Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].Br[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
A mixture of 1.42 g of 2,4-dihydroxy-3-propylacetophenone, 2 g of ethyl 4-bromobutyrate, 1.5 g of potassium carbonate, and 10 ml of N,N-dimethylformamide was stirred overnight at room temperature. After addition of 100 ml of water to the reaction mixture, the product was extracted with 30 ml of toluene. The extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue thus formed was applied to silica gel column chromatography and eluted with toluene to provide 1.5 g of ethyl 4-(4-acetyl-3-hydroxy-2-propylphenoxy)butyrate as an oily product. In a solution of 2 g of potassium hydroxide dissolved in 40 ml of 80% methanol was dissolved 1.3 g of the oily product and the solution was allowed to stand for one hour. To the reaction mixture was added 20 ml of water and methanol was distilled off under reduced pressure. The aqueous solution thus obtained was acidified by 5% hydrochloric acid and extracted by ethyl acetate. The extract thus formed was washed with water, dried over anhydrous magnesium sulfate. The solvent was distilled off to provide 1.1 g of 4-(4-acetyl-3-hydroxy-2-propylphenoxy)-butyric acid.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11]([OH:13])=O.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([N:23]2[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]2)=[C:19]([CH:22]=1)[C:20]#[N:21]>>[C:20]([C:19]1[CH:22]=[C:15]([NH:14][C:11]([CH:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)=[O:13])[CH:16]=[CH:17][C:18]=1[N:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1)#[N:21]
Reactant: N#Cc1cc(N)ccc1N1CCC(O)CC1
Reactant: O=C(O)C1CCc2ccccc2C1
Product: N#Cc1cc(NC(=O)C2CCc3ccccc3C2)ccc1N1CCC(O)CC1
Yield: 59.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (0.45 g) and 5-amino-2-(4-hydroxypiperidin-1-yl)benzonitrile (0.58 g), the title compound (0.57 g) was obtained. melting point: 163-165° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:19]([OH:21])=O)=[N:12][N:13]([CH3:18])[C:14](=[O:17])[C:15]=1[CH3:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH:44]([O:46][CH2:47][CH2:48][O:49][NH2:50])=[CH2:45]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:19]([NH:50][O:49][CH2:48][CH2:47][O:46][CH:44]=[CH2:45])=[O:21])=[N:12][N:13]([CH3:18])[C:14](=[O:17])[C:15]=1[CH3:16]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(C(=O)O)nn(C)c1=O
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=COCCONC(=O)c1nn(C)c(=O)c(C)c1Nc1ccc(I)cc1F
Reaction time: 1.5 h

Procedure:
To a suspension of 4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (41 mg, 0.10 mmol) and HOBt (28 mg, 0.21 mmol) in DMF (1.5 mL) was added EDCl (40 mg, 0.21 mmol) al room temperature. The resulting mixture was stirred for 1.5 hours. O-(2-Vinyloxy-ethyl)-hydroxylamine (21 mg, 0.20 mmol) and TEA (0.030 mL, 0.22 mmol) was added to the activated ester at room temperature. After stirring for 1.5 hours, the reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3 (2×), and brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to give 4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridazine-3-carboxamide that was used directly without further purification. The title compound was prepared by the procedure previously described in Example 1 (step J) using the crude 4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridazine-3-carboxamide (40% yield over two steps). MS APCI (−) m/z 461 (M−1) detected; 1H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.44 (d, 1H), 6.63 (t, 1H), 3.98 (t, 2H), 3.80 (s, 3H), 3.74 (t, 2H), 1.78 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:33])[CH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[O:30])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:19][CH:20]([CH3:22])[CH3:21])([CH3:4])([CH3:3])[CH3:2].[C:34](C1C=CC(C(O)=O)=CC=1NC(=O)CC(C1C=CC(C(=O)CC)=CC=1OC)CCCCC)(C)(C)[CH3:35]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]=1[NH:15][C:16](=[O:33])[CH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:30])[CH2:34][CH3:35])=[CH:25][C:24]=1[O:31][CH3:32])[CH2:19][CH:20]([CH3:22])[CH3:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(C)(C)C)c(NC(=O)CC(CC(C)C)c2ccc(C=O)cc2OC)c1
Reactant: CCCCCC(CC(=O)Nc1cc(C(=O)O)ccc1C(C)(C)C)c1ccc(C(=O)CC)cc1OC
Product: CCC(=O)c1ccc(C(CC(=O)Nc2cc(C(=O)O)ccc2C(C)(C)C)CC(C)C)c(OC)c1

