Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH:17]=2)[C:12](O)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:25][C:26]1[CH:31]=[N:30][C:29]([CH3:32])=[CH:28][N:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:32][C:29]1[N:30]=[CH:31][C:26]([NH:25][C:12](=[O:13])[C:11]2[CH:15]=[C:16]([O:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH:17]=[C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:10]=2)=[N:27][CH:28]=1
Reactant: Cc1cnc(N)cn1
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(OC2CCOCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(OC3CCOCC3)c2)cn1
Yield: 42.7 %

Procedure:
3-[(Phenylmethyl)oxy]-5-(tetrahydro-2H-pyran-4-yloxy)benzoic acid (3.14 g, 9.5 mmol), 2-amino-5 methylpyrazine (2.08 g, 19.0 mmol) and HATU (4.70 g, 12.35 mmol) were dissolved in DMF (12.5 mL) and DIPEA (3.31 mL, 19.0 mmol) added. The resultant mixture was stirred at RT for 20 hours. The mixture was quenched with water (150 mL) and extracted with ethyl acetate (2×75 mL), washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica, eluting with 0-50% ethyl acetate in isohexane, to give the desired compound as a pale yellow gum (1.70 g). m/z 420 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][C:3]=1[C:9]1[NH:13][N:12]=[CH:11][CH:10]=1.Cl[C:15]([O:18]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl>C1(C)C=CC=CC=1.C1COCC1>[O:18]=[C:15]1[N:13]2[N:12]=[CH:11][CH:10]=[C:9]2[C:3]2[CH:4]=[C:5]([CH:7]=[O:8])[S:6][C:2]=2[NH:1]1
Reactant: Nc1sc(C=O)cc1-c1ccn[nH]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=Cc1cc2c([nH]c(=O)n3nccc23)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
5-Amino-4-(1H-pyrazol-5-yl)thiophene-2-carbaldehyde (12 mg, 0.06 mmol) and bis(trichloromethyl)carbonate (55 mg, 0.19 mmol) were dissolved in toluene (3 mL) and THF (0.5 mL), and the reaction heated in a sealed tube at 100° C. for 3 h. The reaction was cooled to room temperature, hexanes (10 mL) added, suspension stirred at room temperature for 30 min, precipitate washed with additional hexanes (10 mL), dried under reduced pressure to yield 5-oxo-4,5-dihydropyrazolo[1,5-c]thieno[3,2-e]pyrimidine-2-carbaldehyde as a powder (11 mg, 81%). 1H NMR (400 MHZ, DMSO-d6) δ 6.99 (s, 1H), 8.12 (s, 1H), 8.45 (s, 1H), 9.93 (s, 1H), 13.06 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[C@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:8])([CH3:4])([CH3:3])[CH3:2].[Br:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6](=[O:16])[CH:7]([NH:8][C:21]1[CH:22]=[CH:23][C:18]([Br:17])=[CH:19][CH:20]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Reactant: OB(O)c1ccc(Br)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C(Cc1ccccc1)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of L-phenylalanine tert-butyl ester (1.47 g, 6.64 mmol), 4-bromophenylboronic acid (2.67 g, 13.28 mmol), triethylamine (1.9 mL, 13.28 mmol) and copper (II) acetate (1.21 g, 6.64 mmol) in dichloromethane (50 mL) was stirred at room temperature for 24 h. The solids were removed by filtration through a pad of silica gel and the desired product was obtained by chromatography eluting with 5% ethyl acetate in hexanes. 1H NMR (CDCl3)7.2 (m, 8 H), 6.48 (d, 2 H), 4.18 (t, 2 H, H-2 and NH), 3.08 (d, 2 H), 1.35 (s, 9 H)
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)=[C:10]([Cl:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:37]3[N:41]([CH3:42])[CH:40]=[N:39][CH:38]=3)([C:27]3[CH:28]=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=3)[OH:26])[CH:8]=2)[N:3]=1.Cl.[CH3:44][O:45][CH:46]1[CH2:49][NH:48][CH2:47]1.CN(C=O)C>CCOC(C)=O>[Cl:24][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([C:37]3[N:41]([CH3:42])[CH:40]=[N:39][CH:38]=3)([C:27]3[CH:28]=[N:29][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:31][CH:32]=3)[OH:26])[CH:8]=2)[N:3]=[C:2]([N:48]2[CH2:49][CH:46]([O:45][CH3:44])[CH2:47]2)[C:11]=1[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH:23]=[CH:22][CH:21]=[N:20]2)=[CH:17][CH:18]=1
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Reactant: COC1CNC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC1CN(c2nc3ccc(C(O)(c4ccc(C(F)(F)F)nc4)c4cncn4C)cc3c(Cl)c2Cc2ccc(-n3cccn3)cc2)C1
Temperature: 100 °C

