Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[CH2:31][CH2:30][CH2:29][CH2:28][C:8]2[C:9]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([NH2:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:40][CH2:41][C:42](Cl)=[O:43]>C(Cl)Cl.O>[Cl:40][CH2:41][C:42]([NH:20][C:17]1[C:16]([O:21][CH3:22])=[CH:15][C:14]2[CH2:13][CH2:12][N:11]3[C:7]4[C:6](=[O:32])[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:31][CH2:30][CH2:29][CH2:28][C:8]=4[C:9]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[C:10]3[C:19]=2[CH:18]=1)=[O:43]
Reactant: O=C(Cl)CCl
Reactant: COc1cc2c(cc1N)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1NC(=O)CCl)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reaction time: 0.25 h

Procedure:
To a solution of 365 mg of 20b and 160 ul of triethylamine in 1 ml of CH2Cl2 was added at 0° C. 90 ul of chloroacetylchloride in ½ ml of CH2Cl2. The reaction was stirred for 15 min, and then diluted with water and extracted with ethyl acetate. The extract was washed several times with water, and then dried and concentrated. The residue was treated with diethylether, to provide, after decantation of the supernatant and drying 390 mg of light grey solid 22a; Rf (heptane/ethyl acetate) 0.50 (Rf 20b: 0.60). NMR (CDCl3) δ 8.73 (bs, 1, NH), 7.42, 7.18, and 6.96 (3×m, 3, thienyl-H), 6.72 and 8.12 (2×s, 2, Ar—H), 4.62 and 3.88 (2×bm, 2, CH2), 4.08 (s, 2, CH2Cl), 3.87 (s, 3, OCH3), 3.90 and 3.50 (2×bm, 2, CH2), 2.90+3.10 (2×b.m, 2, CH2), 2.52 (b.m, 2, CH2), 1.60-2.0 (b.m, 4, 2×CH2), 1.57 (s, 9, tertC4H9).
Reaction SMILES: Cl.[C:2]([C:5]12[CH2:12][CH2:11][C:8]([CH2:13][NH2:14])([CH2:9][CH2:10]1)[CH2:7][CH2:6]2)([OH:4])=[O:3].O.[CH3:16][C:17]([O:20][C:21](ON=C(C1C=CC=CC=1)C#N)=[O:22])([CH3:19])[CH3:18]>C1COCC1>[C:21]([CH:6]1[CH2:7][C:8]2([CH2:13][NH2:14])[CH2:11][CH2:12][C:5]1([C:2]([OH:4])=[O:3])[CH2:10][CH2:9]2)([O:20][C:17]([CH3:19])([CH3:18])[CH3:16])=[O:22]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NCC12CCC(C(=O)O)(CC1)CC2
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C1CC2(CN)CCC1(C(=O)O)CC2
Reaction time: 24 h

Procedure:
A sample of 8.79 g (40.0 mmol) of 4-carboxybicyclo[2.2.2]octanemethylamine hydrochloride salt suspended in 100 ml each of THF and H2O was treated with 20.0 ml (14.6 g=3.3 equiv.) of TEA, followed by 11.8 g (47.9 mmol) of BOC-ON reagent. All went into solution, and after stirring 24 hr the solution was concentrated in vacuo to a volume of about 50 ml and partitioned between 100 ml of ether and 300 ml of H2O. After addition of about 2 ml of TEA the aqueous layer was washed with ether (3×), each ether in turn washed with H2O, and the combined aqueous layer was acidified with 5% KHSO4 to give the title compound as a white solid, isolated by filtration and drying in vacuo.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[CH3:13])[C:8]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(O)c1
Reaction time: 1 h
Yield: 51.8 %

