Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:8](=O)[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:4]2[CH2:3]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:33]2)=CC=1.O>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:8](=[S:33])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:4]2[CH2:3]1
Reactant: CN1Cc2c(C(=O)OC(C)(C)C)ncn2-c2ccccc2C1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CN1Cc2c(C(=O)OC(C)(C)C)ncn2-c2ccccc2C1=S

Procedure:
1 g of t-butyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate in 50 ml of toluene is treated with 0.82 g of 2,4-bis(p-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulphide and the mixture obtained is heated to boiling under reflux for 6 hours. The mixture is poured into water and the toluene phase is separated. After drying the organic phase over magnesium sulphate and evaporation, the crude product is chromatographed on silica gel. There is obtained t-butyl 5,6-dihydro-5-methyl-6-thioxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate on melting point 207°-208°.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[O:23]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:34](=[O:35])[C:33]2[CH:32]=[CH:31][C:30]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:38][CH:37]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.28 mmol) in acetonitrile (20 ml) were added 4-phenoxybenzoic acid (274 mg, 1.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (368 mg, 1.92 mmol) and 1-hydroxy-1H-benzotriazole (196 mg, 1.28 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (451 mg, 69%).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[N:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:7]([O:6][C:5]1[CH:14]=[CH:15][C:2]([C:22]2[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=2)=[CH:3][C:4]=1[N+:16]([O-:18])=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1OCc1ccccc1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 109.1 %

Procedure:
To a solution of 1-((4-bromo-2-nitrophenoxy)methyl)benzene 13.B (1.40 g, 4.55 mmol) and pyridin-4-ylboronic acid (665 mg, 5.45 mmol, available from Aldrich) in DMF (10 mL) was added cesium carbonate (2.93 g, 9.0 mmol). The mixture was stirred overnight at 80° C. and then partitioned between AcOEt and water. The organic phase was concentrated to afford 4-(4-(benzyloxy)-3-nitrophenyl)pyridine 13.0 (1.52 g, 109% yield) which was used in the next step without any further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)=[CH2:15].C([O-])([O-])=O.[K+].[K+].O>CN1C(=O)CCC1>[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:18][CH:17]=1)=[CH2:15]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: C=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: C=Cc1ccc(Oc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A mixture of 2,4-dinitrofluorobenzene (6.38 g, 34 mmol), 4-vinylphenol (4.32 g, 36 mmol), 4.97 g K2CO3 and 2-3 crystals of BHT inhibitor was dissolved in 75 ml NMP and stirred at 40° C. under nitrogen for 4 hr. The reaction mixture was poured into a separatory funnel containing 150 ml water and extracted 3×100 mls with ethyl acetate. The combined organics were washed with 100 ml 10% KOH, and brine, dried with anhydrous MgSO4 and concentrated. The residue was recrystallized from 70% ethyl acetate in hexane yielding 9.5 g product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27](F)[CH:26]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:43][NH2:44]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:25]2[CH:26]=[C:27]3[C:28]([C:31]([NH2:32])=[N:43][NH:44]3)=[CH:29][CH:30]=2)[N:3]=1
Reactant: COc1ccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)cc1
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1ccc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc5c(N)n[nH]c5c4)nc(N)n3)C2)cc1
Temperature: 150 °C
Yield: 11.3 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-[4-(methyloxy)phenyl]-3-piperidinecarboxamide (190 mg, 0.426 mmol), 3 mL of EtOH, Hunig's base (0.223 mL, 1.28 mmol), and hydrazine anhydrous (0.053 ml, 1.702 mmol) were added, and the yellow mixture was heated to 150° C. for 180 minutes in microwave. The solution turned black. LCMS showed mainly product. The black solids were filtered and the yellow filtrate was evaporated. The resulting yellow residue was dissolved in CH3OH at 50° C., and EtOAc was used to triturate. When the solution turned slightly cloudy, it was cooled to room temperature to get pure crystallized light yellow title compound (22 mg). LC-MS (ES) m/z=459 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.46 (m, 1H), 1.65-1.84 (m, 2H), 1.98 (m, 1H), 2.79-3.06 (m, 2H), 3.72 (s, 3H), 4.49 (m, 1H), 4.68 (m, 1H), 5.37 (s, 2H), 6.10 (s, 2H), 6.68 (s, 1H), 6.88 (d, J=9.1 Hz, 2H), 7.53 (d, J=9.1 Hz, 2H), 7.58-7.65 (m, 1H), 7.66-7.78 (m, 1H), 7.97 (s, 1H), 9.87 (s, 1H), 11.49 (s, 1H).
Reaction SMILES: CC(O[C:6](=[O:20])[NH:7][C@@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]([NH:17][CH3:18])=[O:16])[C:9]1=[O:19])(C)C.C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:45][C:46]1[CH:55]=[C:54]2[C:49]([C:50]([N:57]3[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]3)=[CH:51][C:52]([NH2:56])=[N:53]2)=[CH:48][CH:47]=1>>[NH2:56][C:52]1[CH:51]=[C:50]([N:57]2[CH2:58][CH2:59][N:60]([C:6]([NH:7][C@H:8]3[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15]([NH:17][CH3:18])=[O:16])[C:9]3=[O:19])=[O:20])[CH2:61][CH2:62]2)[C:49]2[C:54](=[CH:55][C:46]([Cl:45])=[CH:47][CH:48]=2)[N:53]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: CNC(=O)N1CCCC[C@@H](NC(=O)OC(C)(C)C)C1=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)N1CCCC[C@H](NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)C1=O

Procedure:
As described for example 213, [(3R)-Hexahydro-1-[(methylamino)carbonyl]-2-oxo-1H-azepin-3-yl]carbamic acid-1,1-dimethylethyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a white powder. LC-MS, 473 (M+). 1H NMR (400 MHz, DMSO): 61.38 (m, 1H), 1.57 (m, 1H), 1.9 (m, 2H), 2.03 (br. d, 1H), 2.19 (s, 1H), 2.85 (d, 3H), 3.08 (m, 4H), 3.21 (m, 1H), 3.63 (m, 4H), 4.83 (m, 1H), 4.85 (m, 1H), 4.95 (s, 2H), 5.85 (d, 1H), 6.11 (s, 1H), 7.11 (dd, 1H), 7.56 (d, 1H), 7.67 (d, 1H), 8.91 (q, 1).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]2)[C:6]1=[O:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[N+:54]([C:57]1[CH:65]=[CH:64][C:60]([C:61](O)=[O:62])=[CH:59][CH:58]=1)([O-:56])=[O:55]>C1COCC1>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([C@@H:10]2[CH2:11][CH2:12][C@H:13]([O:16][C:61](=[O:62])[C:60]3[CH:59]=[CH:58][C:57]([N+:54]([O-:56])=[O:55])=[CH:65][CH:64]=3)[CH2:14][CH2:15]2)[C:6]1=[O:17]
Reactant: O=C1C(Cc2ccc(Cl)cc2Cl)CCN1[C@H]1CC[C@H](O)CC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@H]1CC[C@@H](N2CCC(Cc3ccc(Cl)cc3Cl)C2=O)CC1)c1ccc([N+](=O)[O-])cc1
Temperature: -20 °C
Reaction time: 6 h
Yield: 36.9 %

