Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:16])=[CH:10][CH:9]=1.Br[CH2:26][C:27]([O:29][CH3:30])=[O:28]>CC(C)=O>[C:20]([O:19][C:18]([NH:17][C@H:15]([CH3:16])[CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:9][CH:10]=1)=[O:24])([CH3:23])([CH3:22])[CH3:21]
Reactant: C[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C[C@@H](C)NC(=O)OC(C)(C)C)cc1

Procedure:
Potassium carbonate (1.95 g, 14.2 mMol) was added to a solution of (R)-2-(4-hydroxyphenyl)-1-methylethylcarbamic acid, t-butyl ester (2.96 g, 11.8 mMol) in acetone (50 ml) at room temperature under argon. Methyl bromoacetate (1.81 g, 11.8 mMol) was added dropwise and the reaction mixture was heated at reflux for 3 hours. The solvent was removed under reduced pressure and the residue was taken into ethyl acetate and washed with water (2×30 ml). The organic extracts were dried with sodium sulfate and the solvent evaporated in vacuo. The crude product was purified by chromatography on Kieselgel 60 (eluting with 20% ethyl acetate in pentane) to give the title compound as an oil.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:14][C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[C:18]([CH3:29])[CH:17]=1)[C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:6]=2[N:5]=1.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>O1CCCC1>[C:38]([NH:1][CH2:2][C@H:3]([NH:14][C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[C:18]([CH3:29])[CH:17]=1)[C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:6]=2[N:5]=1)(=[O:40])[CH3:39]
Reactant: Cc1cc(C(=O)N[C@@H](CN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
170 mg (0.4 mmol) of (1S)—N-[2-amino-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzamide is placed in 3.4 mL of tetrahydrofuran, while being cooled in the ice bath with 0.1 mL (0.6 mmol) of triethylamine and then combined with 0.05 g (0.45 mmol) of acetic anhydride. Then the mixture is heated to ambient temperature and stirred for 24 hours. Then the solvent is eliminated in vacuo and the residue purified by chromatography (gradient: dichloromethane/methanol=100:2). Yield: 23.5 mg (13%); Rf value: 0.28 (silica gel; dichloromethane/methanol=95:5); C24H26ClN5O3 (467.95); mass spectrum: (M+H)+=468/470 (chlorine isotope).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][C:10]([CH3:18])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]([CH3:18])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(C)nn1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)O)n(-c2ccc(F)cc2)n1
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
Ethyl 1-(4-fluorophenyl)-3-methylpyrazole-5-carboxylate (2 g) was dissolved in a mixed solvent of ethanol (10 ml) and water (10 ml) and sodium hydroxide (0.4 g) was added. The mixture was stirred at a refluxing temperature for 30 min. Ethanol was evaporated and to the residue was added dilute hydrochloric acid. The obtained solid was recrystallized from aqueous methanol solution to give the title compound (1.4 g), melting point: 188° C.
Reaction SMILES: IC.[Cl:3][C:4]1[CH:25]=[CH:24][C:7]([CH2:8][NH:9][C:10]([C:12]2[C:13](=[O:23])[C:14]3[CH:21]=[C:20]([I:22])[CH:19]=[N:18][C:15]=3[NH:16][N:17]=2)=[O:11])=[CH:6][CH:5]=1.[CH2:26](N(CC)CC)C>C(#N)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10]([C:12]2[C:13](=[O:23])[C:14]3[CH:21]=[C:20]([I:22])[CH:19]=[N:18][C:15]=3[N:16]([CH3:26])[N:17]=2)=[O:11])=[CH:24][CH:25]=1
Reactant: CCN(CC)CC
Reactant: O=C(NCc1ccc(Cl)cc1)c1n[nH]c2ncc(I)cc2c1=O
Solvent: CI
Solvent: CC#N
Product: Cn1nc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(I)cnc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Iodomethane (0.6 mL) is added to a mixture of N-(4-chlorobenzyl)-6-iodo-4-oxo-1,4-dihydropyrido[2,3-c]pyridazine-3-carboxamide (Preparation 22, 0.196 g) and triethyl-amine (70 μL) in acetonitrile (10 mL) and the mixture is stirred at room temperature for 48 h. The reaction mixture is concentrated, and the residue is dissolved in chloroform and water. The organic phase is dried (Na2SO4) and concentrated in vacuo. The crude product is purified by flash chromatography on silica gel (240-400 mesh, 7 g) eluting with 2% methanol/chloroform. The product fractions are pooled and concentrated in vacuo to give 0.16 g of the title compound as a yellow solid. Physical characteristics: mp 207-208° C.; 1H NMR (400 MHz, CDCl3) δ 4.39, 4.70, 7.33, 9.0, 9.1, 10.0; IR (drift) 1676, 1608, 1574, 1550, 1493, 1470, 1397, 1393, 1370, 1320, 1267, 1257, 812, 673, 666 cm−1; MS (EI) m/z 454 (M+, 61); HRMS (FAB) m/z 454.9767 (C16H12ClIN4O2+H). Anal. Found: C, 42.10; H, 2.61; N, 12.22.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:12][C:11]([Br:13])=[N:10][C:9]=1[CH3:14])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:19].O>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:15])[N:7]([C:8]1[S:12][C:11]([Br:13])=[N:10][C:9]=1[CH3:14])[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(Br)sc1NC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(Br)sc1N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of (2-bromo-4-methyl-thiazol-5-yl)-carbamic acid tert-butyl ester (2.93 g, 10 mmol) in DMF (50 mL) at 0° C. was added NaH (480 mg, 12 mmol, 60% dispersion in mineral oil) in one portion and the suspension was stirred for 1 h. Iodomethane (0.65 mL, 10.5 mmol) was added in one portion, and after 5 min the reaction mixture was warmed to ambient temperature and stirred for 5 h. Water and ethyl acetate were added and the resulting biphasic mixture was separated. The aqueous layer was extracted one time with ethyl acetate. The combined organic extracts were washed twice with brine, dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel chromatography (0-100% ethyl acetate/hexanes) to give the desired product as a clear oil (1.66 g, 54%): IR (KBr) 1688 cm−1; 1H NMR (300 MHz, CDCl3) δ 2.98 (s, 3H), 2.29 (s, 3H), 1.54 (s, 9H); ESIMS m/z 309 (M+2).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[C:5]=1[NH2:13]>C1COCC1.CO.[Pd]>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:13]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cccc(N)c1N

Procedure:
A mixture of 2-amino-3-nitro-benzoic acid methyl ester (8.0 g, 40.8 mmol) with 10% Pd/C (800 mg) in THF (60 mL) and methanol (60 mL) was rocked under a hydrogen atmosphere (45 psi) for 45 min. Fitration and concentration afforded 2,3-diamino-benzoic acid methyl ester as a tan solid, that was used without further purification. 2-Acetoxymethyl-1H-benzoimidazole-4-carboxylic Acid Methyl Ester
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:20][NH:21][C:22](=[O:35])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O)C1C=CC=CC=1.C(O)(=O)C.[H][H]>CO.[Pd]>[C:16]([O:15][C:13](=[O:14])[C@@H:12]([NH2:11])[CH2:20][NH:21][C:22](=[O:35])[C:23]1[CH:24]=[CH:25][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:28]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)cc1

Procedure:
6.88 g (14.2 mmol) of tert-butyl (2S)-2-benzyloxycarbonylamino-3-(4-(2-methoxycarbonyl-ethyl)-benzoylamino)propionate was dissolved in 200 ml of methanol and 852 mg (14.2 mmol) of acetic acid was added. The mixture was hydrogenated for 7 hours at room temperature over Pd/C (5% strength) at 1 bar of hydrogen. The mixture was filtered and the solvent was removed in vacuo. The residue was washed with n-heptane and dried in vacuo. Yield 6.9 g. MS (ES+): m/e=351.2 (M+H+).
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]>CO.N1C(C)=CC=CC=1C>[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=[N:2][OH:3])[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: NO
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)Nc2ccc(Cl)cn2)cc1Cl
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: CO
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=NO)CC2)C(=O)Nc2ccc(Cl)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
A solution of hydroxylamine hydrochloride (26.0 mg, 0.36 mmol) in methanol (0.7 mL) and 2,6-lutidine (0.7 mL) was treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyridin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (prepared as in Example 63, 114 mg, 0.24 mmol). The reaction mixture was stirred at 25° C. for 30 min and was then concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water (1×5 mL), dried over magnesium sulfate, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 65/35 hexanes/ethyl acetate to 2/8 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyridin-2-yl)-3-(4-hydroxyimino-cyclohexyl)-propionamide (105 mg, 90%) was a white powder: [α]23589=−23.03° (c=0.33 chloroform); EI-HRMS m/e calcd for C21H23Cl2N3O4S (M+H)+ 484.0859, found 484.0862.