Procedure:
3-Hexyl-6-(3-hydroxyphenyl)-6-methyl-3-azabicyclo[3.1.0]hexan-2-one (Preparation 84, 0.34 g, 1.2 mmol) was dissolved in tetrahydrofuran (10 ml). Lithium aluminium hydride (1M in diethyl ether, 1.5 ml, 1.5 mmol) was added under nitrogen and the reaction mixture was stirred for 1 h, before adding more lithium aluminium hydride (1M in diethyl ether, 3.0 ml, 3.0 mmol) and stirring the reaction mixture for 16 h. The reaction mixture was quenched by the addition of aqueous sodium hydroxide solution (1M, 50 ml) and the product was extracted with dichloromethane (150 ml). The organic extracts were dried (Na2SO4) and concentrated in vacuo to give a brown waxy solid. The product was purified by chromatography on silica gel, (20 g) eluting with ethyl acetate to give the pure product as a yellow solid (0.17 g, 51%).
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C@:9]1([F:33])[C@@H:14]2[C@H:10]1[CH2:11][C@@H:12]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)[C@@:13]2([NH2:22])[C:15]([O:17][CH:18]([CH2:20][CH3:21])[CH3:19])=[O:16])=[O:8])C.Cl>O1CCCC1.O>[CH3:19][CH:18]([O:17][C:15]([C@:13]1([NH2:22])[C@H:12]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:11][C@@H:10]2[C@H:14]1[C@@:9]2([F:33])[C:7]([OH:8])=[O:6])=[O:16])[CH2:20][CH3:21]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C[C@@H](OCc3ccc(Cl)c(Cl)c3)[C@@](N)(C(=O)OC(C)CC)[C@@H]21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(C)OC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(=O)O
Yield: 30.1 %

Procedure:
15 mg of lithium hydroxide monohydrate was added to 131 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-butyl ester 6-ethyl ester dissolved in 2 mL of tetrahydrofuran and 1 mL of water, and the mixture was stirred for 1.5 hours at room temperature. After 2 mL of 1N hydrochloric acid was added thereto, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by reverse phase chromatography (Wako gel 50C18 (made by Wako Pure Chemical Industries Ltd.) eluent: water to a 40% acetonitrile solution), thereby yielding 37 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-butyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH:16]=[CH2:17].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)[CH2:16][CH:15]=[CH2:14]
Reactant: C=CCCBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCCOc1ccc(C(=O)O)cc1

