Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:17][C@H:16]([CH3:18])[C@H:15]([NH:19]C(=O)C(F)(F)F)[CH2:14]2)[C:9]([CH3:26])=[C:8]2[C:3]=1[C:4](=[O:33])[C:5]([C:30]([OH:32])=[O:31])=[CH:6][N:7]2[CH:27]1[CH2:29][CH2:28]1.[OH-].[K+].Cl>O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:13]2[CH2:17][C@H:16]([CH3:18])[C@H:15]([NH2:19])[CH2:14]2)[C:9]([CH3:26])=[C:8]2[C:3]=1[C:4](=[O:33])[C:5]([C:30]([OH:32])=[O:31])=[CH:6][N:7]2[CH:27]1[CH2:28][CH2:29]1
Reactant: Cc1c(N2C[C@H](C)[C@H](NC(=O)C(F)(F)F)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1c(N2C[C@@H](N)[C@@H](C)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.7 %

Procedure:
A mixture of 2.00 g of 5-amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-7-(cis-4-methyl-3-trifluoroacetylamino-1-pyrrolidinyl)-4-oxoquinoline-3-carboxylic acid, 1.40 g of potassium hydroxide and 14 ml of water was stirred at room temperature for 1 hour, and then neutralized with 10% aqueous hydrochloric acid to pH 8. The deposited crystals were collected by filtration and washed with water, isopropanol and diethyl ether to give 1.65 g of the desired compound as yellow crystals. The crystals were subsequently recrystallized from a mixture of methylene chloride and methanol and 1.32 g of yellow prisms, m.p. 213.5°-215° C. were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[C:11](/[CH:17]=[CH:18]/[C:19]2[C:20]([O:26][CH3:27])=[N:21][CH:22]=[CH:23][C:24]=2[I:25])=[CH:10][C:9]=1[O:28][CH3:29])([CH3:4])([CH3:3])[CH3:2].O>P(OCC)(OCC)OCC>[C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[CH:13]=[C:12]2[C:11]([CH:17]=[C:18]([C:19]3[C:20]([O:26][CH3:27])=[N:21][CH:22]=[CH:23][C:24]=3[I:25])[NH:14]2)=[CH:10][C:9]=1[O:28][CH3:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(/C=C/c2c(I)ccnc2OC)c([N+](=O)[O-])cc1NC(=O)OC(C)(C)C
Agent: CCOP(OCC)OCC
Solvent: O
Product: COc1cc2cc(-c3c(I)ccnc3OC)[nH]c2cc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 47.6 %

Procedure:
A solution of {4-[(E)-2-(4-iodo-2-methoxy-pyridin-3-yl)-vinyl]-2-methoxy-5-nitro-phenyl}-carbamic acid tert-butyl ester (560 mg, 1.06 mmol) in triethyl phosphite (5.0 ml) was refluxed for 3 h, cooled to 25° C. and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (70/30 hexanes/ethyl acetate) afforded [2-(4-iodo-2-methoxy-pyridin-3-yl)-5-methoxy-1H-indol-6-yl]-carbamic acid tert-butyl ester (250 mg, 48%) as a white solid. MH+ 496.0.
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2.S(Cl)(Cl)=O.CC(C)([O-])C.[K+].CS>O.CN(C)C=O>[CH:16]1[C:3]2[CH2:2][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][O:5][C:4]=2[CH:13]=[CH:14][C:15]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1ccc2c(c1)C(O)c1ccccc1CO2
Agent: CC(C)(C)[O-]
Agent: CS
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)Cc1ccccc1CO2
Temperature: 25 °C
Reaction time: 24 h
Yield: 84 %

