Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([NH:8][CH:9]([CH2:14][CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])[C:10]([O:12][CH3:13])=[O:11])=[O:7])=[CH:4][CH:3]=1.[C:27](=O)([O-])[O-].[Na+].[Na+].CI>CC(C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH:9]([CH2:14][C:15]2([CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][C:16]2=[O:24])[C:10]([O:12][CH3:13])=[O:11])=[O:7])=[CH:25][CH:26]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(CC1C(=O)Nc2ccccc21)NC(=O)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: O
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)C(CC1(C)C(=O)Nc2ccccc21)NC(=O)c1ccc(Cl)cc1

Procedure:
2.4 Grams of methyl 2-(4-chlorobenzoylamino)-3-(oxindol-3-yl)propionate prepared in Example 57 was dissolved in 30 ml of acetone and 10 ml of water, then 0.34 g of sodium carbonate and 1 g of methyl iodide were added thereto and the reaction mixture was refluxed for 6 hours. Acetone was removed by evaporation, and the residue was extracted with chloroform, the chloroform layer was washed with water, dried with anhydrous magnesium sulfate, then the solvent was removed by evaporation. The residue was purified by means of a silica gel column chromatography (euting agent: chloroform/methanol=100/1) then recrystallized from hexane-ethyl acetate to obtain 0.5 g of methyl 2-(4-chlorobenzoylamino)-3-(3-methyloxindol-3-yl)propionate in the form of colorless needel-like crystals. Melting point: 201°-202° C.
Reaction SMILES: [CH:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)[C:10]3[CH:32]=[C:33]([CH3:37])[C:34]([CH3:36])=[CH:35][C:9]=3[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]4[C:20]([C:25]([OH:27])=[O:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:17][CH:18]=3)[C:10]3[CH:32]=[C:33]([CH3:37])[C:34]([CH3:36])=[CH:35][C:9]=3[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc2nc(C3CCCCC3)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2cc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2nc(C3CCCCC3)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2cc1C

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-cyclohexyl-5,6-dimethyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:9]=[C:8]([C:10]3[N:15]=[CH:14][C:13]4[CH:16]=[N:17][N:18]([C:19]5[N:24]=[C:23]([N:25]6[CH2:31][CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]6)[CH:22]=[CH:21][CH:20]=5)[C:12]=4[CH:11]=3)[CH:7]=[N:6]2)[CH2:3][CH2:2]1>Cl.CO>[N:25]1([C:23]2[N:24]=[C:19]([N:18]3[C:12]4[CH:11]=[C:10]([C:8]5[CH:7]=[N:6][N:5]([CH2:4][CH:1]6[CH2:3][CH2:2]6)[CH:9]=5)[N:15]=[CH:14][C:13]=4[CH:16]=[N:17]3)[CH:20]=[CH:21][CH:22]=2)[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(-c5cnn(CC6CC6)c5)cc43)n2)CC1
Agent: Cl
Solvent: CO
Product: c1cc(N2CCCNCC2)nc(-n2ncc3cnc(-c4cnn(CC5CC5)c4)cc32)c1
Yield: 43.3 %

Procedure:
A solution of tert-butyl 4-(6-(6-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]-pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate (200 mg, 0.39 mmol) in HCl/MeOH (2M, 10 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The crude was purified by reverse phase preparative HPLC to afford 161 as a yellow solid (70 mg, 43.5%). 1H NMR (500 MHz, CDCl3) δ (ppm) 9.055-9.057 (d, J=1 Hz, 1H), 8.74 (s, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 7.60-7.63 (t, J=16 Hz, 1H), 7.28 (s, 1H), 6.41-6.43 (d, J=8 Hz, 1H), 4.04-4.06 (d, J=7 Hz, 2H), 3.89-3.94 (m, 4H), 3.17-3.19 (t, J=11 Hz, 2H), 2.91-2.93 (t, J=11.5 Hz, 2H), 2.03-2.06 (t, J=12.5 Hz, 2H), 1.35-1.36 (m, 1H), 0.69-0.73 (m, 2H), 0.43-0.46 (m, 2H); MS (ESI) m/z: 415 [M+H]+.
Reaction SMILES: CN([CH2:4][CH:5]([CH:16]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[CH3:36])[C:17](=[CH2:28])[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=1)=[O:19])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:7])C.C(N(C(C)C)CC)(C)C.IC.[OH-].[K+]>C(#N)C>[F:35][C:31]1[C:30]([CH3:36])=[C:29]([CH:16]([C:17](=[CH2:28])[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=[O:19])[C:5](=[CH2:4])[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[O:7])[CH:34]=[CH:33][CH:32]=1
Reactant: C=C(C(=O)c1cccc(OC)c1)C(c1cccc(F)c1C)C(CN(C)C)C(=O)c1cccc(OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CI
Product: C=C(C(=O)c1cccc(OC)c1)C(C(=C)C(=O)c1cccc(OC)c1)c1cccc(F)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.2 %