Procedure:
The reaction of ethyl 4-hydroxybenzoate and 4-bromo-1-butene in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 4-But-3-enyloxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.57 (s, —CO2H); 7.89 (d, J=6.9, 2 arom. H); 7.00 (d, J=6.9, 2 arom. H); 5.86 (m, —CH═CH2); 5.19, 5.08 (2 d-like, CH═CH2); 4.00 (t, J=6.6, OCH2—CH2—CH═CH2); 2.50 (m, OCH2—CH2—CH═CH2). 13C-NMR (100 MHz, d6-DMSO): 166.95 (—C═O); 162.08; 134.66; 131.32 (2 arom. C); 122.92; 117.14; 114.22 (2 arom. C); 66.92; 32.90.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[C:19][C:20]4[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][N:21]=4)[CH:16]=3)[S:11][C:10]([CH3:32])([CH3:31])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:1][CH:2]([CH2:7][CH3:6])[CH2:3][CH2:4][CH2:5][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH2:18][CH2:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=3)[CH:16]=2)[S:11][C:10]([CH3:32])([CH3:31])[CH:9]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CC(C)(C)S3)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(C)CCCC1=CC(C)(C)Sc2ccc(CCc3ccc(C(=O)O)cn3)cc21
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 6-[[4-(4-methylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-nicotinate (Compound 240, 66.0 mg, 0.15 mmol) in 2.0 mL THF and 2.0 mL EtOH was added NaOH (80.0 mg, 2.0 mmol, 2.0 mL of a 1M aqueous solution). The resulting solution was heated to 45° C. and stirred overnight. Upon cooling to room temperature the reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure to give the title compound as a yellow solid, 50.0 mg (81%). 1H NMR (300 MHz, d6 -acetone) δ: 9.09 (1H, d, J=1.4 Hz), 8.30 (1H, dd, J=2.0, 8.1 Hz), 7.65 (1H, d, J=8.1 Hz), 7.46 (2H, s), 7.24 (5H, m), 5.94 (1H, s), 2.37 (3H, s), 1.48 (6H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]([C:13]1[C:14]([O:23][CH:24]([CH3:26])[CH3:25])=[C:15](B(O)O)[CH:16]=[C:17]([CH3:19])[CH:18]=1)=[O:12]>COCCOC>[CH:24]([O:23][C:14]1[C:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=1[CH:11]=[O:12])([CH3:26])[CH3:25]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1cc(C=O)c(OC(C)C)c(B(O)O)c1
Solvent: COCCOC
Product: Cc1cc(C=O)c(OC(C)C)c(-c2ccc([N+](=O)[O-])cn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
2-Chloro-5-nitropyridine (0.28 g, 1.76 mmol), 3-formyl-2-isopropoxy-5-methylphenylboronic acid (0.78 g, 3.52 mmol) and bis(di-tert-butyl(4-dimethylaminophenylphosphine)dichloropalladium(II) (0.012 g, 0.02 mmol) were added to 1,2-dimethoxyethan (9 ml), degassed and purged with nitrogen three times under reduced pressure. Under nitrogen atmosphere the mixture was stirred at room temperature for 30 minutes, 1M aqueous sodium carbonate (9 ml) was poured in, and the temperature was raised to 80° C. After the reaction at 80° C. for 23 hours, the mixture was cooled to room temperature and crystallized with addition of water. The crystallized crystals were filtered to give the title compound (0.49 g, 92.5%).
Reaction SMILES: Cl[CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[F:7][C:8]([F:24])([F:23])[C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[N:13][CH:14]=1.[OH-].[Na+]>C1(C)C(C)=CC=CC=1.O>[F:24][C:8]([F:7])([F:23])[C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH:2]([CH3:6])[C:3]([OH:5])=[O:4])=[CH:20][CH:21]=2)=[N:13][CH:14]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CC(Cl)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)O
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
100.0 g (0.92 mol) of (RS)-(+)-2-chloropropionic acid are added to the solution of 192.0 g (0.75 mol) of 4-(5-trifluoromethyl-2-pyridyloxy)phenol in 900 g (about 1050 ml) of xylene. The temperature of the reaction mixture is elevated to 80° C. and 78.0 g (1.95 mol) of sodium hydroxide dissolved in water are added dropwise under such a reduced pressure (about 36 kPa) that the mixture boils at 90° C. The water formed in the reaction is continuously distilled off while maintaining the boiling temperature at 90° C. After the addition, the reaction mixture is stirred at 90° C. for additional 15 minutes, then the reduced pressure is ceased. After adding 300 ml of water to the mixture and stirring at 85° C. for 10 minutes, it is acidified by adding phosphoric acid and the phases are separated. The xylene layer is dried, treated with activated charcoal and finally evaporated to dryness.
Reaction SMILES: CO[CH:3](O)[C:4]([O:6][CH3:7])=[O:5].[CH:9](=[O:12])[CH2:10][CH3:11]>C(NCCCC)CCC>[CH:9](/[C:10](/[CH3:11])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5])=[O:12]
Reactant: CCC=O
Reactant: COC(=O)C(O)OC
Solvent: CCCCNCCCC
Product: COC(=O)/C=C(/C)C=O
Yield: 30.4 %

