Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[S:21][C:20]([SH:22])=[N:19][C:18]=1[CH3:23])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]1[S:21][C:20]([S:22][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)=[N:19][C:18]=1[CH3:23])[CH3:13]
Reactant: CCOC(=O)Cc1sc(S)nc1C
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)Cc1sc(Sc2ccc(C(F)(F)F)cn2)nc1C
Temperature: 65 °C
Yield: 57 %

Procedure:
2-Chloro-5-trifluoromethylpyridine (Ishihara Corporation, 600 Montgomery St., San Francisco, Calif. 94111) (0.5 g, 2.8 mmol) and 5-(2-ethoxy-2-oxoethyl)-2-mercapto-4-methyl-1,3-thiazole (K. Fleishmann, K. H. Scheunemann, H. U. Schortemmer, G. Dickneite, J. Blumbad, G. F. Fischer, W. Durckheimer, and H. H. Sedlacek, Arzneim-Forsch./Drug Res., 1989, 39(II), 743) (0.6 g, 2.8 mmol) were dissolved in acetone (15 ml) under a reaction inert atmosphere. Freshly ground K2CO3 (0.42 g, 3.0 mmol) was added to this solution and the reaction was heated to 65° C. for 16 hours. The K2CO3 was filtered off and the acetone was removed via rotary evaporation. The remaining slurry was diluted with a saturated aqueous solution of sodium bicarbonate, extracted three times (200 ml) with methylene chloride, dried over MgSO4 and filtered. The solvent was then stripped off and the resulting solid was purified via flash chromatography (50% ether in hexane) to afford the title compound of this Example (0.57 g, 57% yield). 1H NMR (CDCl3): δ 8.69 (1H, d, J=2), 7.75 (1H, dd, J=8,2), 7.29 (1H, d, J=8), 4.20 (2H, q, J=7), 3.79 (2H, s), 2.43 (3H, s), 1.28 (3H, t, J=7).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:6]1[C:5](=[O:10])[C:4]([CH3:3])([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: CC1(c2ccccc2)CCCCC1=O
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(c2ccccc2)CCCC(Br)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Step AAB (1): A solution of bromine (0.068 ml, 1.328 mmol) in CCl4 (2 mL) was added dropwise, over a period of 10 min, to a solution of 2-methyl-2-phenylcyclohexanone (250 mg, 1.328 mmol) in CCl4 (8 mL) at 0° C. The resulting solution was allowed to warm to rt and stir for 2 hr. The reaction mixture was concentrated in vacuo to afford 6-bromo-2-methyl-2-phenylcyclohexanone. The crude product was used for subsequent chemistry without purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[CH:29]=[CH:28][O:27][N:26]=4)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:30])[C:5]([O:9][CH3:10])=[N:6][C:7]=1Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:37][CH2:38][CH:39]1[CH2:41][CH2:40]1>CC(O)C.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[CH:29]=[CH:28][O:27][N:26]=4)(=[O:22])=[O:23])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:30])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[O:37][CH2:38][CH:39]1[CH2:41][CH2:40]1
Reactant: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reactant: OCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CC(C)O
Product: COc1nc(OCC2CC2)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 90 °C
Reaction time: 16 h
Yield: 55.8 %

Procedure:
A 5-mL vial was sequentially charged with 1-(5,6-dichloro-2-methoxypyridin-3-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (300 mg, 0.642 mmol), cesium carbonate (154 μl, 1.926 mmol), dimethyl sulfoxide (2.1 mL), and (hydroxymethyl)cyclopropane (130 μL, 1.605 mmol). The vial was sealed with a PTFE lined cap and heated to 90° C. After 16 h, the brown reaction mixture was allowed to cool to RT, then diluted with IPA (3 mL) and filtered through a pad of celite. The pad was rinsed with IPA (2×5 mL) and the filtrate was concentrated under reduced pressure to furnish a brown oil, which was dissolved in DMSO (2 mL) filtered through a 0.2 micron filter and purified by reverse-phase HPLC (Waters XBridge Prep Shield RP18 10 μm OBD 19×100 mm) gradient, 20 to 75% MeCN in water (containing 0.1% trifluoroacetic acid as an additive), flow rate 40 mL/min to afford 1-(5-chloro-6-(cyclopropylmethoxy)-2-methoxy-3-pyridinyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide (180 mg, 0.358 mmol, 55.7% yield) as a tan amorphous solid. 1H NMR (500 MHz, DMSO-d6) δ=11.65 (br. s., 1H) 8.72 (s, 1 H) 8.36 (s, 1 H) 8.21 (d, J=9.67 Hz, 1 H) 8.04 (s, 1 H) 7.85 (dd, J=8.95, 1.75 Hz, 1 H) 7.00 (d, J=9.02 Hz, 1 H) 6.79 (d, J=9.67 Hz, 1 H) 6.45 (d, J=1.10 Hz, 1 H) 4.23-4.40 (m, 2 H) 3.78 (s, 3 H) 1.30-1.43 (m, 1 H) 0.62 (d, J=7.66 Hz, 2 H) 0.41 (br. s., 2 H). m/z (ESI) 503.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([CH3:17])=[CH:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=1)[CH3:2].[C:19]([OH:22])(=[O:21])[CH3:20]>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:18])[C:5]([CH3:17])=[CH:6][C:7]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([O:15][CH3:16])=[CH:9][C:8]=1[O:22][C:19](=[O:21])[CH3:20])[CH3:2]
Reactant: CC(=O)O
Reactant: CCOC(=O)C(C)=Cc1ccc(OC)cc1OC
Solvent: c1ccncc1
Product: CCOC(=O)C(C)=Cc1c(OC)cc(OC)cc1OC(C)=O