Procedure:
To a stirred solution of crude 2-((dimethylamino)methyl)-3-(3-fluoro-2-methylphenyl)-1,5-bis(3-methoxyphenyl)-4-methylenepentane-1,5-dione (91 g, 186 mmol) in acetonitrile (769 mL) was added diisopropylethylamine (65 mL, 376 mmol) followed by iodomethane (140 mL, 2.24 mol). The mixture was stirred at room temperature for 16 h. To this mixture was added 2 M KOH (307 mL, 614 mmol), and the temperature was raised to 75° C. for 16 h. The mixture was partitioned between dichloromethane and water. The layers were separated and the aqueous phase extracted with 500 mL dichloromethane. The combined organic layers were dried over MgSO4, filtered, and evaporated to dryness. The residue was treated with 350 mL ether, isolated by filtration, and washed with 2×100 mL of ether. The ether layers were concentrated in vacuum to give 3-(3-fluoro-2-methylphenyl)-1,5-bis(3-methoxyphenyl)-2,4-dimethylenepentane-1,5-dione (63.8 g, 77% yield), (characterized by LCMS and 1H NMR). LRMS (M+H+) m/z=445.3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19](Cl)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[OH-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2N2CCCCC2)CC1
Temperature: 180 °C
Yield: 98.8 %

Procedure:
Place 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (0.4 g, 1.34 mmol, 1 eq) and piperidine (662 μL, 6.69 mmol, 5 eq) in a microwave vial, seal and heat in a CEM™ microwave to 180° C. with up to 300 Watt power for 1 hr. (Caution—pressure build up). Add 2 M aqueous sodium hydroxide solution (5 mL) and DCM (5 mL), and then pass through a hydrophobic frit to separate. Extract the aqueous layer twice with DCM (5 mL) combine the organic extracts and concentrate to give 3′-piperidin-1-yl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (0.46 g, 99%). MS (m/z): 348.3 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[CH:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6]1)[CH3:4].[Cl:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21](O)=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19].C1(N=C=NC2CCCCC2)CCCCC1.Cl>CC(C)=O.CCOCC.C(Cl)Cl>[ClH:12].[Cl:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21]([N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:5]2[CH:3]([N:2]([CH3:1])[CH3:11])[CH3:4])=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: CC(C1CCCCN1)N(C)C
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: ClCCl
Product: CC(C1CCCCN1C(=O)Cc1ccc(Cl)c(Cl)c1)N(C)C
Reaction time: 48 h

Procedure:
Gr 1.6 (moles 0.01) of 2-(1-dimethylaminoethyl) piperidine and gr2.25 (moles 0.011) of 3,4-dichlorophenylacetic acid, dissolved in 20 ml. of CH2Cl2 were added with gr.3.1 (moles 0.015) of dicyclohexylcarbodiimide dissolved in 20 ml. of CH2Cl2. After 48 hours standing, the reaction mixture was worked up as in Ex. No 1 C) giving 2.8 g. of oily mixture of diastereoisomers. This was chromatographed on g.60 of silicagel, eluting with CH2Cl2 containing increasing amounts of methanol (0.2% to 1%). The fast moving diastereoisomer A was so obtained. It was dissolved in acetone and transformed into the hydrochloride by acidifying with HCl dissolved in ether. The precipitate was crystallized from acetone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]([CH3:16])=[C:12]([CH3:15])[N+:13]=2[O-])=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:19])=O.N>C(Cl)(Cl)Cl>[Cl:19][CH2:15][C:12]1[N:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:10][C:11]=1[CH3:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2oc(C)c(C)[n+]2[O-])cc1
Agent: N
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2nc(CCl)c(C)o2)cc1
Temperature: 0 °C

