Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=3[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:28][CH3:29].[CH2:30]([CH:32]1[O:34][CH2:33]1)Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:29][O:28][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:30][CH:32]1[CH2:33][O:34]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[C:20]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
{2-[(7-Hydroxy-6-methoxy-4-quinolyl)oxy]-5-methylphenyl}-(phenyl)methanone (200 mg), epibromohydrin (213 mg), and potassium carbonate (358 mg) were suspended in N,N-dimethylformamide (5 ml), and the suspension was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (176 mg, yield 75%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([F:16])[C:7]1=2)[CH3:2].[H-].[Na+].I[CH:22]([CH3:24])[CH3:23].Cl>CN(C=O)C>[F:16][C:15]1[C:7]2[CH:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:18])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=[C:13]([O:17][CH:22]([CH3:24])[CH3:23])[CH:14]=1
Reactant: CC(C)I
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(F)c21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(OC(C)C)cc(F)c21
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a solution of ethyl-2-(4-fluoro-1,6-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (0.254 g, 1.0 mmol) in DMF (4 mL) was added sodium hydride (0.12 g, 3.0 mmol). The reaction mixture was stirred for 30 min and then 2-iodopropane (0.19 g, 1.1 mmol) was added. After stirring for an additional 2 h, the reaction mixture was acidified to pH=2 using diluted hydrochloride acid and extracted with ethyl acetate (15 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated to give the crude product as a yellow solid (0.25 g, Yield: 84%) which was used immediately without further purification. MS (ESI) m/z=297 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]1[C:8]([C:9]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][C:20]#[N:21])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[O:10])=[C:7]([CH:22]([CH3:24])[CH3:23])[C:6](=[O:25])[NH:5][C:4]1=[O:26])[CH3:2]>[Pd].C(O)C>[CH2:1]([N:3]1[C:8]([C:9]([C:11]2[CH:12]=[C:13]([CH2:18][CH2:19][C:20]#[N:21])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[O:10])=[C:7]([CH:22]([CH3:23])[CH3:24])[C:6](=[O:25])[NH:5][C:4]1=[O:26])[CH3:2]
Reactant: CCn1c(C(=O)c2cc(C)cc(C=CC#N)c2)c(C(C)C)c(=O)[nH]c1=O
Agent: [Pd]
Solvent: CCO
Product: CCn1c(C(=O)c2cc(C)cc(CCC#N)c2)c(C(C)C)c(=O)[nH]c1=O
Reaction time: 17 h
Yield: 94.3 %

Procedure:
3-[3-(3-Ethyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-phenyl]-acrylonitrile (Compound 73) (190 mg, 0.54 mmol) was stirred with 10% palladium on carbon (20 mg) in anhydrous ethanol (10 mL) at room temperature under an atmosphere of hydrogen. After 17 hr., the reaction mixture was filtered through a celite pad and the pad was washed with ethanol and chloroform. The combined filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane (1:2)) to afford 180 mg (94%) of 3-[3-(3-ethyl-5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbonyl)-5-methyl-phenyl]-propionitrile (75) as a white foam. Recrystallization from chloroform-ether resulted in a white solid. m.p. 173-174° C.; 1H-NMR (300 MHz, CDCl3) δ 1.13-1.18 (6H, m), 1.23 (3H, d, J=6.9 Hz), 2.31 (1H, m), 2.47 (3H, s), 2.70 (2H, t, J=6.9 Hz), 3.04 (2H, t, J=6.9 Hz), 3.25 (1H, m), 3.89 (1H, m), 7.45 (1H, s), 7.66 (2H, s), 9.17 (1H, s); m/z (EI) 353 (M+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][S:7][CH2:8][CH2:9][NH2:10])[N:3]=[CH:2]1.[C:11]([N:19]=[C:20]=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[C:11]([NH:19][C:20]([NH:10][CH2:9][CH2:8][S:7][CH2:6][C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)=[S:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCSCc1c[nH]cn1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(NC(=S)NCCSCc1c[nH]cn1)c1ccccc1
Yield: 63.7 %