Procedure:
Dissolve 3-(2,4-dichloro-benzyl)-1-(trans-4-hydroxy-cyclohexyl)-pyrrolidin-2-one (Example 15) (3.32 g, 9.70 mmol) in anhydrous THF (200 mL) and cool to −20 ° C. Add triphenyl phosphine (12.71 g, 48.48 mmol), diethyl azodicarboxylate (8.44 g, 48.48 mmol), and 4-nitro-benzoic acid (8.10 g, 48.48 mmol). Stir the reaction mixture for 6 hours at the same temperature, then warm the reaction to room temperature and continue to stir the reaction overnight. Add water (200 mL) and extract the aqueous layer with ethyl acetate (3×200 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 30-60% of EtOAc-Hexane) to give 1.76 g (100%) of the title compound as a white solid: 1H NMR (CDCl3) δ 8.28-8.32 (m, 2H), 8.17-8.24 (m, 2H), 7.38 (d, 1H), 7.23 (d, 1H), 7.18 (dd, 1H), 5.28-5.32 (m, 1H), 4.05-4.15 (m, 1H), 3.25-3.40 (m, 3H), 2.74-2.83 (m, 2H), 2.10-2.23 (m, 1H), 2.02-2.10 (m, 1H), 1.60-1.92 (m, 8H).
Reaction SMILES: [Na].[CH3:2][C:3]([C:5]1[CH:13]=[CH:12][C:10]([OH:11])=[C:7]([O:8][CH3:9])[CH:6]=1)=[O:4].[Br:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>C(O)C>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][O:11][C:10]1[CH:12]=[CH:13][C:5]([C:3](=[O:4])[CH3:2])=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: BrCCCCBr
Agent: [Na]
Solvent: CCO
Product: COc1cc(C(C)=O)ccc1OCCCCBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
to a warm solution of 12.7 g (0.55 mole) of sodium metal in 500 ml of absolute ethanol was added a slurry of 83.1 g (0.5 mole) of acetovanillone in 250 ml of absolute ethanol. All solids dissolved and then a solid precipitated. The mixture was stirred at ambient temperature for 1 hr and then added over a 3-hr period to a solution at reflux of 177 g (0.82 mole) of 1,4-dibromobutane in 500 ml of absolute ethanol. After addition was complete, the mixture was heated at reflux overnight. The mixture was concentrated under reduced pressure and the residue was partitioned between 1.5 liter of benzene and 1 liter of water. The mixture was filtered to remove undesirable insoluble material. The filtrate layers were separated and the organic layer was washed with four 300 ml portions of a 5% sodium hydroxide solution once with water and once with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 138 g of gummy solid as residue. This solid was purified by column chromatography on 1 kg of silica gel, eluting with 2% ethylacetate in benzene to yield 69.6 g (46%) of title compound as an off-white solid. The solid was recrystallized from isopropyl ether, m.p. 52°-54° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27](Cl)=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.C([O-])([O-])=O.[K+].[K+].[CH3:39][NH2:40].O>CS(C)=O>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[C:27]([NH:40][CH3:39])=[N:28][CH:29]=[CH:30][CH:31]=4)=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1cccnc1Cl
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CNc1ncccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1

Procedure:
A mixture of 1 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2-chloropyridine-3-carboxamide, 1 g of K2CO3 and 10 ml of a 40% solution of monomethylamine is heated in 25 ml of dimethylsulfoxide for 8 hours at 100° C. The reaction mixture is poured over water and the pale yellow solid separated. The reaction mixture is filtered and the collected solid washed well with water. After drying the solid is purified by column chromatography on silica gel by elution with 9:1 ethyl acetate:methanol to give 850 mg of the desired product as a pale yellow solid: M+ =437.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:31][CH2:30][C:29]4[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:34])[F:35])=[CH:33][CH:32]=4)=[O:3])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)NCc3ccc(C(F)(F)F)cc3)(CC1)CC2
Yield: 29.6 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-(trifluoromethyl)benzylamine (60.0 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-(4-[N-(4-trifluoromethylphenylmethyl)amino]carbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile (22.0 mg).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br>O1CCCC1.CN(C)C=O>[Br:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cccc(Br)c1)C(=O)OCC
Reaction time: 0.25 h

Procedure:
Sodium hydride (60%, 1.6 g) was suspended into 20 ml of dry tetrahydrofuran/15 ml of dry N,N-dimethyl formamide, and 7.6 ml of diethyl malonate was added dropwise under ice-cooling. The mixture was stirred for 15 minutes. A solution of 5 g of 3-bromobenzyl bromide/10 ml of dry tetrahydrofuran was then added, and stirred for 1 hour under ice-cooling. To the reaction solution was added ice-cold water, and extracted with ether, washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate=10:1) to provide 5.41 g of the objective compound as colorless oil.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:15]([NH2:16])=[C:14]([NH2:17])[C:12](=[O:13])[N:11]([CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:9]2=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:26][C:27]([C:29]1[CH:30]=[CH:31][C:32]([C:35](O)=O)=[N:33][CH:34]=1)=[O:28].C(N(C(C)C)CC)(C)C>ClCCl>[CH:19]1([CH2:18][N:11]2[C:12](=[O:13])[C:14]3[N:17]=[C:35]([C:32]4[CH:31]=[CH:30][C:29]([C:27]([OH:28])=[O:26])=[CH:34][N:33]=4)[NH:16][C:15]=3[N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[C:9]2=[O:10])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Nc1c(N)n(CC2CCCCC2)c(=O)n(CC2CCCCC2)c1=O
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)c1ccc(-c2nc3c(=O)n(CC4CCCCC4)c(=O)n(CC4CCCCC4)c3[nH]2)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.4 %