Procedure:
82 g of 2-(4-Methoxy-phenyl)-4,5-dimethyl-oxazole 3-oxide are dissolved in 400 ml of chloroform, 37.4 ml of phosphorus oxychloride are added and the mixture is, under reflux, heated at the boil for 30 minutes. The reaction mixture is cooled to 0° C., the pH is made slightly alkaline using ammonia and the mixture is extracted three times with in each case 100 ml of ethyl acetate. The combined organic phases are washed with water and dried over MgSO4, and the solvent then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate=80:1=>5:1. This gives 46.3 g of 4-chloromethyl-2-(4-methoxy-phenyl)-5-methyl-oxazole as a yellow solid. C12H12ClNO2 (237.69), MS (ESI)=238 (M+H+), Rf (n-heptane:ethyl acetate)=7:3)=0.45.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][C:7]([CH:10]=O)=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[CH3:14][NH2:15].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:13]=[CH:12][C:5]2[S:6][C:7]([CH2:10][NH:15][CH3:14])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: CN
Reactant: Cc1c(C=O)sc2ccc(F)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1sc2ccc(F)cc2c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5-fluoro-3-methyl-benzo[b]thiophene-2-carbaldehyde (5.43 g, 28.0 mmol) was added a solution of 2 M methylamine in methanol (94 mL) and the resulting mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and the residue taken up in ethanol (90 mL). The solution was cooled to 0° C. and then NaBH4 (1.06 g, 28.0 mmol) was added in one portion. The mixture was stirred 4 hr, after which time NaBH4 (0.54 g, 14.0 mmol) was added and the mixture was stirred overnight. The mixture was concentrated under reduced pressure and the residue combined with 1 M NaOH (200 mL). The mixture was extracted with diethyl ether (3×150 mL) and the combined organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to the title compound (5.26 g, 90%) as a pale yellow oil: 1H NMR (300 MHz, CDCl3) δ7.71 (dd, J=9.0, 4.8 Hz, 1H), 7.27 (dd, J=9.3, 2.6 Hz, 1H), 7.09-7.04 (m, 1H), 4.00 (s, 2H), 2.51 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [CH2:1]([C:4]1([NH2:15])[CH:11]2[CH2:12][C:7]3([OH:14])[CH2:8][CH:9]([CH2:13][CH:5]1[CH2:6]3)[CH2:10]2)[CH:2]=[CH2:3]>CO.[Pd]>[CH2:1]([C:4]1([NH2:15])[CH:5]2[CH2:6][C:7]3([OH:14])[CH2:8][CH:9]([CH2:10][CH:11]1[CH2:12]3)[CH2:13]2)[CH2:2][CH3:3]
Reactant: C=CCC1(N)C2CC3CC1CC(O)(C3)C2
Agent: [Pd]
Solvent: CO
Product: CCCC1(N)C2CC3CC1CC(O)(C3)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
A solution of 4-allyl-4-amino-adamantan-1-ol (3, 3.6 g, 17.4 mmol) in methanol (50 mL) was treated with 50 mg of 10% palladium on activated carbon and the mixture was stirred overnight under a hydrogen atmosphere (1 atm) at room temperature. The catalyst was removed by filtration, and the filtrate was evaporated in vacuo to give 2.8 g of the title compound as diastereomeric mixture (4). Rt=0.21 min, 0.73 min (Method 3). Detected mass: 210.2 (M+H+).
Reaction SMILES: [O:1]1[C:5]2[C:6]([CH:10]=O)=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(OC([N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:28][NH:29][CH:30]1[C:39]2[N:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH2:33][CH2:32][CH2:31]1)=O)(C)(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[NH:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:28][N:29]([CH2:10][C:6]1[C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=[CH:8][CH:7]=1)[CH:30]1[C:39]2[N:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH2:33][CH2:32][CH2:31]1
Reactant: O=Cc1cccc2c1OCC2
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: c1cnc2c(c1)CCCC2N(Cc1nc2ccccc2[nH]1)Cc1cccc2c1OCC2
Reaction time: 8 h