Procedure:
3.2 g (0.025 mol) of di-n-butylamine were added to a boiling, at 70° C., mixture of 120 g (1 mol) of methyl 2-methoxy-2-hydroxyacetate and 58 g (1 mol) of propionaldehyde. An exothermic reaction started immediately and the temperature rose to 100° C., when part of the reaction mixture boiled out of the flask. The temperature slowly fell to 90° C. and was maintained at this for 30 min. Fractional distillation of the reaction mixture yielded 38.9 g of methyl 3-formylcrotonate of boiling point (b.p.) 56°-68° C./10 mbar, corresponding to a yield of 30.4% of theory. The trans/cis ratio was determined by gas chromatography to be 83/17.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]([CH3:21])([CH3:20])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([OH:19])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:24][C:25]#[N:26].C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]([CH3:21])([CH3:20])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([O:19][CH2:24][C:25]#[N:26])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCBr
Reactant: CC(C)(Cc1c[nH]c2c(O)cccc12)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(Cc1c[nH]c2c(OCC#N)cccc12)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
A mixture of [2-(7-hydroxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester (15.55 g, 51.1 mmol), bromoacetonitrile (10.7 mL, 153 mmol), K2CO3 (17.78 g, 128.6 mmol) and 2-butanone is heated to reflux. After 1 hour the mixture is allowed to cool and is filtered through celite. The filtrate is concentrated to an oil which is purified by flash chromatography with CH2Cl2 followed by 5% ethyl acetate/CH2Cl2 to give 15.18 g of [2-(7-cyanomethoxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester (86%). MS (ES−) m/z 342.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12](=[O:25])[CH2:13][CH2:14][CH2:15][O:16][C:17]1C=CC=C(C)C=1C.CC1C(C)=CC=CC=1[O:29]CCCC(O)=O.COC(=O)CCC(O)=O>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12](=[O:25])[CH2:13][CH2:14][C:15]([O:16][CH3:17])=[O:29]
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(Br)cccc32)c1C
Reactant: Cc1cccc(OCCCC(=O)O)c1C
Agent: COC(=O)CCC(=O)O
Product: COC(=O)CCC(=O)N1CCCc2c(Br)cccc21

Procedure:
The title compound was prepared using a procedure analogous to 1-(5-bromo-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one except that 4-(2,3-dimethylphenoxy)butanoic acid was replaced by 4-methoxy-4-oxobutanoic acid. LCMS, [M+Na]+=349.9. 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J=8.0 Hz, 1H), 7.25 (br. s, 1H), 7.03 (t, J=8.1 Hz, 1H), 3.80-3.73 (m, 2H), 3.68 (d, J=11.0 Hz, 2H), 3.66 (s, 3H), 2.81 (t, J=6.9 Hz, 2H), 2.78-2.72 (m, 2H), 2.71-2.63 (m, 2H), 1.99 (dd, J=12.5, 6.6 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C@:20]4([S:25][CH3:26])[CH2:24][CH2:23][NH:22][CH2:21]4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl[CH2:28][C:29]([CH:31]1[CH2:36][CH2:35][N:34]([C:37]2[S:38][CH:39]=[CH:40][N:41]=2)[CH2:33][CH2:32]1)=[O:30].C(N(CC)CC)C>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([C@:20]4([S:25][CH3:26])[CH2:24][CH2:23][N:22]([CH2:28][C:29](=[O:30])[CH:31]5[CH2:32][CH2:33][N:34]([C:37]6[S:38][CH:39]=[CH:40][N:41]=6)[CH2:35][CH2:36]5)[CH2:21]4)=[O:19])[CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CS[C@@]1(C(=O)Nc2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)CCNC1
Reactant: O=C(CCl)C1CCN(c2nccs2)CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS[C@@]1(C(=O)Nc2ccc3[nH]nc(-c4ccnc(C)c4)c3c2)CCN(CC(=O)C2CCN(c3nccs3)CC2)C1
Temperature: 45 °C
Yield: 77.3 %

