Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]3[C:16]([C:19]([O:21]CC)=[O:20])=[CH:17][N:18]=[C:12]3[CH:11]=2)[CH2:3][CH2:2]1.O.[OH-].[Li+:26]>O1CCCC1.O.O1CCCC1>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]3[C:16]([C:19]([O-:21])=[O:20])=[CH:17][N:18]=[C:12]3[CH:11]=2)[CH2:3][CH2:2]1.[Li+:26]
Reactant: CCOC(=O)c1cnc2cc(OCCN3CCOCC3)ccn12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])c1cnc2cc(OCCN3CCOCC3)ccn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 105.2 %

Procedure:
Ethyl 7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxylate (1 g, 3.13 mmol) was dissolved in tetrahydrofuran/water (4:1, 0.5 M). Lithium hydroxide monohydrate (131 mg, 3.13 mmol) was added and the mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with additional tetrahydrofuran and concentrated. Drying under high vacuum for 6 hours gave lithium 7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxylate as a pale yellow solid (979 mg).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](O)(=[O:23])[C:20]([CH3:22])=[CH2:21].CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[CH3:21][CH:20]1[C:19](=[O:23])[C:9]2[S:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[C:10]=2[CH2:22]1
Reactant: C=C(C)C(=O)O
Reactant: Cc1ccccc1-c1ccsc1-c1ccccc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: Cc1ccccc1-c1c(-c2ccccc2)sc2c1CC(C)C2=O
Reaction time: 0.08 h
Yield: 96.4 %

Procedure:
A mixture of 31.8 g of 2-phenyl-3-o-tolyl-thiophene (0.127 mol) and 13.3 ml of methacrylic acid (0.157 mol) was added within 30 minutes at about 80° C. to 500 ml of Eaton's reagent. On completion of the addition, the reaction mixture was stirred for a further 5 minutes and then gradually added to crushed ice. 300 ml of dichloromethane were added to dissolve the reaction product. The organic phase was removed, washed with a saturated aqueous solution of sodium hydrogencarbonate and dried over magnesium sulfate. After removing the solvent, 39 g of product (3) were obtained which, according to GC-MS, constituted a single, isomer and had a purity of 95%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:17][CH2:18][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)=[CH:7][CH:6]=1
Reactant: BrCCCc1ccc2ccccc2c1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCCc2ccc3ccccc3c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 20.5 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.01 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.262 g), stirred for 15 minutes and treated with 2-(3-bromopropyl)naphthalene (1.7 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material from dichloromethane extraction was purified by HPLC (dichloromethane-hexane; 4:1) and crystallized from diethyl ether-hexane to provide 0.4 g of 4-[[3-(2-naphthalenyl) propyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 97°-99° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@:7]([C:16]([NH:18][CH:19]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:20]([OH:33])[C:21]([F:32])([F:31])[CH:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:17])([CH:13]([CH3:15])[CH3:14])[NH:8][C:9]([O:11][CH3:12])=[O:10].[C:41]([CH2:45][C:46](Cl)=[O:47])([CH3:44])([CH3:43])[CH3:42].C(N(CC)CC)C>ClCCl>[C:41]([CH2:45][C:46]([NH:30][CH:22]([C:21]([F:32])([F:31])[CH:20]([OH:33])[CH:19]([NH:18][C:16](=[O:17])[C@:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH:13]([CH3:15])[CH3:14])[NH:8][C:9]([O:11][CH3:12])=[O:10])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:47])([CH3:44])([CH3:43])[CH3:42]
Reactant: COC(=O)N[C@@](C(=O)NC(Cc1ccccc1)C(O)C(F)(F)C(N)Cc1ccccc1)(c1ccccn1)C(C)C
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@@](C(=O)NC(Cc1ccccc1)C(O)C(F)(F)C(Cc1ccccc1)NC(=O)CC(C)(C)C)(c1ccccn1)C(C)C
Yield: 77 %