Procedure:
Using N-(2-t-butyl-5-methoxycarbonylphenyl)-3-(4-formyl-2-methoxyphenyl)-5-methylhexanamide (prepared as described in Preparation 63B), the procedure described in Preparation 64B was repeated to give the title compound as a foam-like substance.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].N1C=CC=CC=1.[C:22](Cl)(=[O:26])[C:23]([CH3:25])=[CH2:24]>O1CCCC1>[C:22]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])(=[O:26])[C:23]([CH3:25])=[CH2:24]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C(O)CCCCCCCCCCCO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCCCCCCCCCCC(=O)O
Temperature: 0 °C
Yield: 53 %

Procedure:
To a solution of 2.16 g of 12-hydroxydodecanoic acid in 30 ml of tetrahydrofuran (THF) is added 1.09 g of pyridine. The mixture is cooled to 0° C. and a solution of 1.04 g of methacryloyl chloride in 15 ml of THF is added dropwise. The mixture is allowed to warm to room temperature while stirring and is then stirred at ambient temperature for 12 hours. The solvent is then removed under reduced pressure and the residual solid is dissolved in 25 ml of diethylether. The solution is washed with distilled water, dried over magnesium sulfate and then evaporated to dryness. The product is purified by chromatography, using a 1:2 mixture of ethylacetate and hexane to give 1.5 g (53% yield) of 12-methacryloyloxydodecanoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[O:4][N:3]=1.O=S(Cl)Cl.[CH3:15]O>>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH3:15])=[O:9])[O:4][N:3]=1
Reactant: Cc1cc(CC(=O)O)on1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cc(C)no1
Temperature: 50 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged with 10 mL of methanol. To the stirred solvent was added (3-methyl-1,2-oxazol-5-yl)acetic acid (1 g, 7 mmol), was added drop wise SOCl2 (1.25 g, 10.5 mmol) to the reaction mixture at 0° C. and stirred at 50° C. for 4 h. After completion of the reaction, the reaction mixture was concentrated to distill off the solvent; water (25 mL) was added and extracted with ethyl acetate (25 mL). The organic layer was washed with saturated NaHCO3 solution (10 mL) and brine solution (10 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as brown liquid (1 g, yield: 92%). 1H NMR (300 MHz, CDCl3): δ 6.03 (s, 1H), 3.73 (d, 2H), 3.69 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.[CH3:20][O:21][CH2:22][C:23](Cl)=[O:24]>>[CH3:20][O:21][CH2:22][C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)=[O:24]
Reactant: COCC(=O)Cl
Reactant: Nc1ccc2ncnc(Nc3cccc(Cl)c3)c2c1
Product: COCC(=O)Nc1ccc2ncnc(Nc3cccc(Cl)c3)c2c1
Temperature: 25 °C
Yield: 41 %

Procedure:
Using an analogous procedure to that described in Example 13 except that the reaction mixture was stirred at ambient temperature rather than being heated to 100° C., 6-amino-4-(3'-chloroanilino)quinazoline was reacted with 2-methoxyacetyl chloride to give 6-(2-methoxyacetamido)-4-(3'-chloroanilino)quinazoline in 41% yield, m.p. 177°-180° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][O:15]CC2C=CC=CC=2)[CH2:12][O:11][C@@H:10]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][OH:15])[CH2:12][O:11][C@@H:10]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H](COCc2ccccc2)CO1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H](CO)CO1

