Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[C:10]2=[O:19])[CH2:5][CH2:4]1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[N:22]=1.C(N(CC)CC)C.CN1CCCC1=O>[Cu]I>[OH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[CH2:13][CH2:12][C:11]3([CH2:18][CH2:17][CH2:16][N:15]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[N:22]=4)[CH2:14]3)[C:10]2=[O:19])[CH2:5][CH2:4]1
Reactant: COc1cccc(Br)n1
Reactant: O=C1N([C@H]2CC[C@H](O)CC2)CCC12CCCNC2
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COc1cccc(N2CCCC3(CCN([C@H]4CC[C@H](O)CC4)C3=O)C2)n1

Procedure:
A mixture of 2-(trans-4-hydroxycyclohexyl)-2,7-diazaspiro[4.5]decan-1-one hydrochloride (35 mg, 0.00012 mol), 2-bromo-6-methoxypyridine (34 mg, 0.00018 mol), triethylamine (200 μL, 0.001 mol), and copper(I) iodide (28 mg, 0.00014 mol) in N-methylpyrrolidinone (1.0 mL, 0.010 mol) was microwave irradiated at 180° C. for 20 min. After allowing the reaction mixture to cool to rt the crude mixture was purified by prep.-HPLC to afford 8.3 mg of the desired product. LC-MS: 360.3 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([S:10](Cl)(=[O:12])=[O:11])[CH3:9].[CH2:14]([O:18][C:19]1[CH:20]=[C:21]([CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:22]=[CH:23][C:24]=1[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([O:35][CH3:36])[CH:29]=1)[CH2:15][CH2:16][CH3:17].[Cl-].[Na+]>ClCCl>[CH2:14]([O:18][C:19]1[CH:20]=[C:21]([CH2:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:22]=[CH:23][C:24]=1[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][S:10]([CH2:8][CH3:9])(=[O:12])=[O:11])=[C:30]([O:35][CH3:36])[CH:29]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCOc1cc(CCC(=O)OC)ccc1CCCc1ccc(O)c(OC)c1
Reactant: CCS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOc1cc(CCC(=O)OC)ccc1CCCc1ccc(OS(=O)(=O)CC)c(OC)c1
Temperature: -20 °C
Reaction time: 3 h
Yield: 100.4 %

Procedure:
0.2 ml (1.6 mmol) of triethylamine and then 0.15 ml (1.7 mmol) of ethanesulfonyl chloride are added to a solution of 0.5 g (1.25 mmol) of methyl 3-{3-butoxy-4-[3-(4-hydroxy-3-methoxyphenyl)propyl]phenyl}propanoate (prepared according to Example 1d) in 3 ml of dichloromethane, cooled beforehand to −20° C. The reaction medium is stirred at room temperature for 3 hours and is then treated by addition of saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered and evaporated. The residue is purified by chromatography on a column of silica eluted with a 90/10 heptane/ethyl acetate mixture. 618 mg (99%) of methyl 3-{3-butoxy-4-[3-(4-ethanesulfonyloxy-3-methoxyphenyl)propyl]phenyl}propanoate are obtained in the form of a colorless oil.
Reaction SMILES: CS(C)=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[H-].[Na+].[N+]([C:18]1[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=1)([O-])=O>O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:18]2[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=2)=[CH:8][CH:7]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(Oc2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.2 %

Procedure:
To a solution of DMSO (50 mL) of p-fluorophenol (3.6 g) was added NaH (1.3 g/60% in oil) at room temperature, which was stirred for 15 minutes at room temperature. 5-Nitro-furan-2-carbaldehyde (5.0 g) was then added thereto, which was stirred for 40 minutes at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate. The solvent was evaporated from the organic layer under a reduced pressure, and the residue was purified by silica gel chromatography (heptane:ethyl acetate=2:1) to obtain 5-(4-fluoro-phenoxy)-furan-2-carbaldehyde (1.6 g).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C:17](=[O:20])[CH2:18][CH3:19])[CH:12]=[CH:11][C:10]=1[N:21]1[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]1)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CCO.O.[Pd]>[OH:8][C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][C:17](=[O:20])[CH2:18][CH3:19])[CH:12]=[CH:11][C:10]=1[N:21]1[S:25](=[O:27])(=[O:26])[NH:24][C:23](=[O:28])[CH2:22]1
Reactant: CCC(=O)/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCC(=O)CCc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1
Reaction time: 2 h

Procedure:
To a solution of 5-[2-benzyloxy-4-((E)-3-oxo-pent-1-enyl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one (130 mg, 0.325 mmol) in 7 mL of EtOH/water (2:5) is added K2CO3 (53 mg, 0.39 mmol) and 10% Pd/C (65 mg). