Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]2[NH:6][C:7]([CH2:9][CH2:10][CH2:11][N:12]([CH3:30])[CH2:13][CH2:14][C:15]3([OH:29])[CH2:20][CH:19]4[CH2:21][CH2:22][CH:16]3[CH:17]=[C:18]4[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:8][C:4]=2[CH:3]=1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>>[Cl:33][C:32]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([CH2:9][CH2:10][CH2:11][N:12]([CH3:30])[CH2:13][CH2:14][C@:15]3([O:29][C:37]([CH:34]4[CH2:36][CH2:35]4)=[O:38])[CH2:20][C@H:19]4[CH2:21][CH2:22][C@@H:16]3[CH:17]=[C:18]4[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:6][C:5]=2[CH:31]=1
Reactant: CN(CCCc1nc2cc(Cl)c(Cl)cc2[nH]1)CCC1(O)CC2CCC1C=C2c1ccccc1
Reactant: O=C(Cl)C1CC1
Product: CN(CCCc1nc2cc(Cl)c(Cl)cc2[nH]1)CC[C@]1(OC(=O)C2CC2)C[C@H]2CC[C@@H]1C=C2c1ccccc1

Procedure:
Prepared according to procedure P1.4 in Example 1A using rac-(1R*,2R*,4R*)-2-(2-{[3-(5,6-dichloro-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol and cyclopropancarbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN1C(=O)CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
400 mg (1.3 mmol) of [4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 10 ml of DMF. 59 mg (1.4 mmol) of sodium hydride was added to the obtained solution, and they were stirred at room temperature for 30 minutes. 380 mg (2.0 mmol) of t-butyl bromoacetate was added to the obtained mixture, and they were stirred at room temperature for 4 hours. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the crude product was obtained. The crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[CH:12]=[O:13].[CH:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[Cl:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([CH:12]=[O:13])=[CH:6][NH:7]2)=[CH:3][C:2]=1[C:20]1[CH:21]=[CH:22][C:17]([CH:14]([CH3:16])[CH3:15])=[CH:18][CH:19]=1
Reactant: O=Cc1c[nH]c2cc(Cl)c(Br)cc12
Reactant: CC(C)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1ccc(-c2cc3c(C=O)c[nH]c3cc2Cl)cc1
Temperature: 100 °C

Procedure:
A vial was charged with 1 mL of a 0.1M solution of 5-bromo-6-chloro-1H-indole-3-carbaldehyde (100 uM) in dioxane, 150 umol of (4-isopropylphenyl)boronic acid solution in dioxane, 200 uL of a 1.0M cesium carbonate solution in water, and 1,1′-bis(di-tert-butylphosphino) ferrocene palladium dichloride), (2 umol, 0.02 eq). The vial was purged with nitrogen, sealed and heat to 100° C. for 16 h. The solvent was evaporated and the vial diluted with ethyl acetate. The organic layer was collected, washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2>[Ni].O1CCCC1>[CH3:17][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]2[C:6]=1[CH:7]=[N:8][NH:9]2
Reactant: CN(C)CCc1ccc([N+](=O)[O-])c2[nH]ncc12
Agent: [Ni]
Solvent: C1CCOC1
Product: CN(C)CCc1ccc(N)c2[nH]ncc12
Yield: 82.2 %

Procedure:
In the presence of 1.0 g of Raney nickel, 1.2 g of N,N-dimethyl-N-[2-(7-nitro-1H-indazol-4-yl)ethyl]amine is hydrogenated in 60 ml of tetrahydrofuran. The mixture is filtered, concentrated and recrystallized from ethyl acetate/hexane, thus producing 860 mg of N,N-dimethyl-N-[2-(7-amino-1H-indazol-4-yl)ethyl]amine, mp 125° C. This product is treated, in the amount of 460 mg, with ethanol and ethereal hydrochloric acid, recrystallization from methanol/diethyl ether yielding 505 mg of N,N-dimethyl-N-[2-(7-amino-1H-indazol-4-yl)ethyl]amine, dihydrochloride, mp 231°-232° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:22]=[CH:21][C:15]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[CH:14][CH:13]=2)=[N:6][C:7]=1[C:8]([NH:10][NH2:11])=[O:9].[N:23]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[C:24]=S.C(Cl)CCl>C1COCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:18]([CH3:19])[CH3:20])=[O:17])=[CH:21][CH:22]=2)=[N:6][C:7]=1[C:8]1[O:9][C:24]([NH:23][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:11][N:10]=1