Procedure:
3-(4,6-Dimethoxyphenyl)-2-methyl-2-propenic acid ethyl ester (1 g, 3.76 mmol) was dissolved in 5 ml of pyridine. To this was added 0.8 ml of anhydrous acetic acid and it was allowed to react at room temperature for 24 h. After the solvent was removed in vacuo, purification was carried out by silica gel column chromatography (toluene/ethyl acetate 93:7 as a developing solvent) to give 1.2 g of the desired product in a quantitative yield.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9]1>>[OH:13][C:8]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C1CCCC1
Reactant: Brc1ccccn1
Product: OC1(c2ccccn2)CCCC1

Procedure:
Prepared from 2-bromopyridine and cyclopentanone by the method described in Example 10.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)N.N(OCCC(C)C)=O.[CH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCCCCCC>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: c1ccccc1
Reactant: Cc1c(N)cccc1Cl
Agent: CC(C)CCON=O
Solvent: CCCCCCC
Product: Cc1c(Cl)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 11.6 %

Procedure:
During a 45 minute period 3-chloro-2-methylaniline (141.6 g, 1.0 mole) was added to a stirred solution of isoamyl nitrite (175.6 g, 1.5 moles) in benzene (842 g, 10.0 moles). The reaction mixture was stirred at room temperature for two hours, heated at reflux for one hour, then cooled to room temperature. Approximately 2 l of n-heptane was added to the reaction mixture. Most of the solvents were distilled from the mixture under reduced pressure, followed by distillation at atmospheric pressure (until a head temperature of 95° was reached). The pot residue was dissolved in 2 l of n-heptane and the solution filtered through 250 g of silica gel. The filtrate was subjected to column chromatography on 250 g of silica gel, elution with n-heptane, to give an oil. The oil was rechromatographed on 250 g of silica gel, elution with n-heptane, to give an oil. The oil was distilled in a Kugelrohr distillation apparatus (90°/0.05 mm) to give 3-chloro-2-methyl-[1,1'-biphenyl] (23.5 g) as an oil.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].C(=O)(O)[O-].[Na+].[CH:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20]>COCCOC>[NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([C:24]2[CH:25]=[CH:26][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: NC(=O)Nc1sc(Br)cc1C(N)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: NC(=O)Nc1sc(-c2ccc(C=O)cc2)cc1C(N)=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
2-[(Aminocarbonyl)amino]-5-bromo-3-thiophenecarboxamide (11.75 g) was stirred in 1,2-dimethoxyethane (500 ml) and saturated aqueous sodium bicarbonate solution (100 ml), and 4-formylphenyl boronic acid (10 g) was added. The flask was flushed with argon, and tetrakis-(triphenylphosphine)palladium(0) (5.1 g) was then added. The reaction was stirred at 90° C. for 2 h, then cooled and evaporated under reduced pressure. The residue was treated with dichloromethane (200 ml) and 2N sodium hydroxide solution (100 ml), and stirred for twenty minutes. The resulting solid was then isolated by filtration, and purified by trituration with ethanol (100 ml), giving the product as a pale green solid (5.75 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([NH:25][C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:31]1[CH:36]=[C:35]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=2[N:12]2[CH2:17][CH2:16][O:15][C:14]3[CH:18]=[C:19]([S:22]([NH:25][C:26]4[S:30][N:29]=[CH:28][N:27]=4)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]2=3)[CH:34]=[N:33][CH:32]=1
Reactant: OB(O)c1cncnc1
Reactant: O=S(=O)(Nc1ncns1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(Nc1ncns1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1-c1cncnc1
Temperature: 100 °C
Yield: 40.1 %

