Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18](I)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O1CCOCC1.[CH3:26][O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35].C([O-])([O-])=O.[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([C:31]4[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[C:33]([O:34][CH3:35])[CH:32]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: COc1ccc(-c2nn3c(I)cnc3s2)cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(-c2nn3c(-c4ccc(OC)c(OC)c4)cnc3s2)cc1OC
Temperature: 120 °C
Yield: 21.8 %

Procedure:
A mixture of 2-(3,4-dimethoxy-phenyl)-5-iodo-imidazo[2,1-b][1,3,4]thiadiazole (0.10 g, 0.3 mmol, 1 eq), dioxane (5 mL), 3,4-dimethoxyphenylboronic acid (0.12 g, 0.6 mmol, 2.5 eq), Pd(Ph3P)2Cl2 (0.018 g, 0.1 eq), K2CO3 (0.178 g, 1.3 mmol, 5 eq) and water (2 mL) was heated in the microwave oven (120° C., 30 min). The reaction mixture was concentrated, and the residue was purified by column chromatography (SiO2, cyclohexane/5-100% EtOAc). The obtained product was triturated with MeOH/Et2O to give the desired product (yellow solid, 0.026 g, 26%). HPLC-MS: (5-100% B in 10 min, 0.6 mL/min, 50° C.): tR=7.24 min, [M+H]+ m/z 398.1; 1H NMR (300 MHz, DMSO) δ/ppm 7.74 (s, 1H), 7.70 (d, J=2.0, 1H), 7.61 (dd, J=2.0, 8.4, 1H), 7.57-7.50 (m, 2H), 7.17 (d, J=8.2, 1H), 7.09 (d, J=8.5, 1H), 3.88 (s, 6H), 3.86 (s, 3H), 3.81 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]([CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:4].Cl.[NH:29]1[CH:33]=[C:32]([CH2:34][C:35](O)=[O:36])[N:31]=[CH:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:31]1[C:32]([CH2:34][C:35]([NH:1][CH:2]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:3]([NH:5][C:6]2[CH:7]=[CH:8][C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][CH:11]=2)=[O:4])=[O:36])=[CH:33][N:29]=[CH:30]1
Reactant: NC(COCc1ccccc1)C(=O)Nc1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)Cc1c[nH]cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1cnc[nH]1)NC(COCc1ccccc1)C(=O)Nc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.7 %

Procedure:
A flask was charged with 2-amino-3-benzyloxy-N-(4-phenoxyphenyl)propanamide (150 mg, 0.42 mmoles), prepared as in Reference 5, 1H-imidazol-4-ylacetic acid hydrochloride (81 mg, 0.50 mmoles), HATU (188 mg, 0.50 moles) and DMF (1 mL). DIEA (370 μL, 2.1 mmoles) was added and the mixture was stirred at ambient temperature for 18 hours. The reaction mixture was partitioned between ethyl acetate and deionized H2O. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layer was washed with 5% lithium chloride (3×5 mL), 1N sodium bicarbonate (2×5 mL) and then deionized water (2×5 mL) and concentrated in vacuo. Product was purified from the residue by preparative HPLC (ammonium acetate/acetonitrile). The purified product was taken up into methanol and the solution was neutralized with basic resin, filtered and concentrated in vacuo to give Compound 142, 2-(2-(1H-imidazol-5-yl)acetamido)-3-benzyloxy-N-(4-phenoxyphenyl)propanamide (118 mg, 60% yield), as a white solid. 1H-NMR (400 MHz, CDCl3): 9.23 (s, 1H), 7.53-7.40 (m, 4H), 7.35-7.27 (m, 6H), 7.08 (t, 1H), 7.00-6.92 (m, 3H), 6.87 (s, 1H), 4.77 (m, 1H), 4.55 (dd, 2H), 4.18 (dd, 1H), 3.70-3.58 (m, 3H). MS (EI) for C27H26N4O4. found 471.0 (MH+).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH:10]([N:15]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:23]4[CH:32]=[CH:31][C:30]5[CH2:29][CH2:28][CH2:27][NH:26][C:25]=5[N:24]=4)[C:16]3=[O:33])[CH2:11][C:12]([OH:14])=[O:13])[CH:8]=2)[CH:3]=[CH:2]1>C(O)(=O)C.O=[Pt]=O>[O:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH:10]([N:15]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][C:23]4[CH:32]=[CH:31][C:30]5[CH2:29][CH2:28][CH2:27][NH:26][C:25]=5[N:24]=4)[C:16]3=[O:33])[CH2:11][C:12]([OH:14])=[O:13])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)CC(c1cnc2ccoc2c1)N1CCN(CCCc2ccc3c(n2)NCCC3)C1=O
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: O=C(O)CC(c1cnc2c(c1)OCC2)N1CCN(CCCc2ccc3c(n2)NCCC3)C1=O
Reaction time: 1 h

Procedure:
A solution of 24-4 (181 mg, 0.38 mmol) in acetic acid (5 mL) was treated with PtO2 (100 mg) and stirred under a hydrogen atmosphere for 1 h. The catalyst was removed by filtration through celite and the residue chromatographed (75% 20:1:1 EtOH/NH4OH/H2O-25% EtOAc) to afford 24-5 as a colorless glass.