Reactant: S=C=NCc1ccccc1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)NN)n2)cc1
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(NCc4ccccc4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
A mixture of 4-(5-amino-6-(hydrazinecarbonyl)pyrazin-2-yl)-N,N-dimethylbenzamide (75 mg, 0.2497 mmol), isothiocyanatomethylbenzene (37.26 mg, 33.12 μL, 0.2497 mmol) and dry THF (1.500 mL) was stirred at RT for 4 hours. The reaction mixture was evaporated to dryness and treated with DCM followed by EDC (71.81 mg, 0.3746 mmol) and the resultant mixture allowed to stir at RT overnight. The reaction mixture was filtered and the resultant green precipitate dried under vacuum (78 mg, 73% Yield). 1H NMR (400.0 MHz, DMSO) d 2.96 (s, 3H), 3.00 (s, 3H), 4.50 (d, J=6.1 Hz, 2H), 7.29 (d, J=7.2 Hz, 1H), 7.35-7.42 (m, 4H), 7.51-7.53 (m, 2H), 7.65 (br s, 2H), 8.06 (dd, J=1.5, 6.9 Hz, 2H) and 8.81 (d, J=12.4 Hz, 2H) ppm; MS (ES+) 416.2
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[CH2:13]([C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[C:16]=1[C:17](Cl)=[O:18])[CH3:14]>>[CH2:13]([C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH3:25])[C:16]=1[C:17]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2)=[O:18])[CH3:14]
Reactant: CCc1cccc(CC)c1C(=O)Cl
Reactant: CN1CCc2c(N)cccc2C1
Product: CCc1cccc(CC)c1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline was reacted with 2,6-diethylbenzoyl chloride according to the procedure of Example 19 to yield 5-(2,6-diethylbenzamido)-2-methyl-1,2,3,4-tetrahydroisoquinoline; m.p. 185.5°-187.5° C. after purification from ethanol.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([CH:10]=O)=[N:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH:13]([C:15]1[N:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[NH2:14]>>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:16]3[N:17]=[CH:18][CH:19]=[CH:20][C:15]3=[N:13][N:14]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Reactant: NNc1cccnn1
Agent: Cl
Product: Cn1c([N+](=O)[O-])cnc1-c1nnc2cccnn12

Procedure:
4 g. lead tetraacetate were suspended in 40 ml. glacial acetic acid, 1.5 g. of the hydrazone obtained from 1.55 g. 5-nitro-1-methyl-imidazole-2-aldehyde and 1.1 g. 3-hydrazinopyridazine hydrochloride (prepared by heating for 30 minutes in 20 ml. 50% aqueous methanol at 50° C. and subsequent neutralization with sodium acetate) were added, while stirring at 50° - 60° C., the reaction mixture further stirred for 15 minutes, considerably evaporated in a vacuum, the resultant crystals filtered off with suction, triturated with water and dried for 2 hours in a vacuum at 120° C., 1.05 g. of the desired 3-(5-nitro-1-methyl-2 -imidazolyl)-s-triazolo[4,3-b]pyridazine being obtained, which has a melting point of 235° - 237° C.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[N:20])[CH:17]=4)[N:12]([CH3:21])[CH:11]=3)[CH2:6][CH2:5]2)[O:3]C1.C(=O)(O)[O-].[Na+]>O1CCCC1.Cl>[C:19]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:21])[CH:11]=[C:10]2[CH:7]1[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]1)#[N:20]
Reactant: Cn1cc(C2CCC3(CC2)OCCO3)c2cc(C#N)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(C2CCC(=O)CC2)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-(5-cyano-1-methyl-3-indolyl)-cyclohexanone ethylene ketal (5.5 g) in 150 ml (1:1) tetrahydrofuran-hydrochloric acid (1N) was allowed to stir at room temperature for 16 hours, then to above solution sodium bicarbonate (4.49 g) was added. The mixture was extracted with methylene chloride (3×100 ml) and washed with brine (3×150 ml). The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed to afford a light brown solid which was boiled in ethyl acetate-hexanes (1:1). The mixture was cooled to room temperature and solid was collected and dried under vacuum (2.06 g): mp 150-152° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:7][C:8]2([OH:17])[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH3:25]I.[I-]>C(O)C.O=[Pt]=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:7][C:8]2([OH:17])[CH:11]2[CH2:12][CH2:13][N:14]([CH3:25])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccncc2)CC(c2ccc(F)cc2)c2ccc(F)cc21