Procedure:
A microwave vial was charged with INTERMEDIATE D (0.100 g, 0.192 mmol), pyrimidin-5-ylboronic acid (Small Molecules, Inc., Hoboken, N.J., 0.036 g, 0.288 mmol), tetrakis(triphenylphosphine)palladium(0) (0.022 g, 0.019 mmol), and K2CO3 (0.133 g, 0.959 mmol). The solids were diluted with dioxane (1.279 mL) and water (0.639 mL), and the reaction was heated under microwave irradiation at 100° C. for 30 minutes. The reaction mixture was diluted with water, and washed with ether (the ether layer was extracted once more with water). The combined aqueous layers were acidified with 1.0N HCl, and then washed with DCM (×2). The combined organics were dried using a phase separator and concentrated. After concentration, the material was purified by reverse-phase preparative HPLC (Column: Phenomenex 150×30 mm, 5 micron, C18 column; 0.1% TFA in CH3CN/H2O, gradient 25% to 90% over 20 min) to provide 4-(2-(pyrimidin-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.040 g, 0.077 mmol) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.45 (m, J=13.00 Hz, 1H) 3.76 (m, J=11.20 Hz, 1 H) 4.06-4.15 (m, 1 H) 4.31 (m, J=10.50 Hz, 1 H) 6.38 (d, J=8.22 Hz, 1 H) 6.98-7.00 (m, 1 H) 7.01-7.03 (m, 1 H) 7.73 (d, J=8.41 Hz, 1H) 7.94 (dd, J=8.56, 2.01 Hz, 1 H) 7.99 (m, J=1.70 Hz, 1 H) 8.26 (s, 1 H) 8.90 (s, 2 H) 9.07 (s, 1 H). m/z (ESI) 520.8 (M+H)+.
Reaction SMILES: CI.[CH3:3][C@@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C:20](=[CH:21][CH2:22][C@:6]2([CH3:7])[C@H:5]1[C:24]([O-:26])=[O:25])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:23])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3.[CH:27](N(C(C)C)CC)(C)C.[I-]>C(#N)C>[CH3:27][O:25][C:24]([C@H:5]1[C@H:4]([CH3:3])[CH2:9][C@H:8]2[C@H:10]3[C:20](=[CH:21][CH2:22][C@:6]12[CH3:7])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:23])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3)=[O:26]
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)[O-]
Reactant: CCN(C(C)C)C(C)C
Agent: [I-]
Solvent: CI
Solvent: CC#N
Product: COC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Reaction time: 2 h

Procedure:
Methyl iodide (7.9 ml) is added to a solution of 16α-methylandrosta-4,9(11)-dien-3-one 17β-carboxylate (7.9 g) and diisopropylethylamine (17.5 ml) in acetonitrile (175 ml). The mixture is allowed to stand at 20°-25° for 2 hr and then a second addition of amine (9 ml) and iodide (4 ml) is made. The mixture is allowed to stand overnight at 20°-25° and then concentrated under reduced pressure. The residue is partitioned (water and methylene chloride) and the extract is concentrated and chromatographed on silica gel (750 g). Elution is performed with acetone/methylene chloride (2-5%/98-95%). The appropriate fractions are pooled and concentrated to give the title compound, m.p. 126.5° (acetone-hexane).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].O.[NH2:13][NH2:14]>C(O)C>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:13][NH2:14])=[O:5]
Reactant: NN
Reactant: COC(=O)c1ccccc1F
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccccc1F
Temperature: 25 °C
Yield: 96.5 %

Procedure:
Methyl 2-fluorobenzoate (27) (25 g, 160 mmol) was dissolved in ethanol (200 mL) and hydrazine monohydrate (11.8 mL, 240 mmol) was added. The mixture was heated to reflux for 4 hr then allowed to cool to room temperature overnight. The reaction was incomplete. After heating for a further 2 hr, starting material still remained. Additional hydrazine monohydrate (4 mL) was added. After heating for 2-3 hr the reaction was nearly complete. The mixture was cooled and concentrated under reduced pressure. Water (50 mL) was added to the residue and the aqueous layer was saturated with solid NaCl. The product was extracted with EtOAc (3×100 mL). The combined organic solution was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with heptane (100 mL), filtered, and dried to provide 23.8 g (95%) of 13 as a pinkish solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[CH:8]=O.[Br-].[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([CH2:34][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:26]1.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:1][O:2][C:3]1[C:4]([O:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7](/[CH:8]=[CH:34]/[C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:25][N:26]=2)[CH:10]=1
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OCCCN1CCOCC1
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(/C=C/c2n[nH]c3ccccc23)c([N+](=O)[O-])cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 112.6 %