Procedure:
{2,4-Dichloro-3-[4-(1H-pyrazol-1-yl)benzyl]quinolin-6-yl}(1-methyl-1H-imidazol-5-yl)pyrimidin-2-ylmethanol (200 mg, 0.328 mmol, Intermediate 65), 3-methoxyazetidine hydrochloride (427 mg, 3.28 mmol), and DMF (2 mL) were combined in a reaction tube, then sealed and heated to 100° C. and maintained at that temperature overnight. The reaction vessel was then cooled to room temperature and the contents were transferred to a separatory funnel with EtOAc dilution, and extracted once with saturated, aqueous NH4Cl solution, then extracted three times with deionized water. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to provide the title compound. MS (ESI): mass calcd. for C34H29ClF3N7O2, 659.2. m/z found, 660.3 [M+H]+. 1H NMR (600 MHz, CD3OD) δ ppm 8.78 (d, J=2.1 Hz, 1H), 8.11 (dd, J=2.5, 0.4 Hz, 1H), 8.07 (d, J=2.1 Hz, 1H), 8.01 (dd, J=8.2, 2.1 Hz, 1H), 7.80 (d, J=8.2 Hz, 1H), 7.77-7.73 (m, 2H), 7.67 (d, J=1.4 Hz, 1H), 7.62-7.59 (m, 2H), 7.59-7.56 (m, 1H), 7.17 (d, J=8.7 Hz, 2H), 6.49-6.46 (m, 1H), 6.37 (s, 1H), 4.34-4.29 (m, 4H), 4.19-4.13 (m, 1H), 4.02-3.97 (m, 2H), 3.48 (s, 3H), 3.22 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:13]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NCc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)NCc1ccc(Cl)cc1