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[N:18]1([C:24]2[C:32]3[N:31]=[C:30]([C:33]([F:36])([F:35])[F:34])[NH:29][C:28]=3[CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C(OCC)(=O)C>[F:36][C:33]([F:34])([F:35])[C:30]1[NH:31][C:32]2[C:24]([N:18]3[CH2:19][CH2:20][N:21]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:8]4[N:9]=[C:10]5[C:5]([CH2:4][CH2:3][C:2](=[O:1])[NH:11]5)=[CH:6][CH:7]=4)[CH2:22][CH2:23]3)=[CH:25][CH:26]=[CH:27][C:28]=2[N:29]=1
Reactant: FC(F)(F)c1nc2c(N3CCNCC3)cccc2[nH]1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc5nc(C(F)(F)F)[nH]c45)CC3)nc2N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.7 %

Procedure:
To a suspension of 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yloxy)-butyraldehyde (0.297 g, 1.266 mmol, 1.32 eq) and 4-piperazin-1-yl-2-trifluoromethyl-1H-benzoimidazole (0.258 g, 0.953 mmol, 1 eq) in dichloroethane (5 mL) was added NaBH(OAc)3 (0.723 g, 3.413 mmol, 3.58 eq). The slurry was allowed to stir overnight at room temperature (18 h). Analysis by HPLC showed reaction mostly complete. The mixture was diluted with Ethyl Acetate and quenched with saturated NaHCO3. The organic phase was then washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. Purification by silica gel chromatography (2% MeOH/CH2Cl2) followed by formation of the HCl salt using 1N HCl in ether provided the title compound (0.166 g, 35%). MS: APCI: M+1: 489.2 (Exact Mass: 488.21).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Br[C:6]1[N:10]([C@@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[C@H:13]([OH:18])[CH2:12]2)[C:9]2[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:8]=2[N:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH:1]([NH:4][C:6]1[N:10]([C@@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[C@H:13]([OH:18])[CH2:12]2)[C:9]2[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:8]=2[N:7]=1)([CH3:3])[CH3:2]
Reactant: O[C@@H]1C[C@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)CC[C@@H]1O
Reactant: CC(C)N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)Nc1nc2cc(Cl)c(Cl)cc2n1[C@@H]1CC[C@H](O)[C@H](O)C1
Temperature: 100 °C
Yield: 7.5 %

Procedure:
Isopropylamine (227.8 mg, 3.85 mmol) was added to (±)-(1S*,2R*,4R*)-4-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)cyclohexane-1,2-diol (Example 51, part b, 146.5 mg, 385.4 mmol) in ethanol (3.9 ml) and the reaction was heated at 100° C. in a sealed tube for 68 hr. The reaction was cooled, saturated sodium carbonate added, extracted with ethyl acetate, dried with magnesium sulfate, and concentrated. The residue was purified by column chromatography eluting with methanol:ethyl acetate (1:19) to give the title compound (104.1 mg, 75%). Rf=0.20 (1:19 methanol:ethyl acetate); 1H-NMR (CD3OD, 300 MHz) δ7.53 (s, 1H), 7.36 (s, 1H), 4.31 (tt, 1H, J=13, 4), 4.06 (h, 1H, J=7), 3.97 (s, 1H), 3.75-3.68 (m, 1H), 2.50 (q, 1H, J=12), 2.39 (dq, 1H, J=13, 4), 2.02-1.96 (m, 1H), 1.78-1.49 (m, 3H), 1.29 (d, 3H, J=7), 1.28 (d, 3H, J=7); MS (ES) M+H=358.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:20])[C:9](N2[C@H](C(C)C)COC2=O)=[O:10])=[CH:4][CH:3]=1.[OH:21]O.[Li+].[OH-]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([CH3:20])[C:9]([OH:10])=[O:21])=[CH:6][CH:7]=1
Reactant: OO
