Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH:18]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCCCCC.CCOC(C)=O.O>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH2:18][N:29]2[CH2:30][CH2:31][N:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccccc3)CC2)cc1-c1ccccc1

Procedure:
3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal (80 mg, 312 mmol) and 1-phenylpiperazine (0.047 mL, 0.312 mmol) were dissolved in 5 mL of CH2Cl2, and then 0.7 g of 4 molecular sieve powder was added thereto and stirred. Diisopropylethylamine (DIPEA; 54 mL, 0.312 mmol) was slowly added thereto, and stirred for 30 min at room temperature. Then, NaBH(OAc)3 (231 mg, 1.092 mmol) was added thereto and stirred for 12 hours at room temperature. The reaction progress and completion were confirmed by TLC. Upon completion of the reaction, water (0.1 mL) was added to the reaction mixture and then stirred for 3 min. 81 mg (64%) of target compound was obtained via column chromatography (EtOAc:Hexane=4:1, v/v).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)N)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(F)c3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4cccc(F)c4)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 574.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([O:22][C:23]3[CH:33]=[CH:32][C:26]([C:27]([O:29]CC)=[O:28])=[CH:25][CH:24]=3)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C>[F:34][C:2]([F:1])([F:35])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([O:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:32][CH:33]=3)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCCCCCC(Oc1ccc(C(=O)OCC)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(Oc1ccc(C(=O)O)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1

Procedure:
To a solution of 1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-heptan-1-ol (280 mg, 0.83 mmol) in THF (2 mL) and toluene (4 mL) is added 1,1′-(azodicarbonyl)dipiperidine (ADDP, 314.1 mg, 1.24 mmol) at 0° C., followed by the addition of tributylphosphine (0.31 mL, 1.24 mmol) and methyl 4-hydroxybenzoate (151.5 mg, 1 mmol). The reaction mixture is warmed up to room temperature and stirred overnight. The mixture is loaded on silica gel, eluted with hexanes with a gradient from 0% of ethyl acetate to 50% of ethyl acetate giving ethyl 4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-heptyloxy}-benzoate. The ester product is taken into ethanol (2 mL), treated with sodium hydroxide (5N aqueous, 1 mL) for 3 h at room temperature. The mixture is concentrated, diluted with ethyl acetate, acidified with 5 N HCl (1.1 mL), extracted with ethyl acetate. The organic layers are dried and concentrated giving 4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-heptyloxy}-benzoic acid (330 mg).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=O)[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:15][C@H:5]1[CH2:6][C:7](=[N:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]1[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2C(=O)C[C@@H]1C
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)N1c2ccccc2C(=Nc2ccccc2)C[C@@H]1C

Procedure:
A solution of (2S)-1-acetyl-2-methyl-2,3-dihydro-4(1H)-quinolinone (20 mg, 0.098 mmol; preparation see Tetrahedron: Asymmetry (1998), 9(7), 1137–1142), aniline (36 μl, 0.394 mmol) and a catalytic amount of p-toluene sulfonic acid monohydrate was refluxed overnight in toluene (4 ml) containing molcular sieve 3 Å (0.9 g). The resulting mixture was filtered, concentrated and purified on silica (ethyl acetate:heptane 1:2) to obtain the sub-titled product (22.8 mg, 0.082 mmol).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:45])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[C:34]([CH2:36][O:37]C3CCCCO3)[N:33]=[C:32]([CH3:44])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:37][CH2:36][C:34]1[CH:35]=[C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:45])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:17])([F:16])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)[CH:31]=[C:32]([CH3:44])[N:33]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cc(COC2CCCCO2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(CO)n1

Procedure:
The title compound was prepared from (RS)-[5-methyl-2-(3-{3-[2-methyl-6-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-3-oxo-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M298) (0.49 g, 0.76 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (200 mg, 60%).
Reaction SMILES: [C:1]1(=[O:21])[N:5]([CH2:6][CH2:7][CH2:8][CH:9](OCC)[O:10]CC)[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12.S(=O)(=O)(O)O>C(OC(OCC)CCCN)C>[C:4]1(=[O:16])[N:5]([CH2:6][CH2:7][CH2:8][CH:9]=[O:10])[C:1](=[O:21])[C:2]2=[CH:20][CH:19]=[CH:18][CH:17]=[C:3]12
Reactant: CCOC(CCCN1C(=O)c2ccccc2C1=O)OCC
Agent: CCOC(CCCN)OCC
Agent: O=S(=O)(O)O
Product: O=CCCCN1C(=O)c2ccccc2C1=O