Procedure:
A mixture of (4.0 g, 25.9 mmol) of phenylacetyl chloride, 3.15 mL (25.9 mmol) of 4-chlorobenzylamine and 5.1 mL of triethylamine in 120 mL of methylene chloride was prepared at 0° C. and then heated to reflux under a nitrogen atmosphere for 18 hours. The solvent was evaporated and the residue was treated with 2 mL of 4-chlorobenzylamine and 3 mL of triethylamine and reheated to reflux overnight. After cooling, the mixture was suspended in 100 mL of methylene chloride, washed with 0.5 N hydrochloric acid, 0.5 N sodium hydroxide and saturated aqueous sodium chloride, followed by drying with magnesium sulfate (MgSO4). The solvent was removed in vacuo to give a white solid which was recrystallized from ethyl acetate:hexane to provide N-(4-chlorobenzyl)-phenylacetamide as a white crystalline solid, 4.15 g (62%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:38](=[O:37])[CH2:39][OH:40])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f23) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][NH:6][C:7]([C:9]1[C:10](=[O:27])[S:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][C:15]([Cl:20])=[CH:14][C:13]=2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:8])C.[OH-].[Na+]>C1COCC1.CO>[Cl:20][C:15]1[CH:16]=[C:17]2[C:12](=[C:13]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:14]=1)[S:11][C:10](=[O:27])[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:28])=[O:3])=[O:8])=[C:18]2[OH:19]
Reactant: CCOC(=O)CNC(=O)c1c(O)c2cc(Cl)cc(-c3ccccc3)c2sc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1c(O)c2cc(Cl)cc(-c3ccccc3)c2sc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
[(6-Chloro-4-hydroxy-2-oxo-8-phenyl-2H-thiochromene-3-carbonyl)-amino]-acetic acid ethyl ester (200 mg, 0.479 mmol) was dissolved in THF-Methanol (1:1; 13 mL total volume.) Sodium hydroxide (1.5 mmol, 1.5 mL; 1M) was added and the solution stirred overnight at ambient temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved in water (10 mL.) The crude product was precipitated with 1N HCl (3 mL) and isolated via filtration and triturated with hexanes to provide the title compound (177 mg.) MS ESI(+) m/e: 390.118, 392.226 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BrH:13]>C(OCC)(=O)C>[Br:13][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCc1ccccc1
Reactant: Br
Solvent: CCOC(C)=O
Product: BrCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
50 g (0.304 mol) of 5-phenylpentan-1-ol are added to a solution of 416.7 ml (1.83 mol) of 48% strength hydrobromic acid at 0° C., and the mixture is stirred at 0° C. for 30 min. The reaction solution is subsequently stirred at 10° C. for 12 hours. After reaction is complete, the mixture is cooled to room temperature and mixed with 200 ml of ethyl acetate. After extraction, the organic phase is separated off, washed with saturated sodium bicarbonate solution and dried over sodium sulphate. After filtration, the filtrate is evaporated to dryness. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane). 59.4 g (0.26 mol, 86% yield) of a colourless liquid are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)C=Cc1ccc(C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C=Cc1ccc(CBr)cc1
Yield: 55 %

Procedure:
A mixture of ethyl p-methylcinnamate (19.0 g., 0.1 mole), N-bromosuccinimide (19.6 g., 0.11 mole), benzoyl peroxide (200 mg.), and carbon tetrachloride is stirred and heated at reflux for 4 hours. The mixture is cooled and succinimide removed by filtration. The filtrate is washed with 5% sodium hydroxide solution, water, and brine, and dried over sodium sulfate. The solvent is removed at reduced pressure, and the residue is distilled in vacuo to yield 14.8 g. (55%) of the title compound, b.p. 137°-140° C. (0.1 mm.).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH2:8][N:9]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:5]=[C:4]([CH2:26][N:27]([CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:3]=1.[NH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]#[CH:52])=[CH:47][CH:46]=1>C(N(CC)CC)C.C(Cl)(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]#[C:52][C:2]2[CH:3]=[C:4]([CH2:26][N:27]([CH2:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:28][C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])[N:5]=[C:6]([CH2:8][N:9]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH:7]=2)=[CH:47][CH:46]=1
Reactant: C#Cc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)Cc1cc(I)cc(CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)Cc1cc(C#Cc2ccc(N)cc2)cc(CN(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)n1
Reaction time: 1.5 h

Procedure:
A mixture of compound 1 (1.08 g, 1.5 mmol), bis(triphenylphosphine)palladium(II) chloride (21 mg, 0.03 mmol), copper(I) iodide (11 mg, 0.06 mmol) and p-aminophenylacetylene (176 mg, 1.5 mmol) in 10 mL of triethylamine was deaerated with nitrogen and kept at 40° C. for 1.5 h. The mixture was diluted with 40 mL of chloroform, washed with water and dried with sodium sulfate. The solution was evaporated in vacuo and the product was obtained as a yellow oil.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([NH2:33])[CH3:32]>>[CH3:32][C:31]1[N:33]=[C:26]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:27][N:30]=1
Reactant: CC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: Cc1noc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
200 mg (0.50 mmol) of the compound from Example 44A and 74 mg (0.75 mmol) of N′-hydroxyethanimidamide were reacted according to the General Method 2. Yield: 119 mg (52% of theory)
Reaction SMILES: C([O-])=O.[NH4+].C([N:12]1[CH2:18][CH2:17][C:16]2[C:19](Cl)=[N:20][C:21]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[N:22][C:15]=2[CH2:14][CH2:13]1)C1C=CC=CC=1>[Pd].CO>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][C:21]1[N:20]=[CH:19][C:16]2[CH2:17][CH2:18][NH:12][CH2:13][CH2:14][C:15]=2[N:22]=1
Reactant: Fc1ccccc1Cc1nc(Cl)c2c(n1)CCN(Cc1ccccc1)CC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Fc1ccccc1Cc1ncc2c(n1)CCNCC2
Yield: 11.5 %

