35][C:34]5[O:37][C:31]([CH3:30])=[CH:32][CH:33]=5)[CH2:23][CH2:24]4)=[CH:18][C:12]=3[CH2:11][S:10](=[O:26])(=[O:27])[C:9]=2[CH:28]=1)=[O:4]
Reactant: Cc1ccc(C=O)o1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH3-]C#N
Solvent: CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(Cc4ccc(C)o4)CC3)cc(Cl)c1O2

Procedure:
Titanium isopropoxide (0.085 mL, 0.28 mmol) was added to a solution of Example 104k (0.1 g, 0.22 mmol) and 5-methyl furfuraldehyde (0.115 mL, 1.14 mmol) in dry methanol (10 mL). The reaction mixture was processed as described in the synthesis of Example 108k using sodium cyanoborohydride (0.013 g, 0.21 mmol) to obtain the title compound. Yield: 0.085 g, (70%); 1H NMR (CDCl3): δ 2.3 (s, 3H, CH3), 2.6 (t, 4H, 2CH2), 2.7 (s, 3H, CH3), 3.24 (t, 4H, 2CH2), 3.55 (s, 2H, CH2), 3.91 (s, 3H, OCH3), 4.63 (s, 2H, CH2), 5.9 (d, 1H, Ar), 6.1 (d, 1H, Ar), 6.76 (d, 1H, Ar), 6.88 (s, 1H, Ar), 8.06 (s, 1H, Ar), 8.44 (d, 1H, Ar); MS: m/e (EI+) 532 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:9]([N:11]2[CH2:16][CH2:15][C@@H:14]([C:17](O)=[O:18])[CH2:13][C@@H:12]2[C:20]([NH:22][CH2:23][CH2:24][N:25]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])[CH3:26])=[O:21])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:42]([NH:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:9]([N:11]2[CH2:16][CH2:15][C@@H:14]([C:17]([N:49]([CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:18])[CH2:13][C@@H:12]2[C:20]([NH:22][CH2:23][CH2:24][N:25]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH3:35])[CH3:26])=[O:21])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: COc1ccccc1CN(C)CCNC(=O)[C@H]1C[C@H](C(=O)O)CCN1C(=O)N(c1ccccc1)c1cccc(Cl)c1
Product: COc1ccccc1CN(C)CCNC(=O)[C@H]1C[C@H](C(=O)N(Cc2ccccc2)Cc2ccccc2)CCN1C(=O)N(c1ccccc1)c1cccc(Cl)c1
Yield: 32.9 %

Procedure:
According to the procedure given in Example 2, Step E, 0.051 g of trans 1-(N-(3-chlorophenyl)-N-(phenyl)-aminocarbonyl)-2-(RS)-(2-(N-(2-methoxybenzyl)-N-methylamino)ethylaminocarbonyl)-piperidine-4-(RS)-carboxylic acid and 0.035 g of dibenzylamine gave 22 mg (33%) of an oil.
Reaction SMILES: [C:1]1(=[C:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:25])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[OH-].[OH-].[Pd+2]>[CH:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([NH:13][C:14](=[O:25])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH3:24])[CH:17]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(CC(=O)NC2CCC(=C3CCCCC3)CC2)ccc1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(CC(=O)N[C@H]2CC[C@H](C3CCCCC3)CC2)ccc1O
Reaction time: 2 h

Procedure:
The compound (0.5 g) of Example 76 was dissolved in ethanol (20 ml), and 20% palladium hydroxide/carbon (150 mg) was added to the solution, and the mixture was hydrogenated at room temperature. After 2 hours, the catalyst was removed by filtration from the reaction mixture, and the solvent of the mixture was evaporated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give 36 mg of the desired compound.