Procedure:
To 1,3-bis(cyclohexylmethyl)-5,6-diaminouracil (1.45 g, 4.33 mmol), from Example 1, part (d) above, in dichloromethane (25 mL) was added the intermediate 5-(methoxycarbonyl)pyridine-2-carboxylic acid (1.78 g, 5.52 mmol) and diisopropylethylamine (Aldrich, 0.84 g, 6.5 mmol). This reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and the crude material was taken up in 1N sodium hydroxide and heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, diluted with acetic acid and the product precipitated from the reaction mixture to provide 6-(1,3-Bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl)nicotinic Acid (1.44 g, 56%) as a green solid. 1H-NMR (300 MHz, DMSO-d6) δ: 9.68 (s, 1H), 9.10 (d, J=3.1 Hz, 1H), 8.43 (m, 1H), 8.12 (m, 1H), 6.71 (br s, 1H), 4.12-3.60 (br m, 4H), 1.80-1.40 (m, 11H), 1.35-0.91 (m, 11H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].C(N(CC)CC)C.C1C(=O)N([O:28][C:29]([CH2:31][CH2:32][S:33][S:34][C:35]2[N:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=O)C(=O)C1>C1(C)C=CC=CC=1>[N:40]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[S:34][S:33][CH2:32][CH2:31][C:29]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:28]
Reactant: NCCOCCOCCCC(=O)O
Reactant: O=C(CCSSc1ccccn1)ON1C(=O)CCC1=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(O)CCCOCCOCCNC(=O)CCSSc1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(2-(2-aminoethoxy)ethoxy)butanoic acid (Compound 4) (F.W. 312.37, 100 mg, 0.377 mmole) in 20 mL of anhydrous toluene was azetropically distilled under reduced pressure at 60° C. on a rotary evaporator. The azeotropic distillation was repeated with 20 mL of anhydrous toluene. Then, the resulting residue was dissolved in anhydrous DCM (20 ml). To the above solution was added N-succinimidyl-3-(2-pyridithio) propionate (Compound 5) (SDPD, F.W.265.3, 100 mg, 0.32 mmole) and triethylamine (105 μl, 0.75 mmole). The mixture was allowed to stand for overnight under stirring at room temperature. TLC showed the disappearance of SPDP. The reaction solution was washed with diluted phosphoric acid (pH4, 5 ml×2). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting residue was subject to flash chromatography on a Biotage system, giving 140 mg of Compound 6, purity>95% (HPLC).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=[O:18])[CH:4]([CH3:17])[N:5]1[CH:9]=[C:8](C)[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6]1.[CH2:20](I)[CH3:21]>>[CH3:19][N:2]([CH3:1])[C:3]([C:4]1([N:5]2[CH:9]=[CH:8][C:7]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[N:6]2)[CH2:17][CH2:21][CH2:20]1)=[O:18]
Reactant: Cc1cn(C(C)C(=O)N(C)C)nc1-c1ccccc1
Reactant: CCI
Product: CN(C)C(=O)C1(n2ccc(-c3ccccc3)n2)CCC1

Procedure:
Following the procedure of Example 95, but substituting α-(3-bromopropyl)-N,N-dimethyl-3-phenylpyrazole-1-acetamide for N,N,α,4-tetramethyl-3-phenylpyrazole-1-acetamide and without addition of ethyl iodide there was obtained N,N-dimethyl-1-(3-phenylpyrazol-1-yl)cyclobutanecarboxamide having a boiling point of 170°/0.1 mm.
Reaction SMILES: [ClH:1].Br[C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].[CH:12]1(C2C=CC(N)=CC=2)[CH2:17][CH2:16]C[CH2:14][CH2:13]1>>[ClH:1].[CH:9]1([C:7]2[CH:6]=[CH:5][C:4]([NH:10][NH2:11])=[CH:3][CH:8]=2)[CH2:16][CH2:17][CH2:12][CH2:13][CH2:14]1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: Cc1ccc(NN)c(Br)c1
Agent: Cl
Product: NNc1ccc(C2CCCCC2)cc1

