Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>ClCCl>[CH2:37]([O:36][C:34](=[O:35])[N:2]([CH3:1])[CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1C2CCC3C4CC=C5CC(N(C)C(=O)OCc6ccccc6)CCC5(C)C4CCC32CN1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
Compound 7B (20 mg, 0.058 mmol) and triethylamine (9.1 μL, 0.064 mmol) were dissolved in dichloromethane (1 mL). Benzyl chloroformate was added to it. The mixture was stirred at room temperature for 2 hours. The crude reaction mixture was purified on silica gel column using 0.5% ammonium hydroxide and 5% methanol in dichloromethane to give the desired product (18.4 mg, 66.2% yield).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([O:34][C:35]([NH:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([O:34][C:35]([NH:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(OC(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(OC(=O)NC3CCCCC3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-cyclohexylaminocarbonyloxy-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[C:16]1([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>C1(C)C=CC=CC=1>[C:23]1([N:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:2]2[CH:7]=[CH:6][C:5]([C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:9])=[CH:4][CH:3]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reaction time: 24 h
Yield: 83.5 %

Procedure:
(4-bromophenyl)(phenyl)methanone (5.0 g, 19.2 mmol) and diphenylamine (4.2 g, 25.0 mmol) were dissolved in 150 mL of toluene under a nitrogen atmosphere, and then tris(benzylidene acetone dipalladium) (0.4 g, 0.4 mmol) was added thereto under nitrogen. Also, P(t-Bu)3 (0.8 g, 3.8 mmol) was added to the reaction mixture solution, followed by addition of NaOBut (5.5 g, 57.7 mmol). The reaction mixture solution was refluxed and stirred for 24 hours. After the reaction was over, the reaction mixture solution was filtered through a thin silica pad at a high temperature to thereby remove palladium. The filtrate was concentrated, and passed through a silica gel column by using hexane-dichloromethane 7:3 as an eluant. After the solvent was removed, the residue material was dried in vacuum to thereby obtain a white solid (5.6 g, yield: 84%).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[C:7]([O:10][C@@H:11]1[C@@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:16]([O:22][C:23](=[O:25])[CH3:24])[C@@H:15]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[S:14][CH:12]1[OH:13])(=[O:9])[CH3:8].C(=O)(O)[O-].[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(Cl)(Cl)Cl>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[C:12]1([S:14][C@H:15]([CH2:26][O:27][C:28](=[O:30])[CH3:29])[C@@H:16]([O:22][C:23](=[O:25])[CH3:24])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:11]1[O:10][C:7](=[O:9])[CH3:8])[OH:13]
Reactant: CC(=O)OC[C@H]1SC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)OC[C@H]1SC(O)(C2CCCCO2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 104 %

Procedure:
3,4-Dihydro-2H-pyran (1.5 mL, 16.5 mmol) and p-toluenesulfonic acid monohydrate (104 mg, 0.549 mmol) were added to a chloroform (40 mL) solution of 2,3,4,6-tetra-O-acetyl-5-thio-D-glucopyranose (2.0 g, 5.49 mmol) and stirred at room temperature for one hour. The reaction mixture was added with a saturated sodium bicarbonate aqueous solution and extracted with chloroform, and after the organic layer was washed with brine, it was dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain pale yellow amorphous tetrahydro-2H-pyran-2-yl 2,3,4,6-tetra-O-acetyl-5-thio-D-glucopyranose (2.56 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:13]([CH3:15])=O)[C:8]([O:10]CC)=O.[NH2:21][C:22]1[N:27]=[C:26]([NH2:28])[CH:25]=[C:24]([NH2:29])[N:23]=1.O>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH2:21][C:22]1[N:23]=[C:24]([NH2:29])[C:25]2[C:13]([CH3:15])=[C:7]([CH2:6][C:5]3[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:8](=[O:10])[NH:28][C:26]=2[N:27]=1
Reactant: Nc1cc(N)nc(N)n1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(OC)c1)C(C)=O
Solvent: O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(Cc2c(C)c3c(N)nc(N)nc3[nH]c2=O)cc1OC
Yield: 50.8 %