Procedure:
Stir (2R,5S)-5-benzyloxymethyl-2-(2,2-dimethylpropoxy)-morpholine-4-carboxylic acid tert-butyl ester (7.05 g, 17.92 mmol) and 20% palladium hydroxide on carbon in methanol (150 mL) under 1 atmosphere of hydrogen gas at room temperature for 12 hours. Filter and concentrate to give the desired compound as a thick oil which is used directly in the next step without further purification (5.10 g).
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][NH:8][C:9]([CH3:46])([CH3:45])[CH2:10][C:11]([NH:13][C@@H:14]2[CH2:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=3[N:16]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[CH2:38][NH:39][C:40]([NH:42][CH3:43])=[O:41])=[CH:28][CH:27]=3)[C:15]2=[O:44])=[O:12])[CH2:4][O:3]1.FC(F)(F)C(O)=O>CO>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][NH:8][C:9]([CH3:45])([CH3:46])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH2:38][NH:39][C:40]([NH:42][CH3:43])=[O:41])=[CH:30][CH:31]=2)[C:15]1=[O:44])=[O:12]
Reactant: CNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC[C@H]3COC(C)(C)O3)CCc3ccccc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)CC(C)(C)NC[C@H](O)CO)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
To a solution of 137 mg (0.213 mmol) of 3-[[2,2-dimethyl-1,3-dioxolan-4(S)-yl]methyl]amino-3-methyl-N-[2,3,4,5-tetrahydro-1-[[2'-[[[(methylamino)carbonyl]amino]methyl][1,1'-biphenyl]-4-yl]-methyl]-2-oxo-1H-benzazepin-3(R)-yl]butanamide (Step C) in 2 mL of methanol was added 2.0 mL of 50% aqueous trifluoroacetic acid. The resulting solution was stirred at room temperature for 3 hours at which time the solvent was removed under vacuum to give a solid which was purified by reverse phase medium pressure liquid chromatography on C-8, eluting with methanol/0.1% aqueous trifluoroacetic acid (55:45), to afford 108 mg (70%) of the title compound as a white solid. 1H NMR (200 MHz, CD3OD): δ 1.35 (s, 3H), 1.37 (s, 3H), 2.02-2.22 (m, 1H), 2.22-2.43 (m, 1H), 2.50-2.70 (m,4H), 2.64 (s,3H), 2.94 (dd, 12, 9 Hz; 1H), 3.17 (dd, 12, 3 Hz; 1H), 3.51 (m, 2H), 3.82 (m, 1H), 4.16 (s, 2H), 4.38 (dd, 12, 8 Hz; 1H), 5.03 (d, 15 Hz, 1H), 5.14 (d, 15 Hz, 1H), 7.10-7.40 (m, 12H). FAB-MS: calculated for C34H43N5O5 601; found 602 (M+H, 40%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[C:28]([O:29][CH2:30][CH2:31][O:32]C3CCCCO3)=[CH:27][CH:26]=[CH:25][C:24]=2[F:39])[C:19]([Cl:40])=[CH:18][N:17]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[Cl:40][C:19]1[C:20]([NH:22][C:23]2[C:28]([O:29][CH2:30][CH2:31][OH:32])=[CH:27][CH:26]=[CH:25][C:24]=2[F:39])=[N:21][C:16]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:11]([CH3:12])[C:10](=[O:13])[O:9][CH2:8][CH2:7][C:6]=3[CH:14]=2)=[N:17][CH:18]=1
Reactant: Fc1cccc(OCCOC2CCCCO2)c1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)OCCc2cc(N)ccc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CN1C(=O)OCCc2cc(Nc3ncc(Cl)c(Nc4c(F)cccc4OCCO)n3)ccc21
Yield: 10.3 %