Procedure:
A solution of 5-methoxy-4-[3-(morpholin-4-yl) propyloxy]-2-nitrobenzaldehyde (0.26 g, 0.79 mmol) obtained in Step 1 in methanol (8.0 mL) was added with (1H-indazol-3-ylmethyl)triphenylphosphonium bromide (0.73 g, 1.5 mmol) and potassium carbonate (0.34 g, 2.8 mmol), followed by stirring at room temperature for 3.5 hours. The reaction mixture was added with water and the precipitated solid was triturated in methanol to obtain (E)-3-{2-[5-methoxy-4-[3-(morpholin-4-yl)propyloxy]-2-nitrophenyl]vinyl}-1H-indazole (0.39 g, 100%).
Reaction SMILES: [CH:1]([N:4]([CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])[C:5]([NH:7][C@H:8]([C:13]([O:15]C)=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6])([CH3:3])[CH3:2].O.[Li+].[OH-]>O1CCOCC1>[CH:1]([N:4]([CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])[C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6])([CH3:2])[CH3:3]
Reactant: C=CCCCN(C(=O)N[C@H](C(=O)OC)C(C)(C)C)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=CCCCN(C(=O)N[C@H](C(=O)O)C(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution (0.1 M) of methyl N-{[isopropyl(pent-4-en-1-yl)amino]carbonyl}-3-methyl-L-valinate in a 1:1 mixture of water and dioxane, LiOH (4 eq) was added and the resulting mixture was stirred at room temperature for 6 h. The reaction mixture was then concentrated at reduced pressure and the crude residue was dissolved in EtOAc. The organic phase was washed with water. The aqueous phase was brought to pH=2 and re-extracted with EtOAc. After drying over Na2SO4 and evaporation of the volatiles, N-{[isopropyl(pent-4-en-1-yl)amino]carbonyl}-3-methyl-L-valine was recovered as a brownish solid (100%) and used without any further purification. LRMS (ESI) m/z 285 [(M+H)+; calcd for C15H29N2O3: 285.2].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:24]([O:25]CC3C=CC=CC=3)=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[H][H]>O1CCCC1.[Pd]>[CH3:1][O:2][C:3](=[O:34])[C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:24]([OH:25])=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: COC(=O)C(=O)c1ccc(OCCOc2cc3ccccc3cc2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccc(OCCOc2cc3ccccc3cc2O)cc1
Yield: 18.3 %

Procedure:
A mixture of alpha-oxo-4-[[2-[3-(phenylmethoxy)-2-naphthalenyloxy]ethyl]oxy]benzeneacetic acid methyl ester (0.456 g) in tetrahydrofuran (3 mL) was added to a flask containing 10% palladium on carbon catalyst and 5 mL of tetrahydrofuran in a hydrogen atmosphere. The mixture was stirred until one equivalent of hydrogen was absorbed and the reaction was filtered and the organic solvent was removed by evaporation. Chromatography on silica gel and elution with dichloromethane-hexane mixtures provided purified product. Crystallization from dichloromethane-diethyl ether gave 0.067 g of pure 4-[[2-(3-hydroxy-2-naphthalenyloxy)ethyl]oxy]-alphaoxobenzeneacetic acid methyl ester as a colorless solid, mp 177°-178° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[CH:6]=[C:5]2[C:13](Cl)=[O:14].[NH2:16][C:17]1[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:19][O:20][C:21]=1[CH3:22]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[CH:6]=[C:5]2[C:13]([NH:16][C:17]1[C:18]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[N:19][O:20][C:21]=1[CH3:22])=[O:14]
Reactant: Cc1onc(-c2ccccc2)c1N
Reactant: O=C(Cl)c1cc(Cl)nc2ccc(Br)cc12
Solvent: c1ccncc1
Product: Cc1onc(-c2ccccc2)c1NC(=O)c1cc(Cl)nc2ccc(Br)cc12
Temperature: 70 °C
Yield: 71.6 %