Procedure:
A mixture of ethyl α-(3,4-dimethoxybenzyl)acetoacetate (42 g) and 2,4,6-triaminopyrimidine (21 g) in diphenyl ether (120 ml) was heated at 190°-230° C. for 2 hours during which time the ethanol and water formed were azeotropically removed. The reaction was cooled, and methanol (250 ml) and ethanol (50 ml) were added. The resulting solid was collected by filtration and treated with boiling water (1) to give 2,4-diamino-5-methyl-6-(3,4-dimethoxybenzyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine (26 g), m.p. 346°-348° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].Cl[CH2:11][C:12](Cl)=[O:13].C([O-])([O-])=O.[K+].[K+]>>[F:8][C:4]1[C:3]2[O:9][CH2:11][C:12](=[O:13])[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2c(F)cccc2N1
Yield: 86.8 %

Procedure:
2-Amino-6-flourophenol (95MF2085) (0.256 g, 2.0 mmol), 2-chloroacetyl chloride (0.25 g, 2.2 mmol) and K2CO3 (0.583 g, 4.2 mmol) were mixed according to GP1 to give the title compound as a crude (95MF45) (0.29 g)
Reaction SMILES: [CH3:1][CH2:2][C:3](=[O:7])[CH:4]=[CH:5][CH3:6].[CH:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1.Cl(O)(=O)(=O)=O.C([C@@H]1N[C@H](C2OC(C)=CC=2)N(C)C1=O)C1C=CC=CC=1>O>[CH3:6][C@H:5]1[C@@H:10]2[CH2:11][C@H:12]([CH:8]=[CH:9]2)[C@@H:4]1[C:3](=[O:7])[CH2:2][CH3:1]
Reactant: C1=CCC=C1
Reactant: CC=CC(=O)CC
Agent: Cc1ccc([C@H]2N[C@@H](Cc3ccccc3)C(=O)N2C)o1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: CCC(=O)[C@@H]1[C@@H](C)[C@H]2C=C[C@H]1C2
Yield: 89 %

Procedure:
Prepared according to general procedure A from 4-hexen-3-one (70 μL, 0.61 mmol), cyclopentadiene (75 μL, 0.91 mmol), 70% aqueous perchloric acid (10.5 μL, 0.12 mmol) and (2S, 5S)-5-Benzyl-3-methyl-2-(5-methyl-furan-2-yl)-imidazolidin-4-one (30.7 mg, 0.12 mmol) in water (203 μL) for 22 hours at 0° C. Purification by silica gel chromatography (9:1 pentane:ether) provided the title compound as a colorless oil in 89% yield (88.7 mg, 0.54 mmol); 25:1 endo:exo, endo 90% ee. Product ratios were determined by GLC analysis (150° C., 23 psi); (1R, 2R, 3S, 4R) endo isomer tr=3.7 min, and (1S, 2S, 3R, 4S) endo isomer tr=3.6 min, exo isomers tr=3.4, 3.5 min. H NMR, 13C NMR, and IR data 1 were consistent with previously reported values (Zhu et al. (1997) J. Am. Chem. Soc. 119:3507-3512; Ahrendt et al. (2000) J. Am. Chem. Soc. 122:4243-4244). [α]D=+101.7 (c=1.0, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH:20]2[CH3:25]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:19]3[CH2:18][CH2:17][C:16]4[C:21](=[CH:22][CH:23]=[CH:24][C:15]=4[F:14])[CH:20]3[CH3:25])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2c(F)cccc21
Product: CC1c2cccc(F)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[N:4][C:5](F)=[C:6]([Cl:8])[CH:7]=1.[OH-:11].[Na+].[OH2:13]>C(O)CCCO.C(O)CO>[Cl:8][C:6]1[C:5]([O:11][CH2:3][CH2:2][CH2:7][CH2:6][OH:13])=[N:4][C:3]([F:10])=[C:2]([Cl:1])[CH:7]=1
Reactant: O
Reactant: [OH-]
Reactant: Fc1nc(F)c(Cl)cc1Cl
Agent: [Na+]
Solvent: OCCO
Solvent: OCCCCO
Product: OCCCCOc1nc(F)c(Cl)cc1Cl
Reaction time: 4 h