Reactant: CI
Agent: O=[Pt]=O
Agent: [I-]
Solvent: CCO
Product: CN1CCC(C2(O)CC(c3ccc(F)cc3)c3ccc(F)cc32)CC1

Procedure:
6-Fluoro-3-(4'-fluorophenyl)-1-hydroxy-1-pyrid-4-ylindane (5.0 g) was reacted with methyliodide as described in Example 2, and the resulting pyridylium iodide (viscous oil) was dissolved in ethanol (150 ml) and 0.5 g PtO2 added. The estimated amount of hydrogen was consumed in 3 hrs. (3.0-3.5 atm.). The catalyst was filtered off and the ethanol evaporated. Ice-cold NaOH solution (100 ml 0.2M) was added to the residue and the resulting base extracted with ethyl acetate (2×50 ml). The combined organic phases were dried (MgSO4) and the solvent evaporated. The remaining oil was dissolved in isopropylether, and by cooling the product precipitated and was filtered off. Yield: 4.7 g (88.8%) of the title compound. MP: 146°-147° C.
Reaction SMILES: C(N(CC)CC)C.C(NC1C=CC(S([N:21]=[N+:22]=[N-])(=O)=O)=CC=1)(=O)C.[CH3:24][CH:25]1[CH2:30][C:29](=[O:31])[CH2:28][C:27](=[O:32])[CH2:26]1>ClCCl>[N+:21](=[C:28]1[C:29](=[O:31])[CH2:30][CH:25]([CH3:24])[CH2:26][C:27]1=[O:32])=[N-:22]
Reactant: CC1CC(=O)CC(=O)C1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CC(=O)C(=[N+]=[N-])C(=O)C1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
12.25 ml (87.2 mmol; 2.2 eq.) of triethylamine and 8.57 g (35.67 mmol; 0.9 eq.) of 4-acetamidobenzenesulphonylazide are added to a solution of 5 g (39.6 mmol) of 5-methylcyclohexane-1,3-dione in 100 ml of dichloromethane. The reaction mixture is stirred for 75 minutes at ambient temperature, then cooled down to 0° C. and filtered on a silica bed. After concentration under reduced pressure, the solution is washed with 3 times 50 ml of water. The organic phases are combined, dried over sodium sulphate and concentrated. The resulting solid is taken up in ethyl ether followed by filtering and drying under reduced pressure. It is used in the following stage without other purification.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[CH3:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.[CH:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)(=O)C1C=CC=CC=1>>[OH:29][CH:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: Cc1ccc2ccccc2n1
Reactant: O=Cc1ccccc1
Agent: O=C(O)c1ccccc1
Solvent: c1ccc2ncccc2c1
Product: OC(Cc1ccc2ccccc2n1)c1ccccc1
Temperature: 25 °C
Yield: 17.5 %

Procedure:
The method used is that of SKIDMORE and TIDD[The Quinoline series, Part I, 1641-1645, (1959)]. 5.3 ml of 2-methylquinoline (0.039 mol) and 3.56 ml of benzaldehyde 0.035 mol) are mixed with a little benzoic acid. The mixture is stirred at room temperature and the product is then left to crystallize for several weeks. The solution is filtered through sintered glass and the filter is rinsed with cold ethanol. The crystals remaining on the sintered glass are recrystallized in ethanol and then placed in a heating desiccator. 1.53 g of 2-(2-hydroxy-2-phenylethyl)quinoline are thereby obtained (Yld=24%). The filtrates are combined, the solvent is evaporated off therefrom and the products are then deposited on a silica column. 3.66 g of 2-methylquinoline and 1.9 g of 2-styrylquinoline are then obtained (Yld=18%). 69% of the starting 2-methylquinoline is recovered.