Procedure:
2-Amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one (0.0435 g, 0.000226 mol), (2,5-Dichloro-pyrimidin-4-yl)-{2-fluoro-6-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-amine (0.091 g, 0.00023 mol), 10-Camphorsulfonic acid (0.0788 g, 0.000339 mol), and Isopropyl alcohol (2 mL) were added to a 10 mL microwave tube and microwaved at 120° C. for 30 minutes. The reaction mixture was then purified by HPLC, lyophilized and neutralized with MP-carbonate to afford 2-{5-Chloro-4-[2-fluoro-6-(2-hydroxy-ethoxy)-phenylamino]-pyrimidin-2-ylamino}-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one as a yellow solid (11 mg, 10%). MP=199-201° C.; LCMS: 474 (M+H); HNMR (CDCl3): 8.07 (s, 1H), 7.36 (m, 2H), 7.10 (m, 1H), 6.84 (m, 4H), 6.64 (s, 1H), 4.42 (t, J=7.04 Hz, 2H), 4.13 (m, 2H), 3.87 (m, 2H), 3.33 (s, 3H), 2.78 (t, J=6.32 Hz, 2H).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:20]Br.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[CH:36]=[C:35]([CH2:40]O)[CH:34]=[CH:33]2.O>C(Cl)Cl>[Br:20][CH2:40][C:35]1[CH:34]=[CH:33][C:32]2[C:37](=[CH:38][CH:39]=[C:30]([C:24]3[C:23]([Cl:22])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:29])[CH:31]=2)[CH:36]=1
Reactant: OCc1ccc2cc(-c3c(Cl)cccc3Cl)ccc2c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Clc1cccc(Cl)c1-c1ccc2cc(CBr)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of PPh3 (0.251 g) in CH2Cl2 (1 ml) is added drop by drop, at 0° C., a solution of bromine (0.049 ml) in CH2Cl2 (1 ml). After 30 min, [6-(2,6-dichlorophenyl)-2-naphthyl]methanol 287 (0.242 g) is added. The mixture is stirred, under argon, at RT for 6 h. Water (2 ml) is added. The aqueous phase is extracted with CH2Cl2 (3×5 ml). The organic phases are dried over MgSO4 and evaporated under vacuum. The residue is purified by silica gel chromatography using AcOEt/cyclohexane 40/60 as eluent.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:11])=[N:7][C:6]=2[CH:12]=1.Br[CH2:14][CH2:15][Cl:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:11])=[N:7][C:6]=2[CH:12]=1
Reactant: CSc1nc2cc(O)ccc2s1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nc2cc(OCCCl)ccc2s1
Temperature: 70 °C
Yield: 42 %

Procedure:
To a solution of 5-hydroxy-2-methylthio-benzothiazole (2.1 g, 11 mmol) in anhydrous DMF (25 mL) was added bromo-2-chloroethane (4.4 mL, 53 mmol) and powdered K2CO3 (7.3 g, 53 mmol). The reaction slurry was heated at 70° C. for 13 h. The slurry was filtered under vacuum and the filtrate was concentrated under reduced pressure. The crude material was chromatographed (SiO2, 0–20% EtOAc/Hex) to afford the title compound (1.2 g, 46%). 1H-NMR (CDCl3): δ 7.62 (1H, d), 7.39 (1H, d), 6.97 (1H, dd), 4.29 (2H, t), 3.85 (2H, t), 2.79 (3H, s); MS(ESI): 259(MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[O:6][C:7]1[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([Cl:16])[N:10]=[C:9]([Cl:17])[N:8]=1.[C:22]([O-:25])(=[O:24])[CH3:23].[Na+]>>[Cl:17][C:9]1[N:8]=[C:7]([O:6][C:5]2[CH:4]=[C:3]([CH:20]=[C:19]([CH3:21])[CH:18]=2)[CH2:2][O:25][C:22](=[O:24])[CH3:23])[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([Cl:16])[N:10]=1
Reactant: Cc1cc(CBr)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Product: CC(=O)OCc1cc(C)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a stirred solution of (66) (14.4 g, 36.9 mmol) in anhydrous DMF-(50 ml), was added sodium acetate (6.05 g, 73.8 mmol) and the mixture was stirred in an oil bath (90˜100° C.) for overnight. After cooling to room temperature, the mixture was partitioned between ether and water. The ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ether: hexanes (from 1:9 to 1:4)) to afford 10 g (73%) of a white solid. m.p. 76-77° C.; 1H NMR (200 MHz, CDCl3) δ 1.41 (6H, d, J=7.2 Hz), 2.12 (3H, s), 2.39 (3H, s), 3.58 (1H, m), 5.09 (2H, s), 6.88 (1H, s), 6.93 (1H, s), 7.08 (1H, s).
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:16]([O:17][CH3:18])=[CH:15][C:8]([C:9]([O:11]CC#C)=[O:10])=[CH:7][C:6]=1[O:19][CH3:20])[C:2]#[CH:3].[OH-].[Na+].Cl>CO>[CH2:1]([O:4][C:5]1[C:6]([O:19][CH3:20])=[CH:7][C:8]([C:9]([OH:11])=[O:10])=[CH:15][C:16]=1[O:17][CH3:18])[C:2]#[CH:3]
Reactant: C#CCOC(=O)c1cc(OC)c(OCC#C)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C#CCOc1c(OC)cc(C(=O)O)cc1OC
Temperature: 50 °C
Reaction time: 4 h
Yield: 97.4 %