Procedure:
4-Cyclohexylphenylhydrazine hydrochloride (35.6 g) was prepared as described for 2-bromo-4-methyl-phenylhydrazine hydrochloride in Example 4, except using 4-cyclohexylaniline as starting material. ##STR44##
Reaction SMILES: [I:1][CH:2]([O:5][C:6](=[O:16])[CH2:7][NH:8]C(OC(C)(C)C)=O)[C:3]#[CH:4].[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[I:1][CH:2]([O:5][C:6](=[O:16])[CH2:7][NH2:8])[C:3]#[CH:4]
Reactant: C#CC(I)OC(=O)CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#CC(I)OC(=O)CN
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
N-t-Butoxycarbonyl glycine iodopropargyl ester (Compound #1) (4.20 g., 12.39 mmole) was dissolved in anhydrous dichloromethane (20 ml.), cooled to 0° C. with an ice-bath, and treated with 10 ml. of trifluoroacetic acid. The reaction mixture was stirred magnetically at 0° C. for 1 hour and then allowed to warm to ambient temperature. The volatile solvents were removed under reduced pressure leaving a clear syrup which crystallized on standing to a white solid (4.20 g., 96% yield) as the desired trifluoroacetate salt product. m.p. 130°-131° C. 1H-NMR (200 MHz, DMSOd6) δ=3.92, s, 2H; 5.00, s; 2H; s; 9.1, broad m. IR (KBr) 1605, 1670, 1765, 2205, 2640 cm-1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[O:21][CH2:22][O:23][CH3:24])=[CH:10][C:9]=1[NH2:25])([CH3:4])([CH3:3])[CH3:2].[N:27]1([C:32]2[CH:33]=[C:34]([C:38]3[O:43]C(C)(C)[O:41][C:40](=O)[CH:39]=3)[CH:35]=[CH:36][CH:37]=2)[CH:31]=[CH:30][N:29]=[CH:28]1>>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[O:21][CH2:22][O:23][CH3:24])=[CH:10][C:9]=1[NH:25][C:40](=[O:41])[CH2:39][C:38]([C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[CH:33]=1)=[O:43])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCOc1cc(F)ccc1-c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Product: COCOc1cc(F)ccc1-c1ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnc3)c2)c1

Procedure:
Prepared from (3-amino-4′-fluoro-2′-methoxymethoxy-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G42) (181 mg, 0.5 mmol) and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10) (135 mg, 0.5 mmol) according to the general procedure K. Obtained as a yellow amorphous substance (221 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[C:7]([C:11]([OH:13])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:23].N#N>CO.C1(C)C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:14][C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[NH:8][C:7]=2[C:11]([O:13][CH3:23])=[O:12])=[CH:16][CH:17]=1
Reactant: O=C(O)c1[nH]c2cc(F)ccc2c1Sc1ccc(Cl)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: N#N
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1[nH]c2cc(F)ccc2c1Sc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of impure 1g product (0.19 g, 0.59 mmol) in a mixture of methanol and toluene (6 mL, 1:2) was added TMSCHN2 (2.0 M solution in diethyl ether) (0.6 mL, 1.2 mmol) dropwise under N2. The reaction was allowed to warm to rt and stirred for 2 h. The reaction mixture was concentrated and purified by flash column chromatography eluting with a linear gradient ranging from 0 to 50% EtOAc-hexanes to provide 0.15 g (75%) of product 34 as an off white solid. 1H NMR (300 MHz, CDCl3) δ 3.93 (s, 3H), 6.88-6.95 (m, 1H), 7.06-7.16 (m, 5H), 7.45-750 (m, 1H), 9.22 (s, 1H). LC-MS (CI): m/z 336.0 [(M+H)+ C16H11ClFNO2S requires 335.02].