Procedure:
To a solution of 11 grams (0.06 mole) of 3,5-dichloro-2,6-difluoropyridine in 35 milliliters of 1,4-butanediol was added over a 10 minute period 2.44 grams of sodium hydroxide in 35 milliliters of ethylene glycol. The temperature was maintained at between 50°-60° C. during the addition. The mixture was stirred for 13/4 hours while the temperature was maintained between 60°-65° C. The reaction mixture was cooled and poured into water and thereafter extracted three times with 135 milliliter portions of hot hexane. The mixture was heated to remove most of the hexane by evaporation, cooled and filtered to remove the solid 4-(3,5-dichloro-6-fluoro-2-pyridyloxy)-1-butanol product. The product was recovered in a yield of 11 grams (73 percent of theoretical) and melted at 38°-39° C. Upon analysis, the product was found to have carbon, hydrogen, chlorine and nitrogen contents of 43.2, 3.7, 27.9 and 5.7 percent, respectively, as compared with the theoretical contents of 42.5, 3.9, 27.9 and 5.5 percent, respectively, as calculated for the above named compound.
Reaction SMILES: [H-].[K+].[CH3:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:13]=[C:14]([Br:18])[CH:15]=[CH:16][CH:17]=2)=[CH:7][CH:6]=1.[CH2:19](Br)[CH:20]=C.[CH3:23]N(C=O)C>C1COCC1>[CH2:3]([N:4]([CH3:23])[C:5]1[CH:6]=[CH:7][C:8]([S:11][C:12]2[CH:13]=[C:14]([Br:18])[CH:15]=[CH:16][CH:17]=2)=[CH:9][CH:10]=1)[CH:19]=[CH2:20]
Reactant: CNc1ccc(Sc2cccc(Br)c2)cc1
Reactant: CN(C)C=O
Reactant: C=CCBr
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CCN(C)c1ccc(Sc2cccc(Br)c2)cc1
Yield: 75 %

Procedure:
A flask was charged with potassium hydride (0.3 g, 35% oil dispersion, 2.62 mmol) and dry THF (1.5 mL) under a stream of nitrogen. A solution of 3-(N-methyl-p-aminobenzenethioxy)bromobenzene (0.50 g, 1.71 mmol), prepared as in step 4, in dry THF was added via syringe. When gas evolution ceased, allyl bromide (0.38 mL, 4.27 mmol, passed through a neutral alumina pad before addition) was added in a single portion, followed by dry DMF (3.4 mL). After 15 min the reaction was quenched with isopropanol and partitioned between saturated aqueous NH4C1 and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed twice with brine, dried over MgSO4, filtered, and concentrated in vacuo to give 0.91 g of crude product. Purification by chromatography on silica gel (5% ethyl acetate:hexanes) provided pure 3-(N-allyl-N-methyl-p-aminobenzenethioxy)bromobenzene (0.43 g, 75%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.O=[C:11]1[CH2:17][C@H:16]2[N:13]([C:14](=[O:35])[C@H:15]2[C:18]([CH3:34])([O:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[CH3:19])[C@H:12]1[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=1)=[O:37].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[N:64]1[N:65]=[N:66][N:67]2[C:72]=1[CH:71]=[CH:70][C:69]([SH:73])=[N:68]2>ClCCl.CN(C1C=CN=CC=1)C.CN(C)C=O>[CH3:34][C:18]([C@@H:15]1[C:14](=[O:35])[N:13]2[C@@H:16]1[CH2:17][C:11]([S:73][C:69]1[CH:70]=[CH:71][C:72]3[N:67]([N:66]=[N:65][N:64]=3)[N:68]=1)=[C:12]2[C:36]([O:38][CH2:39][C:40]1[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=1)=[O:37])([O:20][C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=1)=[O:22])[CH3:19]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Reactant: Sc1ccc2nnnn2n1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3ccc4nnnn4n3)C[C@H]12
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 71.1 %