Procedure:
6-Bromo-2-chloroquinoline-4-carbonyl chloride (500 mg) and 4-amino-5-methyl-3-phenylisoxazole (400 mg) were dissolved in dichlorormethane (15 mL) and pyridine (1 mL). The reaction solution was heated at 70° C. overnight. The white precipitation was collected by filtration, washed with ethyl acetate and dried to give 6-bromo-2-chloro-N-(5-methyl-3-phenylisoxazol-4-yl)-4-quinolinecarboxamide (520 mg) as a white solid. 1H NMR (DMSO-d6): δ 2.52 (s, 3H), 7.52 (m, 3H), 7.72 (m, 2H), 8.02 (m, 4H), 10.58 (s, 1H); LCMS: ret. time: 32.23 min.; purity: 100%; MS (m/e): 441.82 (M+).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][CH:19]=[O:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH:21]([Mg]Cl)([CH3:23])[CH3:22].Cl.O>O1CCCC1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][CH:19]([OH:20])[CH:21]([CH3:23])[CH3:22])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(SCCC=O)cc(C(C)(C)C)c1O
Reactant: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.0 g of the aldehyde of Example 4 was dissolved in 20 ml of dry tetrahydrofuran under argon and added to 8.5 ml of 2M isopropylmagnesium chloride in tetrahydrofuran that had previously been added under argon gas to a flask that had been dried in vacuo overnight. Reaction temperature was maintained at 10°-15° C. with an ice bath. When addition was complete, the reaction mixture was allowed warm to room temperature and stirred for 3 hours. 2N hydrochloric acid (2 ml) was added followed by 50 ml of water and the mixture extracted with ethyl acetate three times. The organic extracts were combined, washed with water twice and dried over sodium sulfate. The solvent was removed in vacuo after filtration and the crude product chromatographed on silica to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([C:9]2[O:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[N:3]=1.[CH3:15][NH2:16].CCO>CO>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[O:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[N:3]=[C:2]([NH:16][CH3:15])[N:7]=1
Reactant: CN
Reactant: Cc1ccc(-c2cc(Cl)nc(Cl)n2)o1
Solvent: CO
Solvent: CCO
Product: CNc1nc(Cl)cc(-c2ccc(C)o2)n1
Temperature: 80 °C
Yield: 22 %

Procedure:
A solution of 2,4-dichloro-6-(5-methylfuran-2-yl)pyrimidine (0.70 g, 3.07 mmol) in MeOH (5 mL) was treated with 2-M methylamine in EtOH (2 mL, 4 mmol), heated at 80° C. for 30 min, cooled, concentrated in vacuo and purified by chromatography [SiO2; hexane:EtOAc (100:0-90:10)] to give the title compound (0.17 g, 22%) as a white solid; NMR δH (400 MHz, CD3OD) 2.38 (3H, s), 2.93 (3H, s), 6.22-6.23 (1H, m), 6.83 (1H, s) and 7.12-7.13 (1H, m); M/Z 224, 226 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:15][C:16]([O:18]C)=[O:17])[CH:12]=[CH:13][CH:14]=2)[CH2:4][O:3]1.O[Li].O>CO.O>[CH3:1][C:2]1([CH3:20])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:15][C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[CH2:4][O:3]1
Reactant: COC(=O)Cc1cccc(OC[C@@H]2COC(C)(C)O2)c1
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC1(C)OC[C@@H](COc2cccc(CC(=O)O)c2)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.3 %

Procedure:
To a solution of methyl 3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenyl-acetate (23 g, 0.08 mol) in methanol (80 mL) and water (5 mL) was added LiOH-H2O (13.8 g, 4 eq.). After stirring the reaction mixture at room temperature for 4 h, the volatiles were removed under vacuo and the residue was partitioned between EtOAc and H20. The aqueous layer was separated, cooled with an ice bath, and then acidified with 10% aq. HCl. The acidic aqueous layer was extracted with EtOAc. The EtOAc layer was washed with NaCl (sat.), dried over Na2SO4, and concentrated to give 3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenylacetic acid as a white solid (22 g, >99% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([S:6](Cl)(=[O:8])=[O:7])=[CH:2]1.[NH2:10][C:11]1[O:15][N:14]=[C:13]([CH3:16])[C:12]=1[Br:17]>>[Br:17][C:12]1[C:13]([CH3:16])=[N:14][O:15][C:11]=1[NH:10][S:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)(=[O:8])=[O:7]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccsc1
Product: Cc1noc(NS(=O)(=O)c2ccsc2)c1Br
Yield: 22 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-3-sulfonamide was prepared in the same manner as described in Example 2 from thiophene-3-sulfonyl chloride with 5-amino-4-bromo-3-methylisoxazole in 22% yield. Purification by column chromatography using 10% MeOH/CHCl3 as eluent gave a pale brown oil.