Procedure:
Reflux 4.4 gm. of methyl 6,11-dihydro-11-hydroxydibenz[b,e]oxepin-2-carboxylate with 20 ml. of thionyl chloride for 10 minutes. Evaporate excess thionyl chloride and dissolve the residue in 30 ml. of dimethylformamide. Add the mixture to a solution of 3.84 gm. of potassium tert-butoxide in 75 ml. of dimethylformamide saturated with methanethiol. Stir at room temperature for 24 hours, dilute with water and extract with ether. Evaporate to dryness and chromatograph over silica gel, eluting with toluene. Evaporate to dryness to obtain the title product as an oil (yield 3.03 gm., 84%).
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:10]1[CH2:16][N:15]2[C:17]([C:20]3([C:23]([F:26])([F:25])[F:24])[CH2:22][CH2:21]3)=[N:18][N:19]=[C:14]2[C@H:13]([NH:27]C(=O)OC(C)(C)C)[CH2:12][CH2:11]1>O1CCOCC1>[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:10]1[CH2:16][N:15]2[C:17]([C:20]3([C:23]([F:26])([F:24])[F:25])[CH2:21][CH2:22]3)=[N:18][N:19]=[C:14]2[C@H:13]([NH2:27])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c1nnc2C1(C(F)(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c1nnc2C1(C(F)(F)F)CC1
Reaction time: 1.5 h
Yield: 122.7 %

Procedure:
Hydrochloric acid (4.0 M in dioxane; 5 mL, 20.0 mmol) was added to a solution of tert-butyl {(6S,9R)-6-(2,3-difluorophenyl)-3-[1-(trifluoromethyl)cyclopropyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-9-yl}carbamate (440 mg, 0.93 mmol) in 1,4-dioxane (5 mL). After 1.5 h, the reaction was concentrated to give the bis hydrochloride salt of the title compound (425 mg). MS 347.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CS([C:26]1[S:27][C:28]2[C:33]([N:34]=1)=[CH:32][CH:31]=[C:30]([Cl:35])[N:29]=2)(=O)=O>C(#N)C>[Cl:35][C:30]1[N:29]=[C:28]2[S:27][C:26]([O:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:14][CH:15]=3)=[N:34][C:33]2=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)c1nc2ccc(Cl)nc2s1
Reactant: CCOC(=O)C(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)Oc1ccc(Oc2nc3ccc(Cl)nc3s2)cc1

Procedure:
21 g (0.1 mole) of ethyl 2-(4'-hydroxyphenoxy)propionate were heated under reflux for 1 hour with 16.6 g (0.12 mole) of potassium carbonate in 250 ml of acetonitrile in order to form the salt. After adding 24.9 g (0.1 mole) of 2-methylsulfonyl-5-chlorothiazolo[5,4-b]pyridine, the reaction mixture was heated under reflux for a further 10 hours. The salt constituent was filtered off while hot and the solvent was removed. The residue was distilled in a high vacuum. This gave 33.6 g (89% of theory) of ethyl 2-[4-(5-chlorothiazolo[5,4-b]pyridin-2-yloxy)-phenoxy]-propionate, of boiling point 204°-207° C./0.01 mbar, which crystallized completely after a little time (melting point 60°-62° C.). ##STR13##
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([O:6]/[N:7]=[C:8](/[C:14](=[O:16])[CH3:15])\[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2]1.[BrH:17].BrBr>C(Cl)(Cl)(Cl)Cl.ClCCl.CO.C(O)(=O)C>[Br:17][CH2:15][C:14](=[O:16])/[C:8](=[N:7]/[O:6][CH:3]1[CH2:4][CH2:5][S:1][CH2:2]1)/[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)/C(=N\OC1CCSC1)C(C)=O
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)/C(=N\OC1CCSC1)C(=O)CBr
Temperature: 25 °C
Yield: 23 %