Reactant: CC(C)[C@@H]1COC(=O)N1C(=O)[C@H](C)c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](C(=O)O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a solution of (4R)-3-[(2R)-2-(4-fluorophenyl )propanoyl]-4-isopropyl-1,3-oxazolidin-2-one (2.59 g, 9.28 mmol) in 160 mL THF/H2O (3:1) at 0° C., was added 30% H2O2 (8.4 mL, 74.2 mmol) followed by LiOH (780 mg, 18.6 mmol). The resulting mixture was stirred at 0° C. for 2 h and the excess peroxide was quenched at 0° C. with 1.5 N aqueous Na2SO3 (54 mL). After buffering to pH 9–10 with aqueous NaHCO3 and evaporation of the THF, the oxazolidone chiral auxiliary was recovered by EtOAc extraction (50 mL×3). The aqueous layer was acidified with 3N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 1.43 g (8.51 mmol, 92%) of (2R)-2-(4-fluorophenyl)propanoic acid; [α]D=−61.5° (C=1.04, MeOH): 1H NMR (400 MHz, CDCl3) δ 12.2–11.4 (br, 1H), 7.31–7.24 (m, 2H), 7.04–6.97 (m, 2H), 3.72 (q, 1H, J=7.3 Hz), 1.49 (d, 3H, J=7.3 Hz); ESMS m/e: 167.2 (M−H)+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:40])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])=[CH:9][CH:8]=1.Cl>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:40])=[O:4])=[CH:8][CH:9]=2)=[C:14]([CH3:39])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:33])([CH3:34])[CH3:32])=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.296 mL, 0.296 mmol) was added to a solution of (4′-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 51-(1); 54.8 mg, 0.106 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and the mixture was stirred at 60° C. for two hours. The reaction mixture was then poured into 0.5 N hydrochloric acid aqueous solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (52 mg, 98%).
Reaction SMILES: C([SiH](CC)CC)C.[C:8]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([Br:27])=[CH:22][C:21]=2[F:28])=[CH:16][CH:15]=1)(=O)[CH2:9][CH2:10][CH2:11][CH3:12].C([O-])(O)=O.[Na+]>FC(F)(F)C(O)=O>[CH2:8]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[C:24]([F:26])[C:23]([Br:27])=[CH:22][C:21]=2[F:28])=[CH:16][CH:15]=1)[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC(=O)c1ccc(-c2cc(F)c(Br)cc2F)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCCCCc1ccc(-c2cc(F)c(Br)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylsilane (7.0 g) is added dropwise over 2 h to a cooled, stirred (0° C.) solution of 1E (8.0 g) in trifluoroacetic acid (40 ml). The reaction mixture is stirred at room temperature overnight and poured into NaHCO3 solution. The product is extracted into ether twice and the combined ether layers are washed with water and dried (MgSO4). The solvent was removed in vacuo to yield an orange-brown oil. The crude product is distilled under reduced pressure (short path, 110°-120° C. at 0.01 mm Hg) to give a red oil.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[CH2:5][CH:6]([NH:13][CH2:14][CH2:15][CH3:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:21](C(CC)(CC)C([O-])([O-])[O-])[CH3:22]>>[ClH:1].[CH3:21][C:22]1[N:13]([CH2:14][CH2:15][CH3:16])[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[CH:20][C:3]=2[N:2]=1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: CCCNC(Cc1ccccc1N)c1ccccc1
Agent: Cl
Product: CCCN1C(C)=Nc2ccccc2CC1c1ccccc1

Procedure:
90 ml of Ethanolic hydrogen chloride is added dropwise to a stirred suspension of 9.00 g of 2-amino-α-phenyl-N-propylphenethylamine in 90 ml of triethylorthoacetate. After complete addition, the mixture is refluxed for 2 hours. The ethanol is slowly distilled from the mixture and additional ethanolic hydrogen chloride (50 ml) is added. The mixture is then distilled to a volume of 20-30 ml. 100 ml of ether is added causing precipitation of the hydrochloride salt. The salt is collected, washed with ether (100 ml) and dried to give white crystals, mp 272°-275° C. of 4,5-dihydro-2-methyl-4-phenyl-3-propyl-3H-1,3-benzodiazepine hydrochloride.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]([O:36][C:37]([N:39]1[CH2:42][CH2:41][C@H:40]1[CH2:43][OH:44])=[O:38])([CH3:35])([CH3:34])[CH3:33].[Br:45][C:46]1[CH:47]=[N:48][CH:49]=[C:50](O)[CH:51]=1>C1COCC1>[Br:45][C:46]1[CH:51]=[C:50]([O:44][CH2:43][C@@H:40]2[CH2:41][CH2:42][N:39]2[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH:49]=[N:48][CH:47]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Reactant: Oc1cncc(Br)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(Br)c1
Reaction time: 0.17 h

Procedure:
Triphenylphosphine (4.01 g, 15.3 mmol) and DEAD (2.43 mL, 15.3 mnol) were dissolved in 30 mL of THF at 0° C., and the mixture was stirred for 10 minutes. Samples of 1-t-butyloxycarbonyl-2-(S)-azetidinemethanol (2.86 g, 15.3 mmol, Step 7c above) and 3-bromo-5-hydroxypyridine.(1.51 g, 10.2 mmol, Step 10c above) were added, and the mixture was stirred for 40 hours at room temperature. The volatile components were removed under vacuum, and the residue was triturated with hexane. The separated hexane fraction was concentrated, and the residue was chromatographed (silica gel; hexane/ether, 10:1 to 10:2) to afford 5-bromo-3-((1-t-butyloxycarbonyl-(2S)-azetidinyl)methoxy)pyridine as a colorless oil (1.669 g): 1H NMR (CDCl3, 300 MHz) δ 1.42 (s, 9H), 2.31 (m, 2H), 3.89 (m, 2H), 4.12 (m, 1H), 4.322 (m, 1H), 4.52 (m, 1H), 7.43 (m, 1H), 8.29 (m, 2H); MS (CI/NH3) m/z 344 (M+H)+. The 5-bromo-3-(2-(1-BOC-2-(S)-azetidinyl)methoxy)pyridine was treated with with 4 M HCl in dioxane to give the free base of the title compound. This was converted to the dihydrochloride salt and recrystallized from methanol/ether to provide the title compound: mp 163-165° C.; [α]25D -5.1 (c 0.57, methanol); 1H NMR (D2O, 300 MHz) δ 8.36 (d, J=1.8 Hz, 1H), 8.32 (d, J=2.6 Hz, 1H), 7.84 (dd, J=1.8, 2.6 Hz, 1H), 4.98-4.90 (m, 1H), 4.43 (d, J=4.0 Hz, 2H), 4.20-4.02 (m, 2H), 2.67 (q, J=8.5 Hz, 2H); MS (CI/NH3) m/z 243/246 (M+H)+, 260/262 (M+NH4)+. Anal. calcd for C9H13N2OBrCl2 : C, 34.21; H, 4.15; N, 8.86. Found: C, 34.18; H, 4.17; N, 8.89.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:20])=[CH:4][N:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][OH:34].O1CCCC1>O>[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][O:34][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:20])=[CH:4][N:3]=1
Reactant: OCc1ccccn1