Procedure:
(i) A solution of 2-(4-imidazolylmethylthio)ethylamine (6.0 g) and benzoyl isothiocyanate (6.0 g) in chloroform (150 ml) was heated under reflux for one hour. Concentration followed by recrystallisation from ethyl acetate-isopropyl acetate afforded N-benzoyl-N'-(2-(4-imidazolylmethylthio)-ethyl)thiourea (7.5 g). An analytically pure sample (from aqueous isopropyl alcohol) had m.p. 126°-128°.
Reaction SMILES: [C:1]([OH:11])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.[CH:33]1([O:38][C:39]2[CH:40]=[C:41]([CH:47]3[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)[CH:42]=[CH:43][C:44]=2[O:45][CH3:46])[CH2:37][CH2:36][CH2:35][CH2:34]1>C(Cl)Cl>[CH:33]1([O:38][C:39]2[CH:40]=[C:41]([CH:47]3[CH2:48][CH2:49][N:50]([C:1](=[O:11])/[CH:2]=[CH:3]/[C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:51][CH2:52]3)[CH:42]=[CH:43][C:44]=2[O:45][CH3:46])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: COc1ccc(C2CCNCC2)cc1OC1CCCC1
Reactant: O=C(O)/C=C/c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: COc1ccc(C2CCN(C(=O)/C=C/c3ccccc3)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of trans-cinnamic acid (1.20 mmol, 0.178 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (DEC; 1.20 mmol, 0.230 g) and hydroxybenzotriazole (HOBT; 1.20 mmol, 0.162 g) was dissolved in dry CH2Cl2 (20 mL) and stirred at room temperature for 1.5 hours. To this solution was added 4-(3-cyclopentyloxy-4-methoxyphenyl)piperidine (1.00 mmol, 0.275 g) in dry CH2Cl2 (10 mL) dropwise over 10 minutes and the resulting solution was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (70 mL) and 1N NaOH (70 mL). The aqueous phase was extracted with EtOAc (1×70 mL), the combined organics washed with H2O (1×70 mL), dried (Na2SO4) and concentrated in vacuo to yield a colorless oil. Purification by flash chromatography (SiO2 : 5% EtOAc/CH2Cl2) afforded the title compound as a white solid, mp=93°-95° C. (0.385 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:5]=1I.[C:16]1([Sn](CCCC)(CCCC)CCCC)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.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].[Cu](I)I>[CH3:1][O:2][C:3]([C:4]1[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:7]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:9]=1)=[O:15]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(S(C)(=O)=O)ccc1-c1ccccc1
Temperature: 90 °C
Yield: 99 %

Procedure:
A mixture of 3.53 mmol 2-Iodo-5-methanesulfonyl-benzoic acid methyl ester, 3.88 mmol Phenyltri-n-butyltin, 0.25 mmol Tris(dibenzylideneacetone)dipalladium(0), 0.35 mmol Triphenylarsine and 1.62 mmol Copper iodide in N,N-Dimethylformamide (30 ml) was heated at 90° C. for 16 hours. The mixture was cooled to room temperature and concentrated in vacuo. The residue was chromatographed over SiO2 (ethyl acetate/heptane gradient) to provide the title compound (99%) as an off-white crystalline solid. MS (m/e): 291.0 (MH+, 100%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[NH2:15].C(OC([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=O)(C)(C)C.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[F:1][C:2]1[C:3]2[N:15]=[C:25]([C@@H:24]([NH2:23])[CH3:28])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1c(F)cccc1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](N)c1nc2c(F)cccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
A mixture of 3-fluoro-N1-phenylbenzene-1,2-diamine (440 mg, 2.18 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (454 mg, 2.40 mmol), HOAt (327 mg, 2.40 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (460 mg, 2.40 mmol) and 4-methylmorpholine (0.527 mL, 4.79 mmol) in anhydrous DCM (20 mL) was stirred at RT for 2 h. The reaction mixture was diluted with DCM (100 mL) and washed with a saturated solution of NaHCO3. The organic layer was then dried and concentrated in vacuo. The resulting residue was dissolved in AcOH (10 mL) and heated to 70° C. for 2 h and then to 80° C. for 20 h. After cooling to RT, TFA (20 mL) was added and the mixture was stirred at RT for 1 h and 20 min. Volatiles were then removed in vacuo and the residue was dissolved in DCM (100 mL) and washed with a saturated solution of NaHCO3. The organic layer was then washed with brine, dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in TBME) affording (S)-1-(4-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine as a brown oil (396 mg, 71%). LCMS: RT 2.01 min [M−NH2]+ 239.1.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](=O)[CH:9]=[CH:10][CH:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH2:12]2)=[C:6]([O:19][CH2:20]C(OC)=O)[CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].Cl>CO>[OH:1][C:2]1[C:7]2[C:8]([CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)=[CH:20][O:19][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)COc1cccc(O)c1C(=O)C=CC1C=CC(C)=CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(CCc2coc3cccc(O)c23)cc1
Temperature: 25 °C
Yield: 29.2 %