Procedure:
Ethyl (Z)-2-(tetrahydrothien-3-yloxyimino)-3-oxo-butyrate (1.29 g) was dissolved in a mixture of carbontetrachloride (15 ml), dichloromethane (5 ml) and methanol (2 ml). The mixture was cooled to -26°, a solution of hydrogen bromide in acetic acid (0.05 ml, 45% w/v) was added followed by bromine (0.29 ml). The mixture was allowed to warm to room temperature and stirred for 3 dyys. The solvents were removed under reduced pressure, the residue was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium bicarbonate, water and brine, then dried (MgSO4) and evaporated. Purification by flash chromatography with dichloromethane elution gave the title compound (0.4 g, 23%) as a pale yellow liquid. νmax (film) 2970, 2940, 1740, 1695, and 1600 cm-1. δH (CDCl3) 1.34 (3H, t), 2.04 (1H, m), 2.48 (1H, m), 2.90 (2H, m), 3.13 (2H, m), 4.33 (2H, s), 4.37 (2H, q), and 5.18 (1H, m). [Mass spectrum: +ve ion MH+ (324)].
Reaction SMILES: C1([C@H](NC(=O)[O:11][C@@H:12]([C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[C:13]([F:16])([F:15])[F:14])C)C=CC=CC=1.[O-]CC.[Na+]>C(O)C>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([C@H:12]([OH:11])[C:13]([F:15])([F:14])[F:16])=[CH:18][N:19]=1
Reactant: Cc1ccc([C@H](OC(=O)N[C@H](C)c2ccccc2)C(F)(F)F)cn1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc([C@H](O)C(F)(F)F)cn1
Yield: 92 %

Procedure:
(S)-2,2,2-Trifluoro-1-(6-methylpyridin-3-yl)ethyl(R)-1-phenylethylcarbamate (946 mg, 2.80 mmol) was dissolved in ethanol (14 mL). To this, sodium ethoxide (1.90 g, 28.0 mmol) was added and the mixture was heated to reflux for 2 hours. The reaction mixture was concentrated, a 5% aqueous acetic acid solution was added thereto, and extraction with ethyl acetate was performed, followed by washing with a saturated aqueous sodium bicarbonate solution and brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/7) to give Compound EAA (493 mg, yield: 92%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=O)[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[N+:21]([C:24]1[CH:33]=[C:32]([C:34]([NH:36][NH2:37])=[O:35])[CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27])([O-:23])=[O:22].O.S(C1C=CC(C)=CC=1)(O)(=O)=O>>[OH:1][C:2]1[C:3]([C:18](=[N:37][NH:36][C:34]([C:32]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([N+:21]([O-:23])=[O:22])[CH:33]=2)=[O:35])[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:16])[F:15])=[CH:9][CH:8]=1
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(F)(F)F)cc3)c2O)cc1[N+](=O)[O-]
Yield: 60.7 %

Procedure:
From 1-[4-hydroxy-1-methyl-5-(4-trifluoromethylphenyl)-1H-pyrazol-3-yl]ethanone (0.70 mmol, 200 mg) synthesized in Synthetic Example 11, methyl 2-nitro-4-hydrazinocarbonylbenzoate (0.70 mmol, 168.3 mg) of Reference Synthetic Example 40 and tosylic acid monohydrate (36.4 mg, 0.21 mmol), 214.7 mg of the desired product was obtained in the same manner as in Synthetic Example 58 as a yellow solid (yield 60%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[C:14](Cl)(=O)C(Cl)=O>CO>[CH3:14][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CO
Product: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
Heat a solution of 4-fluoro-3-nitro-benzoic acid (5.00 g, 27.0 mmol, Sigma Chemical Co.) in methanol (135 mL, 0.2M) at reflux and slowly add oxalyl chloride (6.86 g, 54.0 mmol, Aldrich Chemical Co.) through reflux condenser. Stir for 2 h at reflux. Concentrate reaction mixture in vacuo. The title compound solidifies upon standing (5.30 g, 26.6 mmol, 99%): 19F NMR (acetone-d6, 400 MHz) δ-121.3.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]([OH:12])=O)[CH:9]=[C:4]2[CH:3]=[CH:2]1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.O1CCCC1.CN(C)C=O.C(Cl)Cl>O>[CH2:13]([NH:20][C:10]([C:8]1[CH:9]=[C:4]2[CH:3]=[CH:2][NH:1][C:5]2=[N:6][CH:7]=1)=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cnc2[nH]ccc2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)c1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.6 %