Procedure:
Ammonium formate (112 mg, 1.78 mmol) and 10% palladium on carbon (27 mg, 0.27 mmol) was added to a solution of 7-benzyl-4-chloro-2-(2-fluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine the product of Preparation 31, Step B, (136 mg, 0.36 mmol) in methanol (12 ml) and heated to reflux for 5 h. The reaction mixture was filtered through Arbocel, the filtrate concentrated in vacuo and the residue purified by HPLC (Phenomenex column, acetonitrile:water:formic acid gradient) to afford the title compound as a colourless oil in 11.5% yield, 10.5 mg.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[CH3:29][O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1>>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([O:30][CH3:29])[CH:36]=2)=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: Cc1c(N(Cc2ccc(O)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 33A and 3-methoxyphenylboronic acid were processed as described in Example 48A to provide the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:9][NH:8][CH2:7]1)=[O:5].C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>C(Cl)Cl>[N:8]1([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:9][CH:6]([C:4]([O:3][CH3:2])=[O:5])[CH2:7]1
Reactant: COC(=O)C1CNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)C1

Procedure:
10 g of azetidine-3-carboxylic methyl ester hydrochloride and then 23 ml of triethylamine are added to 150 ml of CH2Cl2. The mixture is cooled and 13.5 g of benzyl chloroformate are added. After leaving overnight at AT, washing is carried out with water and then with HCl (N). After drying, concentrating to dryness and purifying by chromatography on silica (eluent: heptane-AcOEt (gradient from 0% to 50%)), 13.1 g of the expected compound are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C([O:18][C:19](=[O:50])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38]CC)=[O:37])[CH:31]=2)=[O:29])[CH:25]=[CH:24][C:23]=1[O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]Br)C>CCCCCC.C(OCC)(=O)C>[C:36]([C:32]1[CH:31]=[C:30]([C:28]([C:26]2[CH:25]=[CH:24][C:23]([O:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][O:1][C:2]3[CH:12]=[CH:11][C:5]4[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=4[C:3]=3[CH2:13][CH2:14][CH3:15])=[C:22]([CH2:21][CH2:20][C:19]([OH:50])=[O:18])[CH:27]=2)=[O:29])[CH:35]=[CH:34][CH:33]=1)([OH:38])=[O:37]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OCCCCCCCBr
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCc1c(OCCCCCCCOc2ccc(C(=O)c3cccc(C(=O)O)c3)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 62.7 %

Procedure:
Starting with 0.153 g (0.74 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, and 0.41 g (0.74 mmol) of 2-[(7-bromoheptyl)oxy]-5-[[3-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester, the title compound (0.286 g; 77.8% overall yield) was obtained as a white solid, mp 152°-153° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 22.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][CH2:6][C@@H:7]([OH:21])[CH2:8][NH:9][C@H:10]([CH3:20])[CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CN(C)[CH:27]=[O:28]>>[Si:13]([O:12][CH2:11][C@H:10]([N:9]1[CH2:8][C@@H:7]([CH2:6][O:5][C:4]2[CH:22]=[CH:23][CH:24]=[C:2]([Cl:1])[CH:3]=2)[O:21][C:27]1=[O:28])[CH3:20])([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15]
Reactant: CN(C)C=O
Reactant: C[C@H](CO[Si](C)(C)C(C)(C)C)NC[C@H](O)COc1cccc(Cl)c1
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)N1C[C@@H](COc2cccc(Cl)c2)OC1=O