Reactant: COc1ccc(CNc2nc(Cl)ncc2C(=O)c2ccccn2)cc1Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CNc2nc(OCc3ccccn3)ncc2C(=O)c2ccccn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2-chloro-4-(3-chloro-4-methoxybenzylamino)-5-(2-pyridylcarbonyl)pyrimidine (prepared in Example 90-(3)) 110 mg, 2-pyridinemethanol 34 mg, 10% sodium hydride 12 mg and tetrahydrofuran 3 ml is stirred at room temperature for 5 minutes. The reaction mixture is poured into water and extracted with ethyl acetate. The organic layer is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel chromatography (solvent: ethyl acetate) and triturated with ethyl ether to give 2-(2-pyridylmethoxy)-4-(3-chloro-4-methoxybenzylamino)-5-(2-pyridylcarbonyl)pyrimidine, 104 mg. mp 81–84° C., MS(m/z): 462(M+H)+
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:17]#[C:18][Si](C)(C)C)[CH:6]=[C:7]2[C:12]=1[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]2([CH3:16])[CH3:15])[CH3:2].CO.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CCCCCC>[CH2:1]([C:3]1[CH:4]=[C:5]([C:17]#[CH:18])[CH:6]=[C:7]2[C:12]=1[O:11][C:10]([CH3:13])([CH3:14])[CH2:9][C:8]2([CH3:16])[CH3:15])[CH3:2]
Reactant: CCc1cc(C#C[Si](C)(C)C)cc2c1OC(C)(C)CC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: C#Cc1cc(CC)c2c(c1)C(C)(C)CC(C)(C)O2

Procedure:
Following general procedure E and using 8-ethyl-6-trimethylsilanylethynyl-2,2,4,4-tetramethyl chroman (Intermediate 47, 0.137 g, 0.44 mmol), methanol and potassium carbonate (0.1 g, 0.72 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.066 g, 62%).
Reaction SMILES: [CH3:1][C:2]([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][N:10]=1)([CH3:5])[CH2:3][NH2:4].[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[N:20]=1>>[CH3:5][C:2]([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][N:10]=1)([CH3:1])[CH2:3][NH:4][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][CH:32]=[C:24]([C:21]2[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=2)[CH:25]=1
Reactant: CC(C)(CN)c1ncc(-c2ccccc2)s1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1ncc(-c2ccccc2)s1
Yield: 17 %

Procedure:
This compound was synthesized from 2-methyl-2-(5-phenylthiazol-2-yl)propan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (20 mg, yield 17%). 1H NMR (400 MHz, MeOD) δ 8.55 (m, 1H), 8.29-8.27 (m, 1H), 8.03-8.01 (m, 1H), 7.96 (s, 1H), 7.98 (s, 1H), 7.71-7.67 (t, J=7.8 Hz, 1H), 7.63-7.61 (m, 2H), 7.43-7.39 (m, 2H), 7.35-7.32 (m, 1H), 3.75 (s, 2H), 1.56 (s, 6H). MS (ESI) m/z: Calculated for C23H19F3N4O2S: 472.12. found: 473.1 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[N:4][C:5]([N:10]([CH3:12])[CH3:11])=[N:6][C:7]=1[O:8][CH3:9].C(N)CN.[Li]CCCC.C[O:33]B(OC)OC.OO.Cl>C1COCC1.O>[CH2:13]([C:3]1[C:2]([OH:33])=[C:7]([O:8][CH3:9])[N:6]=[C:5]([N:10]([CH3:12])[CH3:11])[N:4]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCc1nc(N(C)C)nc(OC)c1Br
Reactant: COB(OC)OC
Agent: Cl
Agent: OO
Agent: [Li]CCCC
Solvent: NCCN
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCc1nc(N(C)C)nc(OC)c1O
Temperature: -5 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution at −5° C. containing 500 mg (1.34 mmol) of 5-bromo-4-decyl-6-methoxy-N,N-dimethylpyrimidin-2-amine in 10 mL of anhydrous THF were added 202 μL (1.34 mmol) of N,N,N,N-tretamethyl ethylenediamine followed by 2.09 mL (3.35 mmol) of 1.6 M solution of n-BuLi in hexanes. The reaction mixture was stirred at −5° C. for 20 min. Then to the mixture were added 440 μL (4.02 mmol) of trimethoxy boron and the reaction mixture was stirred at 23° C. for 1 h. Then