Procedure:
A solution of N,N-diisopropyl-N-ethylamine (0.231 ml) in dichloromethane (2.08 ml) was added to a solution of 4-nitrobenzyl (2R, 5R, 6R)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]1-azabicyclo[3.2.0]heptane-2-carboxylate (600 mg) and 4-(N,N-dimethylamino)pyridine (13.5 mg) in dichloromethane (30.0 ml) at -30° C. To this mixture was added a solution of trifluoromethanesulfonic anhydride (0.196 ml) in dichloromethane (3.72 ml) and stirring was continued at -30° C. for 20 minutes. N,N-Diisopropyl-N-ethylamine (0.680 ml) and a solution of tetrazolo[1,5-b]pyridazine-6-thiol (0.256 g) in N,N-dimethylformamide (2.30 ml) were added to the mixture at -30° C. The resultant mixture was allowed to warm to 20° C. over a period of 2 hours, and then evaporated in vacuo. The residue was dissolved in ethyl acetate (100 ml), washed in turn with cold water (x3) and an aqueaus sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on deactivated silica gel with 15% water (7.5 g), eluting with a mixture of benzene and acetone (20:1 to 6:1). The fractions containing the desired compound were collected and diluted with benzene to result in precipitation of crystals, which, after cooling in a refrigerator, were collected by filtration to give 4-nitrobenzyl (5R, 6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-3-(tetrazolo[1,5-b]pyridazin-6-ylthio)-1azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.533 g). Crystallization of the mother liquor from ethyl acetate and n-hexane gave the same product (0.0663 g) as a pale yellow powder.
Reaction SMILES: O[CH:2]([C:4]1([O:13]C)[C:8]([O:9]C)=[CH:7][CH:6]([O:11]C)O1)[CH3:3].C(O)=O.O>CO>[CH3:3][C:2]1[O:11][CH:6]=[CH:7][C:8](=[O:9])[C:4]=1[OH:13]
Reactant: COC1=CC(OC)OC1(OC)C(C)O
Solvent: O
Solvent: CO
Solvent: O=CO
Product: Cc1occc(=O)c1O
Yield: 79.3 %

Procedure:
2(1-hydroxy ethyl)-2,3,5-trimethoxy-2,5-dihydrofuran (2.82 g, 0.015 moles) in 2 ml methanol was added to 15 ml of formic acid over 5 minutes. To the well stirred solution was then added 20 ml of water and the reaction heated to reflux for 1 hour. After cooling, the reaction was extracted with chloroform and the chloroform concentrated to yield 1.5 g maltol, which was recrystallized from methanol to yield the pure white solid, m.p. 159°-160° C. Hydrochloric acid, hydrobromic acid, p-toluene sulfonic acid and acidic ion exchange resins can be used in place of formic acid in this Example.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][NH:11][CH2:12][CH2:13][NH2:14].[CH2:15]([N:17]=[C:18]=S)[CH3:16].[NH2:20][C:21]([NH2:23])=S.N#CN.[Pb]>>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][NH:11][CH2:12][CH2:13][NH:14][C:18]([NH:23][C:21]#[N:20])=[N:17][CH2:15][CH3:16]
Reactant: NC(N)=S
Reactant: NCCNCc1nc2ccccc2[nH]1
Reactant: CCN=C=S
Agent: N#CN
Agent: [Pb]
Product: CCN=C(NC#N)NCCNCc1nc2ccccc2[nH]1

Procedure:
Reacting N-(2-benzimidazolylmethyl)ethylenediamine with ethyl isothiocyanate by the procedure of Example 3(b), then chromatographing and reacting the resulting thiourea with lead cyanamide by the procedure of Example 3(b) gives N-[2-(2-benzimidazolylmethylamino)ethyl]-N'-cyano-N"-ethylguanidine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[CH2:22](O)[CH3:23]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:22][CH3:23])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Cc1ccc(O)cc1