Procedure:
Into a Round bottom flask was added compound 15 (35.0 mg, 0.000216 mol) and benzylamine (0.05 mL, 0.0004 mol) and PyBroP (Bromotri(pyrrolidino)phosphonium hexafluorophosphate, 200.0 mg, 0.0004318 mol) and triethylamine (0.093 mL, 0.00067 mol) and tetrahydrofuran (5.0 mL, 0.062 mol) and N,N-dimethylformamide (10.0 mL, 0.129 mol) and methylene chloride (5.0 mL, 0.078 mol) under an atmosphere of Nitrogen. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with biotage to give product 19 (15 mg).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]([CH3:29])=[CH:7][CH2:8][C:9]1[C:10]([O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[C:11]2[C:15](=[C:16]([CH3:20])[C:17]=1[O:18][CH3:19])[CH2:14][O:13][C:12]2=[O:21].[OH-].[Na+].Cl>CO.O>[CH3:19][O:18][C:17]1[C:16]([CH3:20])=[C:15]2[C:11]([C:12](=[O:21])[O:13][CH2:14]2)=[C:10]([O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:9]=1[CH2:8][CH:7]=[C:6]([CH3:29])[CH2:5][CH2:4][C:3]([OH:30])=[O:2]
Reactant: COC(=O)CCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CCC(=O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.7 %

Procedure:
A mixture of 6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid methyl ester (1.5 g, 3.45 mmol) and sodium hydroxide (552 mg) in a mixture of methanol (20 mL) and water (7 mL) was stirred at room temperature for one hour. The solution was acidified with 1N HCl. The precipitate was collected by suction filtration and washed with water to give the desired product (1.2 g, 83%). 1H NMR (300 MHz, CDCl3) δ 0.02 (s, 9H), 1.15-1.22 (m, 2H), 1.76 (s, 3H), 2.13 (s, 3H), 2.12-2.28 (m, 2H), 2.35-2.41 (m, 2H), 3.37 (d, 2H, J=7 Hz), 3.71 (s, 3H), 4.22-4.28 (m, 2H), 5.07 (s, 2H), 5.13-5.17 (m, 1H) ppm; MS (m/z) 419.3 [M−H]−, 443.2 [M+Na]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[S:8][C:7]([C:9]2[CH:10]=[N:11][C:12]3[CH:13]=[C:14]4[CH:21]=[N:20][NH:19][C:15]4=[CH:16][C:17]=3[N:18]=2)=[CH:6][CH:5]=1.I[CH3:23].O>C1COCC1>[CH3:23][N:19]1[C:15]2=[CH:16][C:17]3[N:18]=[C:9]([C:7]4[S:8][C:4]([Cl:3])=[CH:5][CH:6]=4)[CH:10]=[N:11][C:12]=3[CH:13]=[C:14]2[CH:21]=[N:20]1
Reactant: Clc1ccc(-c2cnc3cc4cn[nH]c4cc3n2)s1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc2cc3ncc(-c4ccc(Cl)s4)nc3cc21
Reaction time: 0.08 h