Procedure:
Reaction of the resultant compound from Example 269 with t-butylacetyl chloride in dichloromethane and 1.1 equivalent of triethylamine provided the desired compound in 77% yield. Mass spectrum: (M+H)+ =653. 1H NMR (CDCl3): 80.80 (s, 9H), 0.82 (d, 3H), 0.93 (d, 3H), 1.83 (q, 2H), 2.12 (m, 1H), 2.70-3.20 (m, 4H), 3.80 (m, 1H), 3.95 (m, 1H), 4.55 (m, 1H), 4.80 (m, 1H), 5.20 (s,0.2H), 5.35 (br d, 1H), 6.50 (br d, 1H), 7.10-7.35 (m, 13H), 7.70 (m, 1H), 8.60 (br d, 1H).
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:7]=[C:6]([NH:14][CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH:5]=1.[OH-].[Na+]>O1CCOCC1>[NH:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:6]2[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[C:8]([C:10]([F:12])([F:11])[F:13])[N:7]=2)[CH2:16][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(CO)cc(C(F)(F)F)n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: OCc1cc(NC2CCNCC2)nc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
4.0 M Hydrogen chloride in dioxane (36 mL, 140 mmol) was added to a solution of tert-butyl 4-{[4-(hydroxymethyl)-6-(trifluoromethyl)pyridin-2-yl]amino}piperidine-1-carboxylate (2.7 g, 7.2 mmol, from Step 3) in 1,4-dioxane (18 mL). After stirring for 30 minutes, the mixture was then basified to pH 12-13 by the addition of 1.0 N NaOH. The product was extracted with DCM (6×). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to afford the product as a white powder (1.64 g, 83%). 1H NMR (400 MHz, d6-DMSO) δ 6.94 (d, J=7.6 Hz, 1H), 6.77 (s, 1H), 6.67 (s, 1H), 5.39 (t, J=5.8 Hz, 1H), 4.42 (d, J=5.5 Hz, 2H), 3.76-3.60 (m, 1H), 2.92 (dt, J=12.4, 3.3 Hz, 2H), 2.57-2.43 (m, 2H), 1.87-1.77 (m, 2H), 1.25 (qd, J=11.8, 3.8 Hz, 2H). 19F NMR (376 MHz, d6-DMSO) δ −67.68 (s).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[Cl:11][CH2:12][CH2:13][O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])=[O:16]>C(Cl)Cl>[CH3:9][O:8][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:27]([NH:26][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:15]([O:14][CH2:13][CH2:12][Cl:11])=[O:16])(=[O:24])=[O:25])=[O:28])[N:7]=1
Reactant: COc1nc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1C(=O)OCCCl
Solvent: ClCCl
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OCCCl)n1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
To 0.7 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine in 10 ml anhydrous methylene chloride solvent was added 1.45 g 2-(β-chloroethoxycarbonyl)benzenesulfonyl isocyanate with stirring at ambient temperature. The mixture was thereafter stirred for sixteen hours. The solvent was evaporated under reduced pressure and the residue triturated with hexane and filtered to yield 1.72 g of compound which melted at 167°-170° C. The solid showed infrared absorption peaks at 1700 and 1705 cm-1, consistent for N-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]-2-(2-chloroethoxycarbonyl)benzenesulfonamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[C:18](O)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[CH:28]=[C:29]([NH:34][C:35](=[O:48])[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[CH:37]=2)[CH:30]=[CH:31][C:32]=1[CH3:33]>>[CH3:33][C:32]1[CH:31]=[CH:30][C:29]([NH:34][C:35](=[O:48])[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([N:42]3[CH2:43][CH2:44][O:45][CH2:46][CH2:47]3)[CH:37]=2)=[CH:28][C:27]=1[NH:26][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:15]([O:14][CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]2)[CH:16]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1N
Reactant: COc1ccc(C(=O)O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(N4CCOCC4)c3)ccc2C)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 48 %

Procedure:
Using an analogous procedure to that described in Example 25, 3-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-methoxybenzoic acid was reacted with N-(3-amino-4-methylphenyl)-3-morpholinobenzamide to give N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-methoxybenzamide in 48% yield and that product was treated with trifluoroacetic acid. The reaction mixture was evaporated, water (40 ml) was added to the residue and the mixture was basified by the addition of 1N aqueous sodium hydroxide solution. The water was decanted and the residue was titurated under diethyl ether. The resultant solid was isolated, dissolved in water (30 ml) and basified by the addition of potassium carbonate. The precipitate was isolated and dried. There was thus obtained the title compound in 26% yield; NMR Spectrum: (DMSOd6) 1.48 (m, 2H), 1.9 (m, 2H), 2.18 (s, 3H), 3.19 (m, 4H), 3.75 (m, 4H), 3.83 (s, 3H), 4.39 (m, 1H), 7.1 (m, 2H), 7.21 (d, 1H), 7.4 (m, 3H), 7.6 (m, 3H), 7.79 (s, 1H), 9.72 (s, 1H), 10.1 (s, 1H); Mass Spectrum: M+H+ 545.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]#[C:28][Si](C)(C)C)=[CH:23][CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2.C(=O)([O-])[O-].[K+].[K+].CO>C(OCC)(=O)C>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][C:24]([C:27]#[CH:28])=[CH:25][CH:26]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2
Reactant: C[Si](C)(C)C#Cc1ccc(-c2nc3c(C(=O)NC4CN5CCC4CC5)cccc3o2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1ccc(-c2nc3c(C(=O)NC4CN5CCC4CC5)cccc3o2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
A mixture of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-trimethylsilylethynylphenyl)benzoxazole-4-carboxamide (20 mg, 0.045 mmol), potassium carbonate (20 mg, 0.14 mmol) and methanol (1 mL) was stirred at room temperature for 2 h, and then was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:10:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-ethynylphenyl)benzoxazole-4-carboxamide (14 mg, 84%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.49 (d, J=7.0 Hz, 1H), 8.22-8.18 (m, 3H), 7.73 (dd, J=8.0, 1.0 Hz, 1H), 7.68 (d, J=8.5 Hz, 2H), 7.48 (t, J=8.0 Hz, 1H), 4.35-4.31 (m, 1H), 3.53 (ddd, J=14.0, 9.5, 2.0 Hz, 1H), 3.30 (s, 1H), 3.15-2.82 (m, 5H), 2.20-2.03 (m, 2H), 1.80-1.62 (m, 3H); MS (ESI+) m/z 372 (M+H); HPLC>99% (AUC), tR=12.77 min.
Reaction SMILES: [CH:1]([C:3]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:4]=1[O:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:2].[OH-].[Na+].Cl>C(O)C.O>[CH:1]([C:3]1[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:4]=1[O:5][CH2:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([OH:12])=[O:11])=[O:2]
Reactant: COC(=O)c1cccc(COc2cccc(O)c2C=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=Cc1c(O)cccc1OCc1cccc(C(=O)O)c1

Procedure:
Methyl 3-(2-formyl-3-hydroxyphenoxy)methylbenzoate (Example 18) (500 mg, 0.00175 M) was dissolved in ethanol (5 ml) and 1 N sodium hydroxide solution (5 ml) and stirred at room temperature (21/2 hr). The solution was diluted with water and acidified with concentrated hydrochloric acid with cooling and the solid produced filtered off and washed with water to give 3-(2-formyl-3-hydroxyphenoxy)methylbenzoic acid, m.p. 209°-211° C. from ethanol/water.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][C:17]([N:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[N:22]=3)[CH3:20])=[CH:18][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][S:36]([NH2:39])(=[O:38])=[O:37])=[CH:31][CH:30]=1>>[ClH:27].[CH2:1]([NH:8][C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][C:17]([N:19]([CH3:20])[C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:28][C:29]4[CH:34]=[CH:33][C:32]([CH2:35][S:36]([NH2:39])(=[O:37])=[O:38])=[CH:31][CH:30]=4)[N:22]=3)=[CH:18][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(CS(N)(=O)=O)cc1
Reactant: CN(c1ccc2c(c1)nc(NCc1ccccc1)n2C)c1ccnc(Cl)n1
Product: CN(c1ccc2c(c1)nc(NCc1ccccc1)n2C)c1ccnc(Nc2ccc(CS(N)(=O)=O)cc2)n1
Product: Cl
Yield: 60.2 %

Procedure:
The title compound was prepared following the procedure of Example 1 with N2-benzyl-N5-(2-chloropyrimidin-4-yl)-N5,1-dimethyl-1H-benzimidazole-2,5-diamine (95 mg, 0.25 mmol) and (4-amino-phenyl)-methanesulfonamide (46 mg, 0.25 mmol) to give the desired product as a white solid (85 mg, 60%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 10.17 (brs, 2H), 9.53 (brs, 1H), 7.90 (d, J=6.6 Hz, 1H), 7.61 (d, J=8.4 Hz, 3H), 7.51 (d, J=7.5 Hz, 2H), 7.22-7.39 (m, 6H), 6.82 (s, 2H), 5.87 (d, J=6.0 Hz, 1H), 4.76 (d, J=5.7 Hz, 2H), 4.19 (s, 2H), 3.74 (s, 3H) 3.49 (s, 3H). MS (ESI) m/z=529 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:15]2[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:16]=2[S:17][CH:18]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)(O)[O-].[Na+]>C(O)C>[NH2:23][C:21]1[CH:20]=[CH:19][C:16]2[S:17][CH:18]=[C:14]([CH2:13][C:12]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[O:2][CH3:1])[C:15]=2[CH:22]=1
Reactant: COC(=O)c1ccc(Cc2csc3ccc([N+](=O)[O-])cc23)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc(Cc2csc3ccc(N)cc23)c(OC)c1
Yield: 54.6 %

Procedure:
Stannous chloride dihydrate (0.38 g.) was added to a stirred solution of (I) (0.12 g.) in ethanol (5 ml.), under an atmosphere of nitrogen. The mixture was heated under reflux for 2 hours. The cooled mixture was basified with saturated aqueous sodium bicarbonate (15 ml.) and extracted with ethyl acetate (2×25 ml.). The extracts were dried (MgSO4) and evaporated. The residual oil was purified by flash chromatography on silica gel (50 ml.), eluting with 3:7 v/v ethyl acetate:hexane to give methyl 4-(5-aminobenzo[b]thien-3-ylmethyl)-3-methoxybenzoate (H) (0.06 g., 54%) as an oil; NMR (80 MHz, DMSO-d6): 3.84 (s,3H, OCH3), 3.91(s,3H, OCH3), 4.03(s,2H, CH2 --Ar), 5.0(br s,2H, NH2), 6.80(m,2H), 7.14(m,2H), 7.52(m,3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:26]([NH:28][C@H:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C:34]([O:36]C(C)(C)C)=[O:35])=[O:27])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:41].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:41].[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:26]([NH:28][C@H:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C:34]([OH:36])=[O:35])=[O:27])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(CN[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)N[C@H]2CCC[C@H]2C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cccc(CN[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)N[C@H]2CCC[C@H]2C(=O)O)c1
Temperature: 25 °C

Procedure:
To a mixture of tert-butyl (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-(3-methoxybenzyl)-L-ornithyl}amino)cyclopentanecarboxylate (0.28 g) and ethyl acetate (3.0 ml) was added a 4 M hydrogen chloride/ethyl acetate solution (3.0 ml) at room temperature, followed by stirring at room temperature over one night. The reaction mixture was concentrated under reduced pressure, and a saturated sodium bicarbonate solution was added to the residue for neutralization, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. To the compound obtained were added ethyl acetate and a 4 M-hydrogen chloride/ethyl acetate solution (0.5 mL), and the solid precipitated was collected by filtration to obtain (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-(3-methoxybenzyl)-L-ornithyl}amino)cyclopentanecarboxylic acid hydrochloride (0.12 g).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[C:6](=[O:11])[NH:7][C:8](=O)O[C:4]=2[CH:3]=1.C[NH2:15].CO>>[CH3:8][NH:7][C:6](=[O:11])[C:5]1[CH:12]=[CH:13][C:2]([Br:1])=[CH:3][C:4]=1[NH2:15]
Reactant: O=c1[nH]c(=O)c2ccc(Br)cc2o1
Reactant: CN
Solvent: CO
Product: CNC(=O)c1ccc(Br)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
30 ml of 2.0 M methylamine-methanol solution was added to 6.28 mg of 7-bromo-1H-benzo[1,3]oxazine-2,4-dion, and the mixture was stirred at room temperature for 2 hours. The reaction solution was distilled outunder reduced pressure, to obtain 6.57 mg of the above compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].[C:15]([N:22]1[CH2:27][CH2:26][CH:25](O)[CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:15]([N:22]1[CH2:23][CH2:24][CH:25]([O:14][C:6]2[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:26][CH2:27]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc([N+](=O)[O-])cc(C(F)(F)F)c2)CC1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
3-Nitro-5-trifluoromethyl-phenol (8.81 g) was dissolved in THF (76 ml). 1-Boc-4-hydroxy-piperidine (8.81 g, Aldrich) and Ph3P (11.15 g) were added and the solution was cooled to −20° C. A solution of DEAD (6.8 ml, Aldrich) in THF (36 ml) was added dropwise, maintaining the temperature between −20 and −10° C. The reaction was warmed to RT and stirred overnight. The reaction was concentrated in vacuo and triturated with hexane. The yellow solid was removed by filtration and washed with Et2O (25 ml), and hexane. The white filtrate was washed with 1N NaOH (2×), brine (1×) and the hexane layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified with flash chromatography (SiO2, 5-10% EtOAc/hexane) to obtain 1-Boc-4-(3-nitro-5-trifluoromethyl-phenoxy)-piperidine.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.Cl[P:10]1(=[O:18])[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][O:11]1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:16][C:13]1([CH3:17])[CH2:14][O:15][P:10](=[O:18])([O:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]2)[O:11][CH2:12]1
Reactant: CC1(C)COP(=O)(Cl)OC1
Reactant: OCC1CC=CCC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC1(C)COP(=O)(OCC2C=CCCC2)OC1