Procedure:
(S)—N-(3-(2-methylpyridin-4-yl)-1H-indazol-5-yl)-3-(methylthio)pyrrolidine-3-carboxamide 6 (176 mg, 0.2 mmol) and 2-chloro-1-(1-(thiazol-2-yl)piperidin-4-yl)ethanone 5 (52 mg, 0.2 mmol) was mixed in DMF (2 mL) together with triethylamine (0.1 mL). The reaction mixture was heated at 45° C. for 3 hrs before concentrated to dryness in vacuo. The resulting crude was purified on silica gel column (eluting with 2% to 4% NH3/MeOH (2 N) in CH2Cl2) to yield 7 as a light yellow solid (89 mg, 77%). LCMS M+1=576.3 retention time=1.73 min.
Reaction SMILES: [Si]([O:18][C:19]1[CH:58]=[CH:57][C:22]([O:23][CH2:24][C@@H:25]([OH:56])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:55]=[CH:54][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([N:43]4[CH2:48][CH2:47][CH:46]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:45][CH2:44]4)=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[CH2:52]([O:51][C:49]([CH:46]1[CH2:45][CH2:44][N:43]([C:41]([N:38]2[CH2:39][CH2:40][CH:35]([NH:34][C:33]3[CH:54]=[CH:55][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:56])[CH2:24][O:23][C:22]4[CH:57]=[CH:58][C:19]([OH:18])=[CH:20][CH:21]=4)=[CH:31][CH:32]=3)[CH2:36][CH2:37]2)=[O:42])[CH2:48][CH2:47]1)=[O:50])[CH3:53]
Reactant: CCOC(=O)C1CCN(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)CC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)C1CCN(C(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)CC1
Yield: 78.1 %

Procedure:
Ethyl 1-({4-[4-(2-{[(2S)-3-(4-{[tert-butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxy-propyl]amino}ethyl)anilino]-1-piperidinyl}carbonyl)-4-piperidinecarboxylate (0.17 g, 0.21 mmol) was reacted according to Procedure H (eluant: 10:1 going to 5:1 chloroform-methanol containing 2% triethylamine) to give the title compound (0.093 g, 0.164 mmol).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=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.[Br:44][C:45]1[CH:46]=[C:47]([NH2:55])[C:48]2[CH:49]=[N:50][N:51]([CH3:54])[C:52]=2[CH:53]=1>CN(C=O)C.O>[Br:44][C:45]1[CH:53]=[C:52]2[C:48]([CH:49]=[N:50][N:51]2[CH3:54])=[C:47]([NH:55][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[O:10])[CH:46]=1
Reactant: Cc1cccc(C(=O)O)n1
Reactant: Cn1ncc2c(N)cc(Br)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cccc(C(=O)Nc2cc(Br)cc3c2cnn3C)n1
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
6-Methyl-2-pyridinecarboxylic acid (74 mg, 0.54 mmol) and HATU (250 mg, 0.65 mmol) were dissolved in DMF (4 ml) and then DIPEA (0.23 ml) was then added. The mixture was stirred under nitrogen for 30 min. 6-bromo-1-methyl-1H-indazol-4-amine (135 mg, 0.60 mmol) was then added and stirring was continued under nitrogen overnight. Addition of water was followed by extraction of the resultant mixture with DCM (2×10 ml). The organics were combined and concentrated in vacuo then the residue was purified by chromatography on silica eluting with a gradient of 0-100% ethyl acetate in DCM. Fractions containing desired material were combined and concentrated in vacuo to afford the title compound (120 mg).
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH2:2][CH2:3][CH3:4].[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:20][C:19](=[O:21])/[CH:18]=[CH:17]/[C:6]2[CH:7]=[CH:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])[C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: CCCCc1c(/C=C/C(=O)O)ccc2c(OC)cccc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCc1c(/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)ccc2c(OC)cccc12
Yield: 75.6 %