Procedure:
Protect the amino function in 4,4-diethoxybutylamine by conversion thereof to a phthalimido function. Hydrolyze the resultant 1-phthalimido-4,4-diethoxybutane with 1N aqueous sulfuric acid at 25° C to obtain 4-phthalimidobutanal. Subject the compound to reductive amination using ammonium chloride and sodium cyanoborohydride in aqueous methanol at 25° C to obtain 4-phthalimidobutylamine.
Reaction SMILES: C(O[C:6]([N:8]([CH3:39])[C@H:9]([CH2:23][O:24][C:25](=[O:38])[NH:26][C:27]1[N:28]=[CH:29][C:30]2[C:35]([CH:36]=1)=[CH:34][C:33]([F:37])=[CH:32][CH:31]=2)[CH2:10][C:11]1[N:12]=[CH:13][N:14](C(OC(C)(C)C)=O)[CH:15]=1)=[O:7])(C)(C)C.Cl.CCN(C(C)C)C(C)C.[Cl:50][C:51]1[C:70]([F:71])=[CH:69][CH:68]=[CH:67][C:52]=1[CH2:53][NH:54]C(=O)OC1C=CC([N+]([O-])=O)=CC=1>C1COCC1>[F:37][C:33]1[CH:32]=[C:31]2[C:30](=[CH:35][CH:34]=1)[CH:29]=[N:28][C:27]([NH:26][C:25](=[O:38])[O:24][CH2:23][C@@H:9]([N:8]([CH3:39])[C:6]([NH:54][CH2:53][C:52]1[CH:67]=[CH:68][CH:69]=[C:70]([F:71])[C:51]=1[Cl:50])=[O:7])[CH2:10][C:11]1[N:12]=[CH:13][NH:14][CH:15]=1)=[CH:36]2
Reactant: O=C(NCc1cccc(F)c1Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](COC(=O)Nc1cc2cc(F)ccc2cn1)Cc1cn(C(=O)OC(C)(C)C)cn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2cc(F)ccc2cn1)Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
To a solution of (S)-tert-butyl 4-(2-(tert-butoxycarbonyl(methyl)amino)-3-(6-fluoroisoquinolin-3-ylcarbamoyloxy)propyl)-1H-imidazole-1-carboxylate (280 mg, 0.51 mmol) in THF (10 mL) was added HCl (4 N in 1,4-dioxane, 2.55 mL, 10.2 mmol). The reaction mixture was stirred at RT for 1 h and concentrated to dryness. The residue was suspended in THF (20 mL). To the suspension were added DIEA (0.27 mL, 1.53 mmol) and 4-nitrophenyl 2-chloro-3-fluorobenzylcarbamate (166 mg, 0.51 mmol). The reaction mixture was stirred at RT for 2 h and concentrated to dryness. The residue was purified on RP-HPLC using a mixture of acetonitrile and water to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-3-(1H-imidazol-4-yl)propyl 6-fluoroisoquinolin-3-ylcarbamate (35 mg, 13%). LRMS (M+H+) m/z 529.5.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][C:6]2[CH:7]=[C:8]3[CH2:24][C:14]4([C:22]5[C:17](=[N:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13][C:9]3=[CH:10][C:11]=2[N:12]=1>C(Cl)(Cl)Cl.CO.[O-2].[Mn+4].[O-2]>[O:23]=[C:15]1[NH:16][C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:22]2[C:14]21[CH2:13][C:9]1=[CH:10][C:11]3[N:12]=[C:3]([CH:2]=[O:1])[CH:4]=[N:5][C:6]=3[CH:7]=[C:8]1[CH2:24]2
Reactant: O=C1Nc2ncccc2C12Cc1cc3ncc(CO)nc3cc1C2
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=Cc1cnc2cc3c(cc2n1)CC1(C3)C(=O)Nc2ncccc21

Procedure:
A mixture of (±)-2-(hydroxymethyl)-6,8-dihydrospiro[cyclopenta[g]quinoxaline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one from Step A (35 mg, 0.11 mmol) and manganese (IV) oxide (158 mg, 1.82 mmol) in CHCl3 (5 mL) and MeOH (0.1 mL) was heated at reflux for 18 h. The cooled mixture was filtered through a pad of Celite, washing with CH2Cl2 and MeOH, and the filtrate was concentrated in vacuo to give the title compound. MS: m/z=358 (M+1+CH3CN).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24]Br)[CH:7]=1)[CH3:2].[CH3:27][C:28]1[S:32][C:31]([SH:33])=[N:30][N:29]=1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][S:33][C:31]2[S:32][C:28]([CH3:27])=[N:29][N:30]=2)[CH:7]=1)[CH3:2]
Reactant: Cc1nnc(S)s1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CBr)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CSc2nnc(C)s2)c1