to reaction mixture were added 3.46 mL of 30% aq H2O2. The reaction mixture was then stirred for 30 min and poured into 100 mL of water. The mixture was neutralized with diluted aq. HCl and extracted with two 100-mL portions of ethyl acetate. The combined organic solution was washed with a 100-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (10×3 cm). Elution with 4:1 hexanes-ethyl acetate afforded the expected product as white solid: yield 111 mg (27%); mp: 59-60° C.; silica gel TLC Rf=0.60 (4:1 hexanes-ethyl acetate); 1H-NMR (methanol-d4) δ 0.87 (t, 3H, J=6.4 Hz), 1.33-1.24 (br m, 14H), 1.62 (quint, 2H, J=7.2 Hz), 2.58 (dd, 2H, J=7.6, 7.6 Hz), 3.09 (s, 6H) and 3.91 (s, 3H); 13C NMR (methanol-d4) δ 13.05, 22.32, 27.62, 29.05, 29.15, 29.17, 29.29, 29.31, 30.58, 31.67, 36.32, 36.32, 52.23, 126.96, 155.92, 155.94 and 159.48.
Reaction SMILES: CN1[C@H]2[C@@H](C(OC)=O)[C@@H]([O:10][C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:12])C[C@@H]1CC2.CN1[C@H]2[C@@H](C(OC)=O)[C@@H](OC(C3C=CC=CC=3)=O)C[C@@H]1CC2.Cl.P(=O)(O)(O)O>C1N(CCCS(O)(=O)=O)CCOC1>[C:11]([OH:12])(=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)[C@H]1[C@@H](OC(=O)c2ccccc2)C[C@@H]2CC[C@H]1N2C
Agent: Cl
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)CCCN1CCOCC1
Product: O=C(O)c1ccccc1

Procedure:
Cocaine esterase in extracts, column fractions and characterisation experiments (e.g. pH optimum, Michaelis constant determinations) was routinely assayed by shaking incubation (250 rpm, 30° C.) of 2 mM cocaine HCl (made up in 1 ml 50 mM MOPS buffer, pH 7.0) with a known quantity of sample (10-200 μl, 0-0.01 U) for a fixed length of time (10-30 min). The reaction was stopped by the addition of 10 μl of concentrated phosphoric acid and protein pelleted at 13,000 rpm in a minifuge. The amount of benzoic acid produced was determined by HPLC analysis of 50 μl of the supernatant and comparison to standard samples (0-1 mM) treated identically. Standard curves of peak height plotted against benzoic acid concentration were linear over the range 0-1 mM. Controls containing no enzyme solution were run to allow for background hydrolysis. An assay was considered invalid if no cocaine remained at the end of the assay (seen by HPLC). One unit of esterase activity is defined as the amount of enzyme required to produce 1 μmol of benzoic acid in 1 min at 30° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:15]N(C=O)C.IC.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: Cc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Product: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a stirred solution of 5-chloro-2-methyl-3-nitrobenzoic acid (1 equiv.) in DMF (3 ml per 1 mmol), iodomethane (4 equiv.) and sodium carbonate (4 equiv.) were added. The resulting reaction mixture was stirred at 60° C. for 8 h. On completion, the reaction mixture was filtered and the inorganic solid residue washed with ethyl acetate. The combined filtrate was concentrated under vacuum till dryness. The residue was re-dissolved in ethyl acetate and washed with 5% sodium bicarbonate solution followed by 5M HCl solution. Organic layer was finally washed with brine, dried over sodium sulfate and concentrated to afford pure methyl 5-chloro-2-methyl-3-nitrobenzoate (90-95%).