Reaction SMILES: [Cl:1][C:2]1[C:7]2=[CH:8][O:9][N:10]=[C:6]2[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[C:4]([CH:18](O)[CH3:19])[CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:33]=[N+:34]=[N-:35].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[N:33]([CH:18]([C:4]1[CH:3]=[C:2]([Cl:1])[C:7]2=[CH:8][O:9][N:10]=[C:6]2[C:5]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=1)[CH3:19])=[N+:34]=[N-:35]
Reactant: CC(O)c1cc(Cl)c2conc2c1-c1cccc(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(N=[N+]=[N-])c1cc(Cl)c2conc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 1-[4-chloro-7-(3-fluorophenyl)-2,1-benzisoxazol-6-yl]ethanol (0.094 g, 0.32 mmol) in methylene chloride (2 mL) was added triethylamine (0.067 mL, 0.48 mmol), followed by methanesulfonyl chloride (0.031 mL, 0.40 mmol). After stirring at room temperature for 30 minutes, the resulting mixture was diluted with dichloromethane, washed with sat. sodium bicarbonate, brine, dried over magnesium sulfate, and then concentrated to dryness under reduced pressure. The resulting 1-[4-chloro-7-(3-fluorophenyl)-2,1-benzisoxazol-6-yl]ethyl methanesulfonate was used directly in the next step. LCMS calculated for C16H14ClFNO4S (M+H)+: m/z=370.0; Found: 370.1. The crude mesylate was dissolved in N,N-dimethylformamide (1 mL) and treated with sodium azide (0.105 g, 1.61 mmol) at room temperature overnight. After diluted with ethyl acetate, the mixture was washed with water, brine and then dried over magnesium sulfate and evaporated to dryness. The crude product was used in the next step (90 mg, 88%). LCMS calculated for C15H11ClFN4O (M+H)+: m/z=317.1; Found: 317.0.
Reaction SMILES: [NH3:1].[I:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](Cl)=[O:11])=[CH:5][CH:4]=1>CCOCC>[I:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH2:1])=[O:11])=[CH:5][CH:4]=1
Reactant: N
Reactant: O=C(Cl)Cc1ccc(I)cc1
Solvent: CCOCC
Product: NC(=O)Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Concentrated aqueous ammonia (density, 0.88 g/cm3) was added to a solution of 4-iodophenylacetyl chloride (2.80 g) in ether (30 ml) and the mixture was stirred at ambient temperature for 15 minutes. The product, 4-iodophenylacetamide, was obtained as a colourless crystalline solid (2.36 g), m.p: 200-204° C.; NMR: 3.34(2H,s), 6.87(H,bs), 7.44(2H,bs), 7.04-7.68(4H,AB); m/z 262(M+H).