Procedure:
To an ice-colded suspension of NaH (0.062 g) in 20 ml of anhydrous THF under N2 is added 7-(5-chlorothien-2-yl)-1H-pyrazolo[3,4-g]quinoxaline (0.63 g). The orange-red mixture is stirred at the same temperature for 5 minutes, then iodomethane (0.374 g) is added dropwise to the orange-red mixture. The resulting mixture is stirred at room temperature overnight, then poured into water, extracted with methylene chloride, separated, dried (MeSO4), concentrated in vacuo to give a yellow solid. Purification is by chromatography eluting first with 5% ethylacetate in hexane, then gradually up to 30% ethylacetate in hexane to isolate 1-methyl-7-(5-chlorothien-2-yl)-1H-pyrazolo[3,4-g]quinoxaline (m.p. 225°-227° C.), then up to 10% hexane in ethylacetate to isolate 2-methyl-7-(5-chlorothien-2-yl)-2H-pyrazolo[3,4-g]quinoxaline (m.p. 222°-224° C.).
Reaction SMILES: [CH2:1]([C:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:7][CH:8]=[CH:9][C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH3:5].[N+:18]([C:21]1[CH:26]=[CH:25][C:24](O)=[CH:23][CH:22]=1)([O-:20])=[O:19].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([O:11][C:10](=[O:12])[CH:9]=[CH:8][CH:7]=[C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCCCCC(=CC=CC(=O)O)CCCCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCC(=CC=CC(=O)Oc1ccc([N+](=O)[O-])cc1)CCCCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.6 %

Procedure:
As in Example 115, 5-pentyl-2,4-decadienoic acid (4.0 g) and 4-nitrophenol (2.8 g) in 30 mL of dichloromethane was treated with 1,3-dicyclohexylcarbodiimide (3.48 g) and the mixture was stirred at room temperature for 18 hours. After the usual work up, the crude ester was purified by HPLC (ether-hexane; 1:24) to furnish 2.45 g of 5-pentyl-2,4-decadienoic acid 4-nitrophenyl ester as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=O)([O-:3])=[O:2].[CH2:14]([C:18]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH2:23][NH:24][CH2:25][CH2:26][C:21]=2[C:20](=[O:27])[O:19]1)[CH:15]([CH3:17])[CH3:16].CCN(C(C)C)C(C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH2:14]([C:18]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH2:23][N:24]([C:11](=[O:13])[CH2:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])[CH2:25][CH2:26][C:21]=2[C:20](=[O:27])[O:19]1)[CH:15]([CH3:17])[CH3:16]
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CNCC2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)Cc1ccccc1[N+](=O)[O-])CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
To a solution of 2-(2-nitrophenyl)acetic acid (79 mg, 0.435 mmol), 3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (50 mg, 0.184 mmol), and N,N′-diisopropylethylamine (112 mg, 0.870 mmol) in THF (5 mL) was added BOP reagent (144 mg, 0.326 mmol) and the mixture was stirred at room temperature for 16 hours. The crude reaction mixture was concentrated to dryness and purified by column chromatography (12 g, SiO2, 0 to 100% ethyl acetate in hexanes) to provide 3-isobutyl-5-(2-(2-nitrophenyl)acetyl)-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (57 mg, 60%) as a white solid: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.80-1.01 (m, 6H), 1.54-1.73 (m, 1H), 1.74-1.87 (m, 1H), 2.20-2.36 (m, 1H), 2.37-2.63 (m, 2H), 3.42-3.58 (m, 1H), 3.76-3.92 (m, 1H), 3.93-4.14 (m, 2H), 4.40 (m, 1H), 4.75 (d, J=19.59 Hz, 1H), 7.19-7.42 (m, 6H), 7.42-7.53 (m, 1H), 7.53-7.64 (m, 1H), 8.04-8.16 (m, 1H); MS m/z 435 (M+H)+, 457 (M+23)+, 433 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:6]([N:8]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[O:21][CH2:22][CH2:23][O:24]C2CCCCO2)[C:9](=[O:11])[CH3:10])[CH:7]=1>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[C:6]([N:8]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[O:21][CH2:22][CH2:23][OH:24])[C:9](=[O:11])[CH3:10])[CH:7]=1
Reactant: COc1ccc(OCCOC2CCCCO2)c(CN(C(C)=O)c2cc(F)ccc2Oc2ccccc2)c1
Solvent: CO
Product: COc1ccc(OCCO)c(CN(C(C)=O)c2cc(F)ccc2Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
To a solution of 1.53 g (3.0 mmol) 1d in 15 ml methanol was added a catalytic amount of tosyl acid. The reaction mixture was stirred for 4 h at 25° C. The reaction mixture was poured in ice-cold ethyl acetate. The solution was washed twice with ice-cold diluted aqueous sodium hydrogen carbonate solution and brine and dried with magnesium sulfate. The crude product was purified by silica column chromatography (ethyl acetate:hexane gradient 1:4-1:2). The desired product 1e was obtained in 71% yield (0.91 g, 2.13 mmol) as yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.N[NH:13][C@@H:14]([CH2:19][OH:20])[CH2:15][CH:16]([CH3:18])[CH3:17]>>[OH:20][CH2:19][C@H:14]([NH:13][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:2]([CH3:1])[CH:3]=1)[CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)C[C@H](CO)NN
Reactant: Cc1ccc(C(=O)O)cc1C
Product: Cc1ccc(C(=O)N[C@@H](CO)CC(C)C)cc1C
Yield: 75 %