Procedure:
Following General Procedure B: To a solution of 2,3-dihydrobenzofuran-7-carboxaldehyde (53.6 mg, 0.362 mmol) and [1-(tert-butoxycarbonyl)-(1H-benzimidazol-2-ylmethyl)]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (136 mg, 0.361 mmol) CH2Cl2 (5 mL) was added NaBH(OAc)3 (112 mg, 0.528 mmol) and the mixture stirred overnight. Purification of the crude product by radial chromatography on silica gel (1 mm TLC plate, 125:1:1 CH2Cl2:CH3OH:NH4OH) to gave the desired freebase (48 mg, 33%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]([CH3:16])[N:6]=[C:7]([O:13][CH2:14][CH3:15])[C@H:8]([CH:10]([CH3:12])[CH3:11])[N:9]=1)[CH3:2].[Cl:17][C:18]1[CH:23]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:35][CH2:36]I>>[Cl:17][C:18]1[CH:23]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:35][CH2:36][C@:5]1([CH3:16])[C:4]([O:3][CH2:1][CH3:2])=[N:9][C@@H:8]([CH:10]([CH3:11])[CH3:12])[C:7]([O:13][CH2:14][CH3:15])=[N:6]1
Reactant: CCOC1=N[C@@H](C(C)C)C(OCC)=NC1C
Reactant: FC(F)(F)c1cccc(Oc2ccc(CCI)c(Cl)c2)c1
Product: CCOC1=N[C@](C)(CCc2ccc(Oc3cccc(C(F)(F)F)c3)cc2Cl)C(OCC)=N[C@H]1C(C)C

Procedure:
(5S)-3,6-diethoxy-5-isopropyl-2-methyl-2,5-dihydropyrazine and 2-chloro-1-(2-iodoethyl)-4-(3-trifluoromethylphenoxy)benzene were reacted in the same manner as in Example 1 to obtain the target product as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:20]2[C:19]3[CH2:18][CH2:17][C@@:15]4([CH3:16])[C:11](=[CH:12][CH2:13][C:14]4=[O:21])[C:10]=3[CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]([O:22][CH3:23])[CH:4]=1>[Pd].C([O-])([O-])=O.[Ca+2].C1COCC1>[CH3:1][O:2][C:3]1[C:20]2[C@@H:19]3[C@@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:21])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C:7]=2[CH:6]=[C:5]([O:22][CH3:23])[CH:4]=1
Reactant: COc1cc2c(c(OC)c1)C1=C(CC2)C2=CCC(=O)[C@@]2(C)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Product: COc1cc2c(c(OC)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@H]1CC2

Procedure:
In the presence of 0.15 g. of palladium/CaCO3 (5%), 0.3 g. of rac.-1,3-dimethoxy-1,3,5(10),8,14-estrapentaen-17-one in 50 ml. of THF is hydrogenated within 17 hours at room temperature and under a hydrogen pressure of 50 atmosphere gauge. Then, the mixture is filtered off from the catalyst, the filtrate is concentrated by evaporation, and the residue is recrystallized from isopropyl ether, thus obtaining 40 mg. of final product, m.p. 158°-160°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([C:27]([OH:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:16]=3)[C:6]=2[CH:30]=1.[C@@H:31]12[C:40](=[O:41])[O:39][C:37](=[O:38])[C@@H:32]1[CH2:33][CH2:34][CH2:35][CH2:36]2>C(Cl)Cl>[CH2:10]([C:8]1[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([C:27]([OH:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[C:6]2[CH:30]=[C:2]([NH:1][C:40]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]3[C:37]([OH:39])=[O:38])=[O:41])[CH:3]=[CH:4][C:5]=2[N:9]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1nc2ccc(N)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Solvent: ClCCl
Product: CCCCc1nc2ccc(NC(=O)C3CCCCC3C(=O)O)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.6 g (1.5 mmol) of 4'-[(6-amino-2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylic acid are dissolved in 150 ml of methylene chloride with heating and cooled to ambient temperature. After the addition of 240 mg (1.55 mmol) of cis-cyclohexan-1,2-dicarboxylic acid anhydride the mixture is stirred for 5 hours at ambient temperature. The reaction product which crystallises out is suction filtered, washed with,methylene chloride and dried in a vacuum drying chamber at 50° C. Yield: 0.58 g (69.8% of theory), Melting point: 186°-188° C. C33H35N3O5 (553.66) Calculated: C 71.59 H 6.37 N 7.59 Found: 71.42 6.56 7.56
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH2:9][N:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1.[NH2:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23]([C:31]3[C:32]([CH3:45])=[CH:33][C:34]([F:44])=[C:35]([NH:37][C:38](=O)[O:39]C(C)=C)[CH:36]=3)[C:24](=[O:30])[N:25]2[CH2:28][CH3:29])=[CH:20][N:19]=1>O1CCOCC1.CN1CCCC1.CS(C)=O>[NH2:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23]([C:31]3[C:32]([CH3:45])=[CH:33][C:34]([F:44])=[C:35]([NH:37][C:38]([NH:6][C:5]4[CH:7]=[CH:8][C:2]([F:1])=[C:3]([CH2:9][N:10]5[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]5)[CH:4]=4)=[O:39])[CH:36]=3)[C:24](=[O:30])[N:25]2[CH2:28][CH3:29])=[CH:20][N:19]=1
Reactant: CN1CCN(Cc2cc(N)ccc2F)CC1
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(N)cc3n(CC)c2=O)c(C)cc1F
Agent: CN1CCCC1
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccc(F)c(CN4CCN(C)CC4)c3)c(F)cc2C)cc2cnc(N)cc21
Temperature: 80 °C
Yield: 21.9 %