Procedure:
As described for Example 10, [3-(2-bromomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and 5-methyl-1,3,4-thiadiazole-2-thiol were reacted to form {4-methoxy-3-[2-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-4-nitro-phenoxy]-phenyl}-acetic acid ethyl ester, which was reduced to {3-[4-amino-2-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and then treated with 4-chlorobenzoyl chloride to provide {3-[4-(4-chloro-benzoylamino)-2-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester to the acid provided Compound 19.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:27][C:28]([CH3:40])([O:31][C:32]1[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=1)[C:29]#[CH:30]>C(NCC)C.[Pd](Cl)Cl.[Cu]I>[CH3:27][C:28]([CH3:40])([O:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]#[N:37])=[CH:38][CH:39]=1)[C:29]#[C:30][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CC(C)(C)Oc1ccc(C#N)cc1
Reactant: Ic1cccnc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: CC(C)(C#Cc1cccnc1)Oc1ccc(C#N)cc1
Reaction time: 72 h

Procedure:
10.25 g of 3-iodopyridine were added at to a solution of 44 mg of palladium(II) chloride, room temperature 131 mg of triphenylphosphine and 95 mg of copper(I) iodide in 200 mg of diethylamine 9.25 g of 4-(1,1-dimethyl-2-propynyloxy)benzonitrile were then added and the mixture was stirred for 3 days. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/petroleum ether (11:9) for the elution to give 11.8 g of 4-[1,1-dimethyl-3-(3-pyridyl)-2-propynyloxy]benzonitrile in the form of an oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]3[CH2:15][CH2:16][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:19][CH:13]3[O:12][N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>C(O)(=O)C.S(=O)(=O)(O)O.[O-2].[O-2].[O-2].[Cr+6]>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:14]3[CH2:15][CH2:16][CH:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:18][CH2:19][C:13]=3[O:12][N:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)C1CCC2ON=C(c3ccc(C(C)C)cc3)C2CC1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: CC(=O)O
Product: COC(=O)C1CCc2onc(-c3ccc(C(C)C)cc3)c2CC1
Reaction time: 0.17 h
Yield: 43.4 %

Procedure:
1 g (0.003 mol) of methyl 3a,5,6,7,8,8a-hexahydro-3-(4-isopropylphenyl)-4H-cyclohept[d]isoxazole-6-carboxylate (diastereoisomer B) was dissolved in 30 ml of glacial acetic acid containing a few drops of concentrated sulfuric acid. The mixture was stirred and heated at 45° C., whereupon 0.79 g (0.0075 mol) of chromium trioxide was added and the heating was continued for 10 minutes. The acetic acid was removed by evaporation. The mixture was made basic with 2N sodium carbonate solution and extracted with ethyl acetate. Evaporation of the ethyl acetate extract and purification of the residue by column chromatography on silica gel using hexane/ethyl acetate (2:1) for the elution gave 0.408 g of methyl 5,6,7,8-tetrahydro-3-(4-isopropylphenyl)-4H-cyclohept[d]isoxazole-6-carboxylate; NMR: δ CDCl3 : 7.47 (m, 2H), 7.3 (m, 2H), 3.74 (s, 3H), 3.2 (m, 1H), 3.02-2.68 (m, 4H), 2.55 (m, 1 H), 2.3-2.1 (m, 2H), 2.01-1.75 (m, 2H), 1.25 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[OH:12].C(OCC)(=O)C.C(=O)([O-])O.[Na+].Cl[C@H:25]([CH2:29][CH3:30])[C:26](Cl)=[O:27]>O>[CH2:29]([C@H:25]1[C:26](=[O:27])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=2[O:12]1)[CH3:30]
Reactant: CC[C@@H](Cl)C(=O)Cl
Reactant: COC(=O)c1ccc(N)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC[C@@H]1Oc2cc(C(=O)OC)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.9 %