Procedure:
To a solution of 4- hydroxyphenylacetic acid (3.00 g) in ethanol (50 ml) was added sulfuric acid (5 ml). The mixture was refluxed with heating for 4 hours. Aqueous sodium bicarbonate solution was added to the reaction solution so as to make basic. Then, the reaction solution was extracted with chloroform. The extract was dried over sodium sulfate anhydride and then concentrated under a vacuum to yield a raw product of ethyl 4-hydroxyphenylacetate. In a manner similar to Reference Example 1, this raw product was reacted with geranyl bromide (7.10 g) and then hydrolyzed to yield 3.54 g (61%) of 4-geranylophenylacetic acid.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][N:6]([C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])[CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.O.CO.O.[OH-].[Li+]>C1COCC1>[CH2:24]([O:23][C:21]([N:6]([CH2:5][C:4]([OH:27])=[O:3])[CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:22])[CH:25]=[CH2:26]
Reactant: C=CCOC(=O)N(CC(=O)OCC)C(c1ccccc1)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=CCOC(=O)N(CC(=O)O)C(c1ccccc1)c1ccc(Cl)cc1
Yield: 66.4 %

Procedure:
(RS)-{Allyloxycarbonyl-[(4-chloro-phenyl)-phenyl-methyl]-amino}-acetic acid ethyl ester (18 g, 46.4 mmol) was dissolved in THF (60 mL), water (60 mL), and MeOH (60 mL) and treated with lithium hydroxide monohydrate (3.9 g, 92 mmol) at 20° C. for 2 h. The mixture was evaporated and extracted with AcOEt, 1 N HCl and 50% NaCl. The crude product was crystallized from heptane/ethyl acetate 10:1 (100 mL). One obtained 11.08 g (66%) of white crystals. MS: m/z=358 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH2:27][C:28]3[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=3)[N:13]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=3)[CH:14]=2)=[CH:6][CH:5]=1.[CH:36]1([C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:39]4[CH:38]=[CH:37][C:36]([CH:42]5[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]5)=[CH:41][CH:40]=4)=[CH:30][CH:29]=3)[N:13]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=3)[CH:14]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)CNc1ccc(-n2cc(-c3ccc(C(=O)OC)cc3)nc2Cc2ccc(Br)cc2)cc1
Reactant: OB(O)c1ccc(C2CCCCC2)cc1
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(C(=O)OC)cc3)nc2Cc2ccc(-c3ccc(C4CCCCC4)cc3)cc2)cc1

Procedure:
4-{2-(4-Bromo-benzyl)-1-[4-(methoxycarbonylmethyl-amino)-phenyl]-1H-imidazol-4-yl}-benzoic acid methyl ester (2.7 g, 5 mmol) was coupled with 4-cyclohexyl-phenylboronic acid (1.25 g, 6.0 mmol) according to general procedure G to give 4-{2-(4′-cyclohexyl-biphenyl-4-ylmethyl)-1-[4-(methoxycarbonylmethyl-amino)-phenyl]-1H-imidazol-4-yl}-benzoic acid methyl ester.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:9]([C:13](=[O:32])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([N:20]2[CH:24]=[CH:23][CH:22]=[C:21]2[C:25]([O:27]C(C)(C)C)=[O:26])=[O:19])[CH:10]=[CH:11][CH:12]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:25]([C:21]1[N:20]([C:18](=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][C:13]([N:9]2[CH:10]=[CH:11][CH:12]=[C:8]2[C:6]([OH:7])=[O:5])=[O:32])[CH:24]=[CH:23][CH:22]=1)([OH:27])=[O:26]
Reactant: CC(C)(C)OC(=O)c1cccn1C(=O)CCCCC(=O)n1cccc1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cccn1C(=O)CCCCC(=O)n1cccc1C(=O)O
Reaction time: 16 h
Yield: 97.8 %