Procedure:
A procedure similar to that described in Preparation 11 was repeated, except that 0.92 g of 1(S)-(3-chlorophenoxymethyl)-2-[2-t-butyldimethylsilyloxy-1(R)-methylethylamino]ethanol (prepared as described in Preparation 26), 0.48 g of N,N'-carbonyldiimidazole and 10 ml of anhydrous dimethylformamide were used, to give 0.92 g of the title compound having an Rf value of 0.25 (on silica gel thin layer chromatography, using a 1:2 by volume mixture of ethyl acetate and hexane as the developing solvent) and having [α]D =+34.1° (methanol, c=0.960).
Reaction SMILES: Br[C:2]1[CH:3]=[N+:4]([O-:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C>[N+:8]([C:7]1[CH:6]=[CH:5][N+:4]([O-:11])=[CH:3][C:2]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Br
Reactant: C1CCNCC1
Solvent: CCO
Product: O=[N+]([O-])c1cc[n+]([O-])cc1N1CCCCC1
Yield: 92 %

Procedure:
3-bromo-4-nitropyridine-N-oxide (1.0 equiv.) and piperidine (2.0 equiv.) in ethanol, at a concentration of 0.2 M, was heated at reflux for 16 hours. Upon cooling the ethanol was removed in vacuo. The residue was partitioned between EtOAc and Na2CO3(sat), and washed further with H2O, NaCl(sat.), was dried over MgSO4, was filtered and the volatiles were removed in vacuo yielding 4-nitro-3-(piperidin-1-yl)pyridine 1-oxide (92%). LCMS (m/z): 224.0 (MH+); LC Rt=2.48 min.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.CN(C)C=O.Cl[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>O>[N:2]1([O:1][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: CCCCCCCCCl
Reactant: On1nnc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOn1nnc2ccccc21
Temperature: 135 °C

Procedure:
A mixture of 1-hydroxybenzotriazole (30.6 g), N,N-dimethylformamide (150 ml), 1-chlorooctane (32.7 g) and potassium carbonate (50 g) was heated at 135° C. for 0.5 hr. while stirring. The reaction mixture was poured into water and the resulting mixture was extracted with benzene. The benzene extract was dried and stripped of solvent by rotary evaporation and distillation to a pot temperature of 100 C. at a pressure of less than 0.1 mm of mercury. The product, n-octyl 1-benzotriazolyl ether was obtained as a clear yellow oil residue. The elemental analysis was as follows:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:17]=[CH:16][C:11](/[C:12](/[NH2:15])=[N:13]/[OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[F-].[CH2:23]([N+](CCCC)(CCCC)CCCC)[CH2:24]CC>C1COCC1>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]3[N:15]=[C:23]([CH3:24])[O:14][N:13]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: N/C(=N\O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(Oc3ccc(C(F)(F)F)cc3)cc2)no1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 12.2 %

Procedure:
(Z)-4-(4-(Trifluoromethyl)phenoxy)-N′-hydroxybenzamidine (79 mg, 0.23 mmol) was placed under nitrogen and THF was added. Then tetrabutylammonium fluoride (67 μL, 0.23 mmol) was added dropwise and the solution was stirred at room temperature for 92 hours 40 minutes. The product was purified by column chromatography over silica gel (EtOAc/Hex 1:12) to give a white solid (9.0 mg, 12%). 1H NMR (500 MHz, CDCL3) δ(ppm): 2.66 (3H, s), 7.11-7.14 (4H, m), 7.62 (2H, d, J=8.4 Hz), 8.08 (2H, d, J=9.0 Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 12.61 (CH3), 119.0 (CH), 119.7 (CH), 122.9, 125.3, 126.0 (C, q, J=32.5 Hz), 127.5 (CH, q, J=3.8 Hz), 129.6 (CH), 158.7, 159.6, 167.9, 176.8. 19F (282 MHz, CDCL3) δ(ppm): −61.89 (3F, s). MS (FAB+): 321 (MH+). HRMS for C16H11F3N2O2 (MH+): calculated: 320.0773; found 320.0779.