Procedure:
To 50 ml of methanol were added 15.5 g of 2-propynyl 4-(2-propynyloxy)-3,5-dimethoxybenzoate and 40 ml of 15% aqueous sodium hydroxide solution and the mixture obtained was stirred at 50° C. for 4 hours. Then, the reaction mixture was added to hydrochloric acid for acidification. Crystals precipitated were collected by filtration and dried to obtain 13.0 g of 4-(2-propynyloxy)-3,5-dimethoxybenzoic acid represented by the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([O:34]C)=[O:33])[CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([C@@H:36]([CH3:39])[CH2:37][CH3:38])[O:11][N:10]=1.O1CCCC1.[OH-].[Na+].Cl>CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[N:28]=[C:27]([C:32]([OH:34])=[O:33])[CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([C@@H:36]([CH3:39])[CH2:37][CH3:38])[O:11][N:10]=1
Reactant: CC[C@H](C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)OC)ccc3c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@H](C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 80 °C
Yield: 100 %

Procedure:
To a solution of methyl 6-{4-[({3-(2,6-dichlorophenyl)-5-[(1S)-1-methylpropyl]-4-isoxazolyl}methyl)oxy]phenyl}-2-quinolinecarboxylate (50 mg, 0.089 mmol) in 2:1 tetrahydrofuran:methanol (1.5 mL) was added 1 N sodium hydroxide (0.13 mL, 0.13 mmol). The solution was heated in a microwave reactor at 80° C. for 10 minutes and then 1 N hydrochloric acid (0.13 mL, 0.13 mmol) was added. The solution was concentrated and the residue was taken up with ethyl acetate and water. The layers were separated and the organic layer was dried over magnesium sulfate and concentrated to afford 50 mg of 6-{4-[({3-(2,6-dichlorophenyl)-5-[(1S)-1-methylpropyl]-4-isoxazolyl}methyl)oxy]phenyl}-2-quinolinecarboxylic acid as a yellow solid (0.089 mmol, 100%). 1H-NMR (400 MHz, DMSO-d6) δ 13.37 (br s, 1H), 8.53 (d, J=9 Hz, 1H), 8.27 (s, 1H), 8.18-8.08 (m, 3H), 7.73 (d, J=9 Hz, 2H), 7.63-7.51 (m, 3H), 6.99 (d, J=9 Hz, 2H), 4.88 (app q, J=12 Hz, 2H), 3.31-3.22 (m, 1H), 1.73-1.66 (m, 2H), 3.32 (d, J=7 Hz, 3H), 0.83 (t, J=7 Hz, 3H). HRMS (ESI) C30H24Cl2N2O4 calculated: 547.1186 (M+H)+, found: 547.1182 (M+H)+.
Reaction SMILES: C(O[Cl:6])(C)(C)C.[CH2:7]([CH:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:11]1=[O:17])[CH:8]=[CH2:9]>CO>[Cl:6][C:10]1([CH2:7][CH:8]=[CH2:9])[C:11](=[O:17])[CH2:12][CH2:13][CH2:14][C:15]1=[O:16]
Reactant: CC(C)(C)OCl
Reactant: C=CCC1C(=O)CCCC1=O
Solvent: CO
Product: C=CCC1(Cl)C(=O)CCCC1=O
Yield: 91.1 %