Procedure:
To a solution of 6′-hydroxy-2′-methoxycarbonylmethoxy-4-methyldihydrochalcone (0.58 g) in methanol (10 mL) was added sodium methoxide (28% methanol solution, 0.68 mL), and the mixture was heated for reflux overnight. The reaction mixture was cooled to room temperature and poured into 1 mol/L hydrochloric acid. The resulting mixture was extracted with ethyl acetate, and the extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1) to give the title compound (0.13 g).
Reaction SMILES: Cl[CH:2]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:6]=2[CH:7]=1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=1>>[CH:14]1([CH:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:3]2[O:4][C:5]3[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:6]=3[CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: COc1ccc2oc(C(Cl)C3CCCCC3)cc2c1
Product: COc1ccc2oc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)cc2c1
Yield: 14.5 %

Procedure:
Using 2-[chloro(cyclohexyl)methyl]-5-methoxy-1-benzofuran (361 mg) synthesized in Example A22(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (325 mg) synthesized in Example 2(2) and in the same manner as in Example A22(4), the title object compound (87.0 mg, 14%) was obtained as a white solid.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1B(O)O)=[O:5])C.Br[C:16]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:17]=1[NH2:18].C([O-])(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(O)C>[F:23][C:20]1[CH:21]=[CH:22][C:16]2[C:17]([CH:19]=1)=[N:18][C:4]([OH:5])=[C:6]1[C:7]=2[CH:8]=[CH:9][CH:10]=[CH:11]1
Reactant: Nc1cc(F)ccc1Br
Reactant: CCOC(=O)c1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCO
Product: Oc1nc2cc(F)ccc2c2ccccc12
Temperature: 80 °C
Reaction time: 18 h
Yield: 52.8 %

Procedure:
A mixture of 2-(ethoxycarbonyl)phenylboronic acid (7.0 g, 39 mmol), 2-bromo-5-fluoroaniline (7.4 g, 39 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos, 0.32 g, 0.78 mmol), sodium acetate (4.1 g, 39 mmol), and palladium acetate (0.087 g, 0.39 mmol) in 18 ml. of ethanol was heated with stirring at 80° C. for 18 h. Additional 2-(ethoxycarbonyl)phenylboronic acid (2.0 g), S-Phos (0.095 g), palladium acetate (0.020 g), and sodium carbonate (1.2 g) was added and the mixture was stirred for 18 h. The solvent was removed by evaporation under reduced pressure, and the resulting solid was isolated by vacuum filtration, washing the remaining solid with water and then hexane. The remaining solid and dried in vacuo @50° C. to provide the title compound (4.39 g, 53% yield) which was used without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C@H:11]3[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=O)[CH3:19])[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[ClH:29].C(OCC)C>O1CCCC1.O>[ClH:29].[CH2:18]([NH:17][C@H:14]1[CH2:13][CH2:12][C@H:11]([O:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][N:2]=[CH:3]3)[CH2:16][CH2:15]1)[CH3:19]
Reactant: CC(=O)N[C@H]1CC[C@H](Oc2ccc3[nH]ncc3c2)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCN[C@H]1CC[C@H](Oc2ccc3[nH]ncc3c2)CC1
Reaction time: 12 h