Procedure:
To a solution of 2-amino-5-methoxycarbonylphenol [Tetrahedron, 46(15), 5177-5186 (1990)] (7.50 g) in a mixed solvent of ethyl acetate (60 ml) and water (60 ml) were added sodium hydrogen carbonate (5.20 g) and (R)-2-chlorobutyryl chloride (7.50 g) and the mixture was stirred at room temperature for 10 minutes. The organic layer was separated and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in dimethylformamide (90 ml), to the solution was added potassium carbonate (6.20 g) and the mixture was stirred at room temperature overnight. Water was added to the reaction solution and the resulting crystals were taken by filtration to give (S)-2-ethyl-7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (9.38 g).
Reaction SMILES: C1O[C:4]([NH:29][OH:30])([CH2:5][C:6]2([S:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]2)[O:3]C1>CC(C)=O.Cl>[O:22]([C:19]1[CH:18]=[CH:17][C:16]([S:13]([C:6]2([CH2:5][C:4]([NH:29][OH:30])=[O:3])[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]2)(=[O:15])=[O:14])=[CH:21][CH:20]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1CCC(CC2(NO)OCCO2)(S(=O)(=O)c2ccc(Oc3ccccc3)cc2)CC1
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCC(CC(=O)NO)(S(=O)(=O)c2ccc(Oc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Following the procedure outlined in Example 15A, N-hydroxy-2-[4-(4-phenoxyphenylsulfonyl)-cyclohexanone-4-yl]-acetamide ethylene ketal (400 mg) was prepared from the corresponding N-tert-butoxy precursor. The above product was dissolved in a 1:1 mixture of acetone and 1M hydrochloric acid (40 ml) and stirred at room temperature for 18 hours. The reaction was concentrated under reduced pressure and extracted with ethyl acetate. Silica gel chromatography using 10% methanol/methylene chloride gave 2-[4-(4-phenoxyphenylsulfonyl)cyclohexanone-4-yl]-N-hydroxyacetamide as a white solid: m.p. 106° C. (dec), m/e=404 (MH+, FABMS).
Reaction SMILES: [OH:1]O.[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[CH:7]2>C(Cl)Cl.O=[Mn]=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N+:10]([O-:1])=[CH:9][CH:8]=[CH:7]2
Reactant: OO
Reactant: COc1cc2ncccc2cc1Cl
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1cc2c(ccc[n+]2[O-])cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In a 100 mL round bottom flask, 6-chloro-7-methoxyquinoline was dissolved in DCM (25.8 mL) and MTO (0.051 g, 0.207 mmol) was added. The reaction mixture was capped and vented with a needle, then placed in an ice bath to cool. Once cool, hydrogen peroxide (0.633 mL, 10.33 mmol) was added drop-wise. When the addition was complete, the reaction mixture was removed from cooling, warmed to room temperature and stirred overnight (18 h). MnO2 (10 mg, 0.115 mmol) was added and the reaction mixture was stirred for an additional 2 h. The reaction mixture was filtered through celite, washing with DCM, then concentrated in vacuo to yield 6-chloro-7-methyoxyquinoline 1-oxide (1.036 g) MS [M+H+]=210.3.
Reaction SMILES: [N:1]12CCCCC1C=N[CH2:4][CH2:3][CH2:2]2.Cl.[Cl:13][CH2:14][C:15]([NH2:17])=[NH:16].O.C(OCC)(=O)C>C(#N)C>[NH2:1][C:2]1[CH:3]=[CH:4][N:17]=[C:15]([CH2:14][Cl:13])[N:16]=1
Reactant: N=C(N)CCl
Reactant: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1ccnc(CCl)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
Solutions of 2-chloroacryloitrile (15.7 g.) in acetronitrile (20 ml.) and 1,5-diazabicyclo[5,4,0]undec-5-ene (27 g.) in acetonitrile (20 ml.) were added simultaneously over 30 minutes to a stirred, ice-cooled solution of 2-chloroacetamidine hydrochloride (19.2 g.) and 1,5-diazabicyclo[5,4,0]undec-5-ene (22.5 g.) in acetonitrile (200 ml.), keeping the temperature below 30° and the mixture stirred a further 4 hours at room temperature after the addition was complete. The resulting mixture was stirred with a mixture of water (100 ml.) and ethyl acetate (200 ml.) and then filtered through a pad of diatomaceous earth and the ethyl acetate phase separated. The aqueous phase was further extracted with ethyl acetate (2×100 ml.) and the combined ethyl acetate extracts dried and evaporated to dryness to give 4-amino-2-chloromethylpyrimidine (14.5 g.) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[NH:5][C:6](=[O:8])[CH3:7].C1C(=O)N([Br:25])C(=O)C1>C1COCC1.S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:17])[CH:4]([NH:5][C:6](=[O:8])[CH3:7])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[C:14]([Br:25])[CH:15]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(C)=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccc(O)c(Br)c1)NC(C)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To N-acetyl-L-tyrosine methyl ester (6 g, 25.3 mmol) in THF (60 mL) at rt was added NBS (5.4 g, 30.3 mmol) followed by five drops of sulfuric acid. The mixture was stirred for 16 h at rt The solvent was removed under reduced pressure and then water was added. The aqueous layer was extracted twice with EtOAc, and the combined extracts were dried over magnesium sulfate and concentrated to a solid. The solid was recrystallized from ethyl acetate/hexane (6 g, 75%). MS (M+H]+ 316.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][CH:10]=[C:11]3[C:16]=2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]3[CH3:20])[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.FC(F)(F)S(O[CH2:51][CH:52]1[CH2:56][C:55](=[O:57])[O:54][CH2:53]1)(=O)=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH2:51][CH:52]3[CH2:56][C:55](=[O:57])[O:54][CH2:53]3)[CH:10]=[C:11]3[C:16]=2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]3[CH3:20])[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]cc2n(C)c1=O
Reactant: O=C1CC(COS(=O)(=O)C(F)(F)F)CO1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n(CC3COC(=O)C3)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5-(3-Fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (2.50 g, 9.2 mmol) was added portionwise to a mixture of potassium tert-butoxide (1.18 g, 10.5 mmol) and 18-crown-6 (242 mg, 0.92 mmol) in THF (15 mL), and stirred at room temperature for 15 minutes. A solution of (5-oxotetrahydrofuran-3-yl)methyl trifluoromethanesulfonate (2.61 g, 10.5 mmol) in THF (7.5 mL) was then added, maintaining the temperature at ˜20° C. using a water bath. The solution was stirred at room temperature for 1 hour. The reaction was quenched with saturated NH4Cl(aq) (10 mL), diluted with dichloromethane (100 mL) and washed with saturated NH4Cl(aq) (2×50 mL). The organic phase was dried over magnesium sulfate and the solvent evaporated under vacuum. Purification by chromatography on silica, eluting with 40-100% EtOAc/hexane, afforded the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[C:5]([O:11]C)=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[C:5]([OH:11])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c2ncsc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Oc1ccc(F)c2ncsc12
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of 4-fluoro-7-methoxy-1,3-benzothiazole (C13) (10.50 g, 57.30 mmol) in dichloromethane (250 mL) was added aluminum chloride (30.56 g, 229.2 mmol) in one portion at room temperature. The reaction mixture was stirred for 12 hours and additional aluminum chloride (30.56 g, 229.2 mmol) was added. After another 12 hours, the reaction mixture was poured into ice water (1.0 L). The resulting precipitate was collected by filtration, washed with water, and with 1:1 dichloromethane/hexanes to afford the title compound as a yellow solid. Yield: 6.60 g, 39.0 mmol, 68%. Melting point: 165-167° C. LCMS m/z 170.4 (M+1). 1H NMR (300 MHz, DMSO-d6) δ 6.82 (m, 1H), 7.21 (m, 1H), 9.37 (s, 1H), 10.57 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[OH:13].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:30](=[O:37])[CH:31]=[C:32]([CH2:35][OH:36])[O:33][CH:34]=1.O>CN(C=O)C>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[O:13][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[C:30](=[O:37])[CH:31]=[C:32]([CH2:35][OH:36])[O:33][CH:34]=1
Reactant: Oc1ccnc2c(C(F)(F)F)cccc12
Reactant: O=c1cc(CO)occ1OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1cc(CO)occ1OCCCCCOc1ccnc2c(C(F)(F)F)cccc12
Reaction time: 0.17 h
Yield: 35 %

Procedure:
8-Trifluoromethyl-quinolin-4-ol (0.84 g, 2.88 mmol) was dissolved in DMF (5 mL). Cs2CO3 (0.98 g, 3.02 mmol) was added at room temperature and the mixture was stirred for 10 min. A solution of 5-(5-bromo-pentyloxy)-2-hydroxymethyl-pyran-4-one 10 (0.86 g, 3.02 mmol) in DMF (5 mL) was added via syringe. This mixture was stirred at 50° C. for 18 h. Water (10 mL) was added and the mixture extracted with EtOAc (2×50 mL), washed with water (3×50 mL), brine (3×50 mL) dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent (CH2Cl2:MeOH)=90:10. 5-(5-(8-(Trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 14 was obtained (0.53 g, 35% yield) as a pale yellow foam.