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH:23]([C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH2:32][C:31](=O)[CH2:30][CH2:29]2)([CH3:25])[CH3:24]>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:31]2[CH2:30][CH2:29][C:28]3[C:33](=[CH:34][CH:35]=[C:26]([CH:23]([CH3:25])[CH3:24])[CH:27]=3)[CH2:32]2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Reactant: CC(C)c1ccc2c(c1)CCC(=O)C2
Product: CCCC(NC1CCc2cc(C(C)C)ccc2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 6-Isopropyl-3,4-dihydro-1H-naphthalen-2-one to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.1, 19.5, 19.6, 24.2, 26.6, 26.7, 28.2, 28.4, 29.6, 30.6, 33.9, 36.3, 36.5, 37.2, 53.4, 53.7, 56.0, 59.1, 60.3, 60.8, 67.3, 104.6, 124.1, 126.7, 126.8, 129.5, 129.6, 131.1, 132.1, 135.7, 136.0, 137.3, 146.7, 146.8, 172.4, 172.6; MS m/z 480.5 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](B(O)O)=[CH:4][N:3]=1.Br[C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[C:14]([CH3:20])[CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.O.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]>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:12]2[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[C:14]([CH3:20])[CH:13]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(B(O)O)cn1
Reactant: Cc1cc(Br)cc(C)c1O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2cnc(N)nc2)cc(C)c1O
Reaction time: 0.25 h
Yield: 27.8 %

Procedure:
2-Aminopyrimidin-5-ylboronic acid (0.76 g, 5.4 mmol) was dissolved in dimethoxyethane/water (2:1). 4-Bromo-2,6-dimethylphenol (0.91 g, 4.52 mmol) and Pd(dppf)Cl2 (0.19 g, 0.14 mmol), sodium carbonate (1.4 g, 14 mmol) were added thereto, followed by reacting in microwave reactor at 120° C. for 15 minutes. After the completion of the reaction, the reaction mixture was added with water, and extracted with dichloromethane. The obtained organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 4-(2-aminopyrimidin-5-yl)-2,6-dimethylphenol (0.27 g, 27%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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]>[CH:23]1([N:20]2[CH2:21][CH2:22][N:17]([C:15](=[O:16])[CH2:14][N:11]3[CH2:12][CH2:13][N:8]([C:4]4[CH:5]=[CH:6][C:7]([N:27]5[CH2:31][CH2:30][CH2:29][C:28]5=[O:32])=[CH:2][CH:3]=4)[CH2:9][CH2:10]3)[CH2:18][CH2:19]2)[CH2:26][CH2:25][CH2:24]1
Reactant: O=C(CN1CCN(c2cccc(Br)c2)CC1)N1CCN(C2CCC2)CC1
Reactant: O=C1CCCN1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: O=C(CN1CCN(c2ccc(N3CCCC3=O)cc2)CC1)N1CCN(C2CCC2)CC1
Temperature: 120 °C

Procedure:
In a sealed tube, place 1-(3-bromophenyl)-4-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]piperazine (150 mg, 0.355 mmol), 2-pyrrolidone (90 mg, 1.07 mmol), Cs2CO3 (346 mg, 1.065 mmol), xantphos (20 mg, 0.036 mmol), and Pd2dba3 (32 mg, 0.355 mmol). Add dioxane (6 mL) and degas the mixture with N2. Seal the tube and heat at 120° C. overnight. Cool and partition between EtOAc (50 mL) and 1N NaOH (50 mL). Extract with EtOAc (2×50 mL). Combine, dry and evaporate the organic extracts. Purify the crude product by PTLC eluting with EtOAc/MeOH/TEA(95:5:5) to yield the title compound. 1H NMR (CDCl3) δ 7.48 (d, 2H) 6.3 (d, 2H), 3.84 (t, 2H), 3.66 (br m, 4H), 3.25 (s, 2H), 3.18 (t, 4H), 2.76-2.57 (m, 7H), 2.35-2.30 (m, 4H), 2.20-2.02 (m, 4H), 1.98-1.86 (m, 2H), 1.77-1.68 (m, 2H); LC-MS (M+1) 426.09.