Procedure:
As in Example 113, (E)-3-(1-butyl-5-methoxy-2-naphthalenyl)-2-propenoic acid (1.4 g) was reacted with 4-nitrophenol (0.76 g) in dichloromethane (25 mL) in the presence of 1,3-dicyclohexylcarbodiimide (1.02 g) to give 1.51 g of (E)-3-(1-butyl-5-methoxy-2-naphthalenyl)-2-propenoic acid 4-nitrophenyl ester. Crystallization of a portion from diethyl ether afforded the analytical sample, mp 115°-116° C. Anal. Calcd for C24H23NO5 : C, 71.10; H, 5.72; N, 3.45 Found: C, 71.25; H, 5.75; N, 3.39
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([CH2:22][S:23][CH3:24])[CH:21]=1)[NH:18][CH:17]=[CH:16]2.O[CH:26]([C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)[CH:27]1[CH2:29][CH:28]1[C:30]#[N:31]>ClCCl>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([CH2:22][S:23][CH3:24])[CH:21]=1)[NH:18][CH:17]=[C:16]2[CH:26]([C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=1)[CH:27]1[CH2:29][CH:28]1[C:30]#[N:31]
Reactant: Cc1ccc(C(O)C2CC2C#N)cc1
Reactant: CSCc1cc(F)cc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cc(F)cc2c(C(c3ccc(C)cc3)C3CC3C#N)c[nH]c12

Procedure:
130 mg (0.59 mmol) of indium(III) chloride and 0.05 ml (0.64 mmol) of trifluoroacetic acid were added to 104 mg (0.53 mmol) of the compound from Example 11A and 100 mg (0.53 mmol) of the compound from Example 158A in 6 ml of dichloromethane, and the mixture was stirred under reflux for 1 h. It was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 39.6 mg (20% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[C:5]#[C:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O)[CH3:2].[C:18]([O:22][CH3:23])(=[O:21])[CH2:19][SH:20].CO.C([O-])([O-])=O.[Cs+].[Cs+].[O-]S([O-])(=O)=O.[Mg+2]>C1COCC1>[CH3:23][O:22][C:18]([C:19]1[S:20][C:5]([CH:4]([O:15][CH2:16][CH3:17])[O:3][CH2:1][CH3:2])=[CH:6][C:7]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:21]
Reactant: CCOC(C#CC(=O)c1ccccc1)OCC
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(OCC)c1cc(-c2ccccc2)c(C(=O)OC)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
A solution of 4,4-Diethoxy-1-phenyl-but-2-yn-1-one (5.7 g, 24.54 mmol) in THF (75 ml) was cooled to 0° C. (ice bath). Methyl thioglycolate (2.2 ml, 24.54 mmol) was added in one portion and the mixture was stirred at 0° C. for 2 h. Methanol (25 ml) and Cs2CO3/MgSO4 (8 g/16 g, pre-dried at 200° C. in vacuum) were added at 0° C. The mixture was stirred at 0° C. for 15 min and then at rt for 15 h. The reaction mixture was quenched by pouting into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-40% EtOAc in hexane to afford the desired product (5.07 g, 64% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH:11]([O:19][C:20](=O)[CH3:21])[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C([O-])(=O)C.[NH4+:28]>C(O)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:28]=[C:20]([CH3:21])[O:19][C:11]=3[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: [NH4+]
Reactant: CC(=O)OC(C(=O)c1ccc2c(c1)OCO2)c1cccc(C)n1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1cccc(-c2oc(C)nc2-c2ccc3c(c2)OCO3)n1
Yield: 20.8 %

Procedure:
A solution of acetic acid 2-benzo[1,3]dioxol-5-yl-1-(6-methyl-pyridin-2-yl)-2-oxo-ethyl ester (80 mg, 0.26 mmol), ammonium acetate (200 mg, 2.6 mmol, 10 equiv) in acetic acid (4 mL) was heated to 105° C. for 3 hours. The resulting reaction mixture was concentrated in vacuo, and reverse phase high pressure liquid chromatography (a gradient from 5-30% acetonitrile in 0.1% aqueous formic acid) provided 2-(4-Benzo[1,3]dioxol-5-yl-2-methyl-oxazol-5-yl)-6-methyl-pyridine (15.9 mg, 21%).[LCMS: Rt=2.10 min; M+H=295.2]
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][CH3:17]>>[CH2:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH2:16][CH3:17]
Reactant: O=C1CCNCC1
Reactant: CCCOCCCCCCl
Product: CCCOCCCCCN1CCC(=O)CC1

Procedure:
1-(5-Propoxypentyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-5-propoxypentane essentially as described above in Example 38, Scheme C, step a.