Procedure:
The trans-N-[4-(1H-indazol-5-yloxy)cyclohexyl]acetamide (0.066 g, 0.24 mmol) obtained in Example 391 was added to a suspension of lithium aluminum hydride (0.040 g, 1.05 mmol) in tetrahydrofuran (5 ml) and stirred for 12 hours with heating under reflux. The resulting solution was cooled on an ice bath, followed by adding dropwise thereto water (0.05 ml), a 2N-aqueous sodium hydroxide solution (0.10 ml) and water (0.15 ml) in that order. Thereafter, the insoluble material was removed by filtration using Celite. The filtrate was purified by a silica gel chromatography (eluent: chloroform/methanol/30%-aqueous ammonia=10/1/0 to 100/10/1). A solution of the purified material in ethyl acetate was prepared and a 1N-hydrochloric acid/diethyl ether solution (0.5 ml) was added thereto. The solid precipitated was subjected to decantation with ethyl acetate and dried up to obtain trans-N-ethyl-4-(1H-indazol-5-yloxy)cyclohexanamine monohydrochloride (0.057 g, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@H:10]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[CH:20]=1)[O:11][CH2:12][C:13](=[CH2:18])[C:14](OC)=[O:15].[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.C(O)(=O)C(C(C(O)=O)O)O.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@H:10]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[CH:20]=1)[O:11][CH2:12][C:13](=[CH2:18])[CH2:14][OH:15]
Reactant: C=C(CO[C@H](CCc1ccccc1Br)c1cccc(COC2CCCCO2)c1)C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=C(CO)CO[C@H](CCc1ccccc1Br)c1cccc(COC2CCCCO2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of the ester of Step 3 (29.69 g, 59 mmol) in 300 mL of CH2Cl2 at -78° C. was added slowly a solution of diisobutylaluminum hydride 1.5M in toluene (99 mL, 149 mmol) and the mixture was stirred at -78° C. for 30 min. 2M Tartaric acid was then added and the solution was neutralized with 10 N NaOH. The product was extracted in EtOAc, dried over Na2SO4, and concentrated to give 26.90 g, 96%, of the title alcohol.
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]2[CH2:17][CH2:16]2)[CH:10]=1)(C)C)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O.O>[CH:15]1([C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C2CC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Oc1cccc(C2CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
To a solution of tert-butyl-(3-cyclopropyl-phenoxy)-dimethyl-silane (390 mg, 1.57 mmol) in THF (5 mL) was added a solution of 1M-TBAF (in THF, 2 mL, 1.3 mmol), and the mixture was stirred for 30 min at room temperature. The residue was diluted with EtOAc and water. The organic layer was washed with saturated ammonium chloride, water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 3-cyclopropyl-phenol (200 mg, 95%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:18]([O:22][C:23]([N:25]([CH2:27][C:28](O)=[O:29])[CH3:26])=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]([CH2:27][C:28]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:29])[CH3:26])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: Cc1ccc(Cn2cnc(N)c2C(N)=O)cc1
Product: Cc1ccc(Cn2cnc(NC(=O)CN(C)C(=O)OC(C)(C)C)c2C(N)=O)cc1
Yield: 60 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 17, using 1.61 g (6.99 mmol) of 4-amino-1-(4-methylbenzyl)-5-imidazolecarboxamide prepared in the same manner as in Example 87 and 2-(N-t-butyloxycarbonyl-N-methylamino)acetic acid instead of 3-pyridylacetic acid hydrochloride to obtain 1.70 g of 4-(2-(N-t-butyloxycarbonyl-N-methylamino)acetylamino)-1-(4-methylbenzyl)-5-imidazolecarboxamide (yield 60%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=O)[CH2:12][CH2:13][CH2:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=[O:26])[CH3:25])[CH:19]=2)=O)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[C:28]([NH:31][NH2:32])([NH2:30])=[NH:29].[ClH:33]>CO.Cl.Cl.NNC(N)=N>[ClH:33].[ClH:33].[C:28]([NH:31][N:32]=[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24](=[O:26])[CH3:25])[CH:19]=1)[CH2:14][CH2:13][CH2:12][C:11](=[N:32][NH:31][C:28](=[NH:29])[NH2:30])[NH:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1)(=[NH:30])[NH2:29]
Reactant: N=C(N)NN
Reactant: CC(=O)c1cccc(NC(=O)CCCC(=O)Nc2cccc(C(C)=O)c2)c1
Agent: Cl
Solvent: CO
Product: CC(=O)c1cccc(NC(CCCC(=NNC(=N)N)Nc2cccc(C(C)=O)c2)=NNC(=N)N)c1
Yield: 98.2 %