Procedure:
(R)—N-(1-hydroxy-4-methylpentan-2-yl)-3,4-dimethylbenzamide was prepared in a similar manner as described in example 4 using 3,4-dimethylbenzoic acid and with (R)-aminoleucinol. Yield: 75%. MS (M+H, 250.3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[N:25]=[C:24](Cl)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.O>CN1C(=O)CCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[N:25]=[C:24]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc(Cl)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: C1COCCN1
Solvent: O
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1c(C)nc(N2CCOCC2)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-2-chloro-6-methylpyrimidine-5-carboxylate (0.6 g, 1.23 mmol) was dissolved in NMP (5 mL), morpholine (0.14 mL) was added and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4 and evaporated to give the desired product (0.53 g). 1H NMR (400 MHz, DMSO-d6): δ 10.48 (s, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 4.30 (q, J=6.8 Hz, 2H), 3.75 (s, 2H), 3.64 (m, 4H), 3.46-3.21 (m, 8H), 2.69 (s, 3H), 2.41 (m, 4H), 1.38 (s, 9H), 1.33 (t, J=6.8 Hz, 3H); MS m/z 541.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]1([S-:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na+]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([S:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [S-]c1ccccc1
Agent: [Na+]
Product: COc1ccc(Sc2ccccc2)c([N+](=O)[O-])c1

Procedure:
A solution of 1-Chloro-4-methoxy-2-nitro-benzene (3.75 g, 20.0 mmol) was reacted with sodium thiophenolate (3.96 g, 30.0 mmol) at 70° C. for 48 h following the procedure in Example 1e giving the title compound as a yellow oil after silica gel column chromatography eluting with 25% EtOAc/hexane (2.70 g, 54%).
Reaction SMILES: Cl[N:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(COC)OC>[C:12]1([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:10]=[CH:11][N:2]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClN1C=Cc2ccccc2C1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: c1ccc(-c2nccc3ccccc23)cc1
Yield: 96.9 %

Procedure:
2-Chloro-isoquinoline (28.8 g, 0.176 mol), phenylboronic acid (25.7 g 0.211 mol), triphenylphosphine (4.6 g 17.6 mmol), palladium acetate (0.99 g 4.4 mmol) and 2M solution of potassium carbonate (65.7 g 0.475 mol) were added to 270 ml of dimethoxyethane. This mixture was stirred at reflux for 17 hrs. The mixture was then cooled and the aqueous layer was separated from the organic layer. The aqueous extraction was then extracted with ethyl acetate. The combined organic extractions were then extracted with brine and dried over magnesium sulfate. The solvent was then evaporated to give a liquid which was then purified by Kugelhor distillation at 220° C. @1200 microns to yield 35 g (96.9%) of 1-phenylisoquinoline.