Procedure:
A 100 mL round bottom flask equipped with a stirrer bar was charged with 15.04 g (0.134 mol) 3-cyclohexene-1-methanol, 22.52 g (0.122 mol) of 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one, and 10.6 g (0.134 mol) of pyridine. After the above mixture was reacted at 80° C. for 3 hrs. The reaction mixture was added to chloroform (100 mL), and then washed with chloroform (2×100 mL), dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#N)=[CH:15][CH:14]=2)=[N:10][O:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=[O:34].[Na+].[K+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[O:34])=[CH:15][CH:14]=2)=[N:10][O:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1conc1-c1ccc(C#N)cc1
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: CC(C)C[AlH]CC(C)C
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1conc1-c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of [3-(4-cyano-phenyl)-isoxazol-4-yl]-carbamic acid tert-butyl ester (1.88, 6.6 mmol) in toluene (50 mL) was cooled to 0° C. under Ar. DIBAL (6.7 mL, 1M in CH2Cl2, 6.7 mmol) was added dropwise to the solution and the reaction mixture was allowed to warm to rt and stirred for 1 h. DIBAL (6.7 mL, 1M in CH2Cl2, 6.7 mmol) was added again and the reaction mixture was stirred an additional 30 min. Saturated, aqueous Rochelle salt was added and the reaction mixture was stirred overnight. The phases were extracted three times with ethyl acetate. The combined organic phases were washed with brine and dried over MgSO4. Filtration followed by removal of volatiles under reduced pressure afforded a waxy solid from which [3-(4-Formyl-phenyl)-isoxazol-4-yl]-carbamic acid tert-butyl ester was isolated as a white solid (1.34 g, 70%) by column chromatography (50% ethyl acetate in hexane).
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]4[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=4)=[CH:12][C:11]=3[CH:23]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[NH:28]1[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]1.C([BH3-])#N.[Na+]>C(Cl)Cl.CO.CO>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:15]4[CH:16]=[CH:17][C:18]([CH2:19][N:28]5[CH2:31][CH:30]([C:32]([OH:34])=[O:33])[CH2:29]5)=[CH:21][CH:22]=4)=[CH:12][C:11]=3[CH:23]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1ccc(-c2cc3cc(C4CCCCC4)ccc3o2)cc1
Reactant: O=C(O)C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(O)C1CN(Cc2ccc(-c3cc4cc(C5CCCCC5)ccc4o3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
A mixture of 4-(5-cyclohexylbenzofuran-2-yl)benzaldehyde (30 mg, 0.1 mmol), acetic acid (9 μL, 0.15 mmol) and azetidine-3-carboxylic acid (15 mg, 0.15 mmol) in DCM/MeOH (1:1, 2 mL) was stirred at room temperature for 1 h. Sodium cyanoborohydride (3.1 mg, 0.05 mmol) was added and the reaction mixture was stirred for 3 h at room temperature. After concentration of solvent under reduced pressure, the resulting residue was dissolved in hot MeOH and filtered. The filtrate and the white solid, which was redisolved in hot DMSO, were both purified by reverse phase preparative HPLC (Phenomenex reverse phase Luna 5μ C18(2) column, 60×21.2 mm ID) to yield the desired final product (16 mg, 42% yield) as a white powder: >95% purity by LCMS, ESI-MS: 459.1 (M+H)+, 1H NMR (400 MHz, CD3OD) δ 7.95 (d, 2H), 7.56 (d, 2H), 7.45 (d, 1H), 7.42 (d, 1H), 7.24 (s, 1H), 7.19 (dd, 1H), 4.45 (s, 2H), 4.34 (dd, 4H), 3.69 (m, 1H), 2.64-2.57 (d, 1H), 1.89 (t, 4H), 1.58-1.40 (m, 4H), 1.38-1.26 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[OH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6]([C:5]3[CH:28]=[CH:29][C:2]([N:34]4[CH2:35][CH2:36][CH:31]([OH:30])[CH2:32][CH2:33]4)=[N:3][CH:4]=3)=[O:7])=[CH:11][N:12]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: OC1CCNCC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(N2CCC(O)CC2)nc1

Procedure:
4-Hydroxy-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-5′-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate E and 4-hydroxypiperidine. MS calcd. for C27H25ClN4O3 [(M+H)+] 489.2, obsd. 489.