Procedure:
A mixture of Example D2 (0.100 g, 0.448 mmol) and prop-1-en-2-yl (5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)carbamate (0.142 g, 0.358 mmol) in dioxane (3 mL) was treated with 1-methylpyrrolidine (3 drops) and heated at 80° C. overnight. The mixture was treated with DMSO (2 drops) and heated at 80° C. for an additional 24 h. The mixture was cooled to RT, concentrated to dryness and purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure, the aqueous residue treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over MgSO4 and concentrated to dryness to afford 1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-(4-fluoro-3-((4-methylpiperazin-1-yl)methyl)phenyl)urea (44 mg, 22% yield). 1H NMR (400 MHz, pyridine-d5): δ 9.87 (s, 1H), 8.89 (s, 1H), 8.71 (m, 1H), 8.60 (s, 1H), 7.97 (dd, J=6.5, 2.8 Hz, 1H), 7.79 (dt, J=8.7, 3.6 Hz, 1H), 7.64 (s, 1H), 7.26 (s, 2H), 7.15 (t, J=9.2 Hz, 1H), 7.07 (d, J=12.0 Hz, 1H), 6.56 (s, 1H), 4.17 (q, J 7.1 Hz, 2H), 3.58 (s, 2H), 2.53 (s, 4H), 2.30 (m, 7H), 2.13 (s, 3H), 1.16 (t, J=7.1 Hz, 3H); MS (ESI) m/z: 562.2 [M+H]+.
Reaction SMILES: [C:1]([CH2:4][CH:5]([CH3:11])[S:6][C:7](=[N:9][OH:10])[CH3:8])(=[O:3])[NH2:2].[CH3:12][N:13]=[C:14]=[O:15]>C(N(CC)CC)C.CC(C)=O>[CH3:12][NH:13][C:14]([O:10][N:9]=[C:7]([S:6][CH:5]([CH3:11])[CH2:4][C:1](=[O:3])[NH2:2])[CH3:8])=[O:15]
Reactant: CN=C=O
Reactant: CC(=NO)SC(C)CC(N)=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CNC(=O)ON=C(C)SC(C)CC(N)=O
Reaction time: 48 h
Yield: 75 %