Procedure:
N,N′-bis(3-acetylphenyl)pentanediamide (3.66 g), aminoguanidine hydrochloride (2.75 g), and aminoguanidine dihydrochloride (0.05 g) were heated in methanol (35 mL) for 18 hr. Cooling and filtration gave 5.412 g of N,N′-bis(3-acetylphenyl)pentanediamide bis(amidinohydrazone) dihydrochloride, mp 187-191° C.
Reaction SMILES: [CH:1]1([C:7]2([CH3:10])[CH2:9][O:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C-]#N.[Na+]>>[CH:1]1([C@@:7]2([CH3:10])[CH2:9][O:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C2CCCCC2)CO1
Agent: [C-]#N
Agent: [Na+]
Product: C[C@]1(C2CCCCC2)CO1
Temperature: 24 °C
Reaction time: 24 h
Yield: 52.7 %

Procedure:
200 mg (1.42 mmol) of racemic 2-cyclohexyl-2-methyloxirane was dissolved in 25 mL Tris-SO4 buffer (200 mM, pH 7.5), followed by addition of purified enzyme (9 mg of halohydrin dehalogenase HheC in 1.2 ml buffer) and 35 mg (0.71 mmol) NaCN. The reaction mixture was stirred at room temperature (24° C.) and monitored by gas chromatography (GC). The reaction was stopped after 24 h and extracted three times with 15 mL ethylacetate. The combined organic phases were dried over Na2SO4 and the solvent was evaporated. The crude product was chromatographed on a silica gel 60 H using pentane/CH2Cl2 (4:6) as eluent, which yielded pure (S)-2-cyclohexyl-2-methyloxirane (105 mg, 52% yield, e.e. 71%) and (S)-3-cyclohexyl-3-butanenitrile (95 mg, 40% yield, e.e. 100%). Optical purities were determined by GC using a Chiraldex G-TA column (30 m×0.25 mm×0.25 μm). The NMR data were identical with those of synthesized racemic reference compounds.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([Cl:20])=[N:9][S:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=1)(=O)=O.O[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:24]([CH3:35])[C:23]=1[CH3:36]>>[Cl:20][C:8]1[C:7]([CH2:6][O:5][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:24]([CH3:35])[C:23]=2[CH3:36])=[C:11]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[S:10][N:9]=1
Reactant: CCc1ccc(-c2snc(Cl)c2COS(C)(=O)=O)cc1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Product: CCOC(=O)CCc1ccc(OCc2c(Cl)nsc2-c2ccc(CC)cc2)c(C)c1C

Procedure:
The title compound was prepared according to the procedure described in Example 127 following Step 6 by coupling [3-chloro-5-(4-ethylphenyl)-1,2-thiazol-4-yl]methyl methanesulfonate and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate to afford the desired product as a yellow oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)[S:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[CH2:26]1[O:38][C:37]2[CH:36]=[C:35]3[C:30]([CH2:31][CH2:32][NH:33][CH2:34]3)=[CH:29][C:28]=2[O:27]1>C(#N)C>[CH3:25][O:24][C:18]1[CH:17]=[C:16]([CH:7]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:33]2[CH2:32][CH2:31][C:30]3[CH:29]=[C:28]4[O:27][CH2:26][O:38][C:37]4=[CH:36][C:35]=3[CH2:34]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: c1c2c(cc3c1OCO3)CNCC2
Reactant: COc1ccc(C(CCCCCBr)Sc2ccc(C)cc2)cc1OC
Solvent: CC#N
Product: COc1ccc(C(CCCCCN2CCc3cc4c(cc3C2)OCO4)Sc2ccc(C)cc2)cc1OC
Yield: 91.7 %

Procedure:
The procedure of Example 46 is repeated using 3.67 g of 4-[6-bromo-1-[(4-methylphenyl)thio]hexyl]-1,2-dimethoxybenzene in 40 mL of acetonitrile and 2.65 g of 6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline. This affords 4.13 g of the desired product as a yellow gum.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>>[C:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([NH:18][C:4]2[CH:5]=[CH:6][C:7]([C:8](=[O:9])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])=[C:2]([NH2:1])[N:3]=2)[CH2:20][CH2:21]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: Nc1nc(Cl)ccc1C(=O)c1ccccc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(=O)c3ccccc3F)c(N)n2)CC1

Procedure:
The title compound was prepared from (2-Amino-6-chloro-pyridin-3-yl)-(2-fluoro-phenyl)-methanone (Example 7) and 4-amino-1-N-Boc-piperidine (Astatech, >96%) using the procedure described in Step B, Example 6. HRMS, observed: 415.2143, Calcd for (M+H)+: 415.2140.