Procedure:
t-Butylhypochlorite (104.6 g, 0196 mol) was added dropwise to a solution of 2-allyl-1,3-cyclohexanedione (132 g, 0.87 mol) in 650 ml of methanol at 0° C. The temperature was not allowed to rise above 20° C. The methanol was removed at reduced pressure in a 40° water bath and the residual oil was taken up in benzene. The benezene solution was washed with 5 percent sodium thiosulfate (3 × 250 ml), 5 percent sodium bicarbonate (3 × 250 ml) and water (1 × 250 ml). Evaporation of the benzene gave 148 g (91 percent) of 2-chloro-2-allyl-1,3-cyclohexanedione as a light yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:31][N:21]([C:15]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[O:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:23])=[O:24]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(NS(=O)(=O)c2ccccc2)c(OCCCCNC(=O)OC(C)(C)C)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1ccc(N(C)S(=O)(=O)c2ccccc2)c(OCCCCNC(=O)OC(C)(C)C)c1
Reaction time: 18 h
Yield: 99.1 %

Procedure:
To a solution of 176 mg (0.405 mmol) of N- [2- [4-(tert-butoxycarbonylamino)butyloxy]-4-methylphenyl]benzenesulfonamide in 1.5 mL of anhydrous DMF was added 78.4 mg (0.567 mmol) of powdered anhydrous potassium carbonate and 28 mL (0.446 mmol) of iodomethane. After stirring for 18 h, the mixture was partitioned between 20 mL of ethyl acetate and 20 mL of water. The organic layer was washed with water (2×15 mL), brine (15 mL), dried (Na2SO4) and concentrated to give 180 mg (99%) of the title compound as a colorless syrup. 1 H-NMR (300 MHz, CDCl3) δ 7.70 (m, 2H), 7.56 (m, 1H), 7.46 (m, 2H), 7.14 (d, 1H, J=2.2 Hz), 7.05 (dd, 1H, J=8.4, 2.2 Hz), 6.68 (d, 1H, J=8.4), 4.53 (br s, 1H), 3.61 (t, 2H, J=6.0 Hz), 3.19 (s, 3H), 3.06 (q, 2H, J=6.3 Hz), 2.28 (s, 3H), 1.46 (s, 9H), 1.30-1.41 (m, 4H). Mass spectrum (MALDI-TOF, gentisic acid matrix) calcd. for C23H32 N2O5S: 349.2 (M-BOC+2H). Found: 349.8.
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][OH:13]>CCO>[OH:13][N:12]=[C:10]([NH2:11])[CH2:9][CH2:8][NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: N#CCCNc1ccccc1
Solvent: CCO
Product: NC(CCNc1ccccc1)=NO
Yield: 62.8 %

Procedure:
A solution of 3-(phenylamino)propanenitrile (1 g, 6.84 mmol) and NH2OH (50% in water, 0.63 cm3, 10.26 mmol) in EtOH (10 cm3) were heated to reflux for 24 hours, after which the solvent and excess hydroxylamine were removed by rotary evaporator. To the residue was added water (10 cm3) and the mixture was extracted with CH2Cl2 (100 cm3). The extracts were concentrated under reduced pressure and the residue was purified by column chromatography (silica, Et2O) to give N′-hydroxy-3-(phenylamino)propanimidamide (0.77 g, 62.8%) as a white solid, mp 93-95° C. (lit mp 91-91.5° C.).
Reaction SMILES: O.NN.[F:4][C:5]1[C:10]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[C:7]([N+:18]([O-])=O)[C:6]=1[NH2:21]>C(O)C>[F:4][C:5]1[C:10]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[C:7]([NH2:18])[C:6]=1[NH2:21]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: CN1CCN(c2ccc(N)c(N)c2F)CC1
Temperature: 25 °C

Procedure:
Hydrazine monohydrate (0.13 mL, 2.7 mmol) was added to a solution of phthalimide 1 (134 mg, 0.39 mmol) in ethanol (4 mL). The reaction was maintained overnight at rt and then was filtered through Celite. The filter cake was rinse with EtOAc (3×) and the organic portions were combined and concentrated to give diamine 2 which was carried forward without further purification: LCMS m/z 215.1 (MH+), tR=1.77 min.