Procedure:
A mixture of 3.0 g (0.017 m) of 1-(2-carbamoyl-1-methylethylthio)acetaldoxime, 200 ml. of dry acetone, 3.0 g. (0.053 m) of methyl isocyanate, and two drops of triethylamine was allowed to stand at room temperature, with occasional shaking, for two days. The acetone and excess methyl isocyanate was removed from the product under reduced pressure. The white solid residue was recrystallized from isopropanol and dried at room temperature to give 3.0 g (75% yield) of 1-(2-carbamoyl-1-methylethylthio)acetaldehyde O-(methylcarbamoyl)oxime; melting point=119-121. The nmr spectra confirmed the structure.
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1)[C:6]([NH2:9])=[N:7][OH:8])(=[O:3])[CH3:2].[N+:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)([O-:28])=[O:27]>O1CCCC1>[C:1]([O:4][CH:5]([CH2:10][CH2:11][CH2:12][CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:17][CH2:18]1)[C:6]([NH2:9])=[N:7][O:8][C:33](=[O:34])[C:32]1[CH:31]=[CH:30][C:29]([N+:26]([O-:28])=[O:27])=[CH:37][CH:36]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(CCCC1CCN(Cc2ccccc2)CC1)C(N)=NO
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: CC(=O)OC(CCCC1CCN(Cc2ccccc2)CC1)C(N)=NOC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
A solution of 2-acetoxy-5-(1-benzylpiperidin-4-yl)-1-hydroxyiminopentylamine (0.59 g) in tetrahydrofuran (5 ml) was added dropwise to a solution of 4-nitrobenzoyl chloride (0.29 g) in tetrahydrofuran (5 ml) and the mixture was stirred overnight at ambient temperature and extracted with ethyl acetate. The extract was washed with a sodium hydrogencarbonate aqueous solution and water, dried over magnesium sulfate and evaporated in vacuo to give 2-acetoxy-5-(1-benzylpiperidin-4-yl)-1-(4-nitrobenzoyloxyimino)pentylamine (0.35 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH:11]([OH:32])[CH2:12][CH:13]([CH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)[C:14]([O:16]C(C)(C)C)=[O:15])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O.O>[CH2:1]([N:8]([CH2:10][C:11](=[O:32])[CH2:12][CH:13]([CH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1)[C:14]([OH:16])=[O:15])[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)CC(O)CC(Cc1cccc2ccccc12)C(=O)OC(C)(C)C
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN(CC(=O)CC(Cc1cccc2ccccc12)C(=O)O)Cc1ccccc1
Reaction time: 2 h
Yield: 71.6 %

Procedure:
5.64 g of a sulfur trioxide/pyridine complex were added to a solution of 3.13 g (7.22 mmole) of t-butyl 5-(N-benzyl-N-methylamino)-4-hydroxy-2-(1-naphthylmethyl)pentanoate (prepared as described in Preparation 29) and 5 ml of triethylamine dissolved in 20 ml of dimethyl sulfoxide at room temperature, and the mixture was stirred for 2 hours. At the end of this time, the reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, after which it was concentrated by evaporation under reduced pressure. 20 ml of a 4N solution of hydrogen chloride in dioxane were added to the residue, and the mixture was stirred for 2 hours; it was then concentrated by evaporation under reduced pressure. The residue was dissolved in water, and the resulting solution was neutralized by adding a 1N aqueous solution of sodium hydroxide. It was then concentrated by evaporation under reduced pressure. The residue was dissolved in methylene chloride and the resulting insoluble materials were removed by filtration. The filtrate was concentrated by evaporation under reduced pressure to afford 1.94 g of the title compound as a colorless amorphous substance.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[C:7]([OH:9])[C:6]([O:10][CH2:11][CH2:12][CH3:13])=[CH:5][N:4]=1.CO[CH:16]=[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([N:27]3[CH:31]=[CH:30][CH:29]=[CH:28]3)[CH:25]=2)[C:20](=[O:32])[NH:19][C:18]1=[O:33]>CN(C)C=O>[OH:9][C:7]1[C:6]([O:10][CH2:11][CH2:12][CH3:13])=[CH:5][N:4]=[C:3]([CH2:2][NH:1][CH:16]=[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[CH:28]4)[CH:25]=3)[C:20](=[O:32])[NH:19][C:18]2=[O:33])[CH:8]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(-n3cccc3)cc21
Reactant: CCCOc1cnc(CN)cc1O
Solvent: CN(C)C=O
Product: CCCOc1cnc(CNC=C2C(=O)NC(=O)c3ccc(-n4cccc4)cc32)cc1O

Procedure:
A mixture of 2-aminomethyl-5-propoxy-pyridin-4-ol (137 mg, 0.75 mmole) IN 10 mL of N,N-dimethylformamide is stirred, then 4-methoxymethylene-6-pyrrol-1-yl-4H-isoquinoline-1,3-dione (201 mg, 0.75 mmole) is added and the reaction mixture stirred for one hour. The reaction mixture is evaporated to dryness, triturated with 5% methanol in chlororform, filtered, washed with fresh 5% methanol in chloroform, washed with acetonitrile and dried to give a grey solid, 290 mg, (92%); MS (ES+): m/z 419.1 (M+H).