Procedure:
To a stirred solution of 55 mg (0.12 mmol) 1-[6-(2-tert-butoxycarbonyl-pyrrol-1-yl)-6-oxo-hexanoyl]-1H-pyrrole-2-carboxylic acid tert-butyl ester in 8 ml dichloromethane at 0° C. was added dropwise 0.15 ml (1.97 mmol) trifluoroacetic acid and stirring continued for 16 h at room temperature. Concentration in vacuo and azeotroping three times with chloroform on a rotary evaporator afforded 39 mg (95%) of the title compound as an off-white crystalline solid. MS m/e (%): 350 (M+NH4+, 100).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([OH:12])([C:10]#[CH:11])[CH3:9])[CH:4]=1.C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:30][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:1][CH2:2][C:3]2[O:7][N:6]=[C:5]([C:8]([OH:12])([C:10]#[CH:11])[CH3:9])[CH:4]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C#CC(C)(O)c1cc(CO)on1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CC(C)(O)c1cc(COS(=O)(=O)c2ccc(C)cc2)on1
Temperature: 25 °C

Procedure:
To a solution of 2-[5-(hydroxymethyl)isoxazol-3-yl]but-3-yn-2-ol (500 mg, 2.99 mmol) in DCM (5 mL) at 0° C. under an atmosphere of nitrogen was introduced triethylamine (333 mg, 3.29 mmol) and p-toluenesulfonyl chloride (627 mg, 3.29 mmol) in one portion. After warming to RT for 3 hr, the reaction mixture was diluted with DCM (10 mL) and washed with brine (5 mL). The organic extract was dried (Na2SO4), filtered and the filtrate adsorbed onto silica gel in vacuo. Purification by silica gel flash column chromatography (heptane/EtOAc gradient of increasing polarity) furnished the title compound as a colorless oil: 1H NMR (500 MHz, CDCl3) delta 1.84 (3H, s), 2.26 (3H, s), 2.66 (1H, s), 2.86 (1H, br. s), 5.14 (2H, s), 6.41 (1H, s), 7.36 (2H, d, J=8.1 Hz), 7.80 (2H, d, J=8.1 Hz); LC-MS: m/z=+321.9 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=2)=[O:13])[N:3]=1.[CH3:21][C:22]1[NH:26][N:25]=[C:24]([NH2:27])[CH:23]=1.CCN(C(C)C)C(C)C.[I-].[K+]>CN(C)C=O.O>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]([C:4]2[N:3]=[C:2]([NH:27][C:24]3[CH:23]=[C:22]([CH3:21])[NH:26][N:25]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:13])=[N:15][CH:16]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=C(c1ccc(F)cn1)c1nc(Cl)c2ccccc2n1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)cn3)nc3ccccc23)n[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 6.6 %

Procedure:
To a stirred mixture of (4-chloroquinazolin-2-yl)(5-fluoropyridin-2-yl)methanone (244 mg, 0.85 mmol) and 5-methyl-3-aminopyrazole (99 mg, 1.02 mmol) in N,N-dimethylformamide (3 mL) were added DIEA (0.3 mL, 4.22 mmol) and potassium iodide (141 mg, 0.85 mmol) and the mixture was stirred at rt for 15 h and then at 60° C. for 2.5 h. The mixture was allowed to cool to rt, and then water was added. The precipitated solid was collected by filtration. A portion of the solid (180 mg) was purified by preparative reverse-phase HPLC eluting with 30% to 70% acetonitrile/0.05% aq HOAc to afford (5-fluoropyridin-2-yl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone (19.6 mg). 1H NMR (300 MHz, CDCl3) δ 12.19 (s, 1H), 10.65 (s, 1H), 8.72-8.69 (m, 2H), 8.26 (m, 1H), 8.00 (td, J=3 Hz, J=8.7 Hz, 1H), 7.92-7.80 (m, 2H), 7.66 (t, J=7.5 Hz, 1H), 6.34 (s, 1H), 2.16 (s, 3H); LC-MS (ESI) m/z 349 (M+H)+.