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@:9]1([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C@H:10]([O:23][C@H:24]([C:39](OC)=[O:40])[C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1[C@@H]2[C@H](C(OC(C)(C)C)=O)C[C@@]1(C1C=CC=CC=1)[C@H](O[C@@H](C(OC)=O)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)CC2)C1C=CC=CC=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:15][C@@:9]1([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C@H:10]([O:23][C@H:24]([C:25]1[CH:26]=[C:27]([C:35]([F:36])([F:37])[F:38])[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)[CH2:39][OH:40])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](O[C@@H]1CC[C@H]2[C@H](C(=O)OC(C)(C)C)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: COC(=O)[C@H](O[C@@H]1CC[C@H]2[C@H](C(=O)OC(C)(C)C)C[C@]1(c1ccccc1)N2Cc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](O[C@@H](CO)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Yield: 92 %

Procedure:
(1R*,2R*,5S*,6R*)-8-Benzyl-2-{(1S*)-1-[3,5-bis(trifluoromethyl)phenyl]-(methoxycarbonyl)methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane and (1R*,2R*,5S*,6R*)-8-benzyl-2-{(1R*)-1-[3,5-bis(trifluoromethyl)phenyl]-(methoxycarbonyl)methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 125; 0.99 g, 1.5 mmol) in methanol (15 ml) at 0° C. was treated with sodium borohydride (55 mg, 1.4 mmol) and stirred at room temperature. The reaction was quenched with acetone and concentrated in vacuo. The residue was partitioned between ethyl acetate and water, the organics were separated, dried (MgSO4), filtered and concentrated in vacuo to afford the title compounds as a clear foam (869 mg, 92%).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([N:10]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:11]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[NH:22])[NH2:21])[CH2:16][CH2:15]2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:3].C(=O)([O-])[O-].[NH4+:34].[NH4+]>C(O)C>[C:2]([C:4]1[CH:5]=[C:6]([N:10]([CH:23]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[C:11]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20](=[NH:21])[NH2:22])[CH2:16][CH2:15]2)=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[NH:34])[NH2:3]
Reactant: N#Cc1cccc(N(C(=O)NC2CCN(C(=N)N)CC2)C2CCCCCC2)c1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: N=C(N)c1cccc(N(C(=O)NC2CCN(C(=N)N)CC2)C2CCCCCC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dry hydrogen chloride gas was bubbled through an ice cooled solution of N-(3-cyanophenyl)-N'-(1-amidinopiperidin-4-yl)cyclo-heptylurea (0.03 g, 0.075 mmol) in anhydrous ethanol (5 ml) for 15 min. The reaction was stoppered, allowed to warm to ambient temperature and stirred for 24 h. The reaction was concentrated to give a viscous residue which was dissolved in anhydrous ethanol and ammonium carbonate (0.06 g, 0.63 mmol) was added. The reaction was stirred over night at ambient temperature and then concentrated in vacuo. The crude product appeared to be about 1:2 ratio of the desired product to starting material. Pure N-(3-amidinophenyl)-N'-(1-amidinopiperidin-4-yl)cycloheptylurea was isolated by HPLC on a Vydec® C-18 column eluting with solvent mixture A (acetonitrile:water:TFA 80:20:0.3) and solvent mixture B (water:TFA 99.7:0.3) using a gradient starting with A:B at 3:97 and changing to A:B at 70:30 over 20 min, to give two major fractions: N-(3-amidinophenyl)-N'-(1-amidinopiperidin-4-yl)cycloheptylurea, the desired product eluted at 13.3 minutes, (8.2 mg); LRMS (M+2H)+2 m/z 179.8; HRMS calc. 358.2355, found 358.2349; 1H NMR (DMSO-d6): 9.25(s, 2H), 9.0(s, 2H), 7.55-7.4(m, 4H), 7.32(s, 4H), 3.95(m, 3H), 3.65(m, 2H), 3.25(m, 2H), 3.07(m, 2H), 1.8-1.6(m, 8H).