Reaction SMILES: Cl[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]=1[C:9]([C:11]1[C:20]([Cl:21])=[C:19]2[C:14]([C:15]([CH3:25])([CH3:24])[CH2:16][CH2:17][S:18]2(=[O:23])=[O:22])=[CH:13][CH:12]=1)=[O:10].[C:26]1([SH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.O>O1CCCC1>[Cl:21][C:20]1[C:11]([C:9]([C:3]2[C:4](=[O:8])[CH2:5][CH2:6][CH2:7][C:2]=2[S:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:10])=[CH:12][CH:13]=[C:14]2[C:19]=1[S:18](=[O:23])(=[O:22])[CH2:17][CH2:16][C:15]2([CH3:25])[CH3:24]
Reactant: CC1(C)CCS(=O)(=O)c2c1ccc(C(=O)C1=C(Cl)CCCC1=O)c2Cl
Reactant: Sc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)CCS(=O)(=O)c2c1ccc(C(=O)C1=C(Sc3ccccc3)CCCC1=O)c2Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.7 g (1.75 mmol) of 1-chloro-2-(8-chloro-4,4-dimethyl-1,1-dioxothiochroman-7-yl)carbonylcyclohex-1-en-3-one were dissolved in 10 ml of tetrahydrofuran, and 0.19 g (1.75 mmol) of thiophenol and 0.19 g (1.92 mmol) of triethylamine were added dropwise. The mixture was stirred at 25° C. for two hours and then stirred into water, extracted with ethyl acetate and the organic phases were extracted with 1N hydrochloric acid, dried and concentrated. This gave 0.8 g of beige crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.[CH3:9][C:10]([CH3:12])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClC(Cl)C.[OH-].[Na+]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][CH:10]([CH3:12])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: Nc1ccc(Cl)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)Nc1ccc(Cl)nc1
Reaction time: 24 h
Yield: 76.3 %

Procedure:
To a solution of 2-chloro-5-aminopyridine (500 mg, 3.88 mmol) and acetone (250 μL, 4.27 mmol) in dichloroethane (13 mL) was added NaBH(OAc)3 (989 mg, 4.66 mmol) and AcOH (330 μL, 5.82 mmol). The reaction was stirred for 24 hours and was diluted with 1N NaOH. The aqueous solution was washed with CH2Cl2 (3×). The combined organic solutions were dried (Na2SO4), filtered and concentrated. Purification by medium pressure chromatography eluting with a solvent gradient (2% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2) provided 505.2 mg of (6-chloro-pyridin-3-yl)-isopropyl-amine. 1H NMR (CD3OD) δ 7.64 (d, 1H), 7.10 (d, 1H), 6.99 (dd, 1H), 3.55 (m, 1H), 1.17 (d, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[N+:19]([O-])=O)=[CH:6][CH:5]=1.O.NN>CO.C(Cl)Cl.[Pd]>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[NH2:19])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CNc2ccc(C)cc2[N+](=O)[O-])cc1
Agent: [Pd]
Agent: NN
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(CNc2ccc(C)cc2N)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
A stirred solution 4-[(4-methyl-2-nitrophenylamino)methyl]benzoic acid methyl ester (7.0 g, 23 mmol,) in CH3OH was treated with 5% Pd/C (50% wet, 30% w/w) and hydrazine hydrate (5.8 g, 116 mmol). The reaction mixture was heated to reflux temperature for 2 h, cooled to room temperature and filtered through celite. The filtrate was evaporated to give a residue. The residue was dissolved in CH2Cl2, washed with water, dried over anhydrous Na2SO4 and evaporated to afford 4-[(2-amino-4-methylphenylamino)methyl]benzoic acid methyl ester, which was used in the next step without further purification. Yield: 93%. 1H NMR (400 MHz, CDCl3) 8.0 (d, J=8 Hz, 2H); 7.70 (d, J=8 Hz, 2H); 6.60 (m, 2H); 6.49 (d, 1H); 4.3 (s, 2H); 3.90 (d, 3H); 2.21 (s, 3H). LCMS (ESI+) 271 (MH+). A stirred solution of crude 4-[(2-amino-4-methylphenylamino)methyl]benzoic acid methyl ester (6 g, 22 mmol) in trimethylorthoformate was treated with formic acid (1.0 g), refluxed for 2 h, cooled to room temperature and evaporated under reduced pressure. The resultant residue was purified by column chromatography using 1% MeOH/CHCl3 to afford 4-[(5-methylbenzimidazol-1-yl)methyl]benzoic acid methyl ester Yield: 61%. 1H NMR (400 MHz, CDCl3): 8.0 (d, J=8 Hz, 1H); 7.93 (s, 1H); 7.62 (s, 1H); 7.26 (s, 1H); 7.21 (d, J=8 Hz, 2H); 7.08 (m, 2H); 5.39 (s, 2H); 3.90 (s, 3H); 2.47 (s, 3H). LCMS (ESI+) 281 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:34](=[O:39])[C:35]([O:37][CH3:38])=[O:36].C(N(CC)CC)C.O>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([C:34](=[O:39])[C:35]([O:37][CH3:38])=[O:36])[CH2:29][CH2:28]3)=[CH:23][CH:24]=2)=[O:18])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(=O)Cl
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(OCC3CCNCC3)cc2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C(=O)N1CCC(COc2ccc(C(=O)N3CCN(c4ccccc4C(C)(C)C)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)-4-{[4-(piperidin-4-ylmethoxy)phenyl]carbonyl}piperazine (0.44 g, 1.01 mmol), methyl chloro(oxo)acetate (0.153 g, 1.25 mmol) and triethylamine (0.279 mL, 2.0 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford a solid (0.527 g, 100%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[S:9][C:10]([NH2:13])=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O[CH:17]=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C>N1C=CC=CC=1.O>[N:1]1([CH2:7][C:8]2[S:9][C:10]([NH:13][CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:11][N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cnc(CN2CCOCC2)s1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)C(=CNc1cnc(CN2CCOCC2)s1)C(=O)OCC
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of 2-(morpholin-4-ylmethyl)-1,3-thiazol-5-amine (Preparation 27, 1.13 g) in pyridine (10 mL) at 45° C. is added diethyl ethoxymethylenemalonate (2.26 mL). The mixture is stirred overnight, diluted with water (100 mL), and extracted with EtOAc (3×75 mL). The organic layer is dried (MgSO4) and the solvent removed. The residue is purified by column chromatography (eluent 50% EtOAc/hexane) to afford 1.51 g (86%) of the title compound as a brown oil. Physical characteristics: 1H NMR (CDCl3) δ 1.27-1.37, 2.58, 3.72, 3.73, 4.20-4.30, 8.10, 11.02; IR (diffuse reflectance) 1687, 1637, 1596, 1416, 1337, 1301, 1274, 1268, 1243, 1234, 1114, 1094, 1011, 867, 801 cm−1; HRMS (FAB) m/z 370.1420 (C16H23N3O5S+H). Anal. Found: C, 51.80; H, 6.32; N, 11.26.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[N+:14]([C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]([OH:29])=O)([O-:16])=[O:15].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O.O1CCCC1>[CH2:30]([NH:37][C:27]([C:22]1[C:23]2[C:18](=[C:17]([N+:14]([O-:16])=[O:15])[CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:20][CH:21]=1)=[O:29])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cccc2c([N+](=O)[O-])cccc12
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCc1ccccc1)c1cccc2c([N+](=O)[O-])cccc12
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
Triethylamine (0.16 ml, 1.15 mmol) and ethyl chloroformate (0.11 ml, 1.115 mmol) were added to a suspension of 5-nitronaphthalene-1-carboxylic acid (250 mg, 1.15 mmol) and anhydrous tetrahydrofuran (3 ml) under ice cooling, and the mixture was stirred for 0.5 hour. Benzylamine (0.13 ml, 1.20 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction solution, and after the mixture was stirred for 10 minutes, the resulting precipitate was collected. The precipitate was washed with water and isopropyl ether, and dried to give the title compound as a light brown solid (189 mg, 53.5%).
Reaction SMILES: C([S:4][CH2:5][CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[C:16]([N+:28]([O-:30])=[O:29])[C:17](=[O:27])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7])(=O)C.C1COCC1.[Li+].[OH-].C(O)(=O)C>CO>[SH:4][CH2:5][CH:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[C:16]([N+:28]([O-:30])=[O:29])[C:17](=[O:27])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: CC(=O)SCC(C)[C@H]1CC[C@H]2[C@@H]3CCC4=C([N+](=O)[O-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: CC(CS)[C@H]1CC[C@H]2[C@@H]3CCC4=C([N+](=O)[O-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 50 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
The thioacetate prepared in Example 9A (65 mg, 0.15 mmol) was dissolved in 2 mL methanol and 1 mL THF with 0.3 mL of 1N LiOH. After stirring for 1 hour, 0.1 mL of acetic acid was added. The solution was extracted into ethyl acetate, washed with water and dried over magnesium sulfate. The product was dissolved into 1.0 ml acetic acid, heated to about 50° C. and concentrated in vacuo to give a light yellow solid (30 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[CH2:13][CH:12]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)[CH:8]=[CH:9][CH:10]=1.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:37]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]([Cl:22])([Cl:23])[Cl:24])=[O:18])[CH2:13][CH:12]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCC(c2cccc(OCCO)c2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C(Cl)c1ccccc1
Product: O=C(OCCOc1cccc(C2CCN(C(=O)OCC(Cl)(Cl)Cl)CC2OCc2ccc3ccccc3c2)c1)c1ccccc1

Procedure:
In an analogous manner to that described in Example 22(k), by acylating 2,2,2-trichloro-ethyl (3RS,4RS)-4-[3-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with benzoyl chloride there was obtained 2,2,2-trichloroethyl (3RS,4RS)-4-[3-(2-benzoyloxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil.
Reaction SMILES: [CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][C:20]=3[CH3:26])=[C:16]([F:27])[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1.[C:28]([Si](C)(C)C)#[CH:29]>C(#N)C.C(N(CC)CC)C.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.[Cu]I>[CH:1]1([CH2:4][O:5][NH:6][C:7]([C:9]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:28]#[CH:29])=[CH:21][C:20]=3[CH3:26])=[C:16]([F:27])[C:12]3[N:13]=[CH:14][NH:15][C:11]=3[CH:10]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)NOCC2CC2)cc2[nH]cnc2c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C#Cc1ccc(Nc2c(C(=O)NOCC3CC3)cc3[nH]cnc3c2F)c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
7-Fluoro-6-(4-iodo-2-methyl-phenylamino)-3H-benzoimidazole-5-carboxylic acid cyclopropylmethoxyamide 11ccc (0.025 g, 0.052 mmol) is dissolved in 1:1 acetonitrile/triethylamine (0.50 mL). Ethynyltrimethylsilane (0.013 mL, 0.092 mmol), Pd(PPh3)2Cl2 (0.004 g, 0.006 mmol), and CuI (0.002 g, 0.011 mmol) are added consecutively and the reaction mixture is stirred at 60° C. for 1 hour under N2. The reaction mixture is cooled to room temperature and concentrated under reduced pressure. The residue is purified by FCC (eluting with 20:1 methylene chloride:methanol) to yield 0.020 g (87%) of the desired product.
Reaction SMILES: Br[C:2]1[C:3]([CH3:18])=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C([Li])CCC.CN(C)[CH:26]=[O:27]>C1COCC1>[Si:8]([O:7][CH2:6][CH2:5][C:4]1[C:3]([CH3:18])=[C:2]([CH:17]=[CH:16][CH:15]=1)[CH:26]=[O:27])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: Cc1c(Br)cccc1CCO[Si](C)(C)C(C)(C)C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(C=O)cccc1CCO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A colourless solution of (3-bromo-2-methylphenethoxy)(tert-butyl)dimethylsilane [Aromatic Intermediate 22, step c] (2.06 g) in THF (40 mL) was cooled to −78° C. under an atmosphere of nitrogen and treated with butyllithium (2.1M in hexanes, 3.3 mL), added dropwise over 3 minutes. The resulting pale yellow solution was stirred at −78° C. for 30 minutes, treated with N,N-dimethylformamide (0.73 mL) added dropwise over 2 minutes to give a colourless solution, stirred at −78° C. for a further 30 minutes, then removed from the cooling bath and allowed to warm to room temperature over 45 minutes. The solution was quenched by the addition of 10% aqueous ammonium chloride (100 mL), and the resulting mixture was extracted twice with diethyl ether. The combined organic phases were washed with brine, dried over anhydrous magnesium sulphate and concentrated in vacuo to afford the titled compound as a pale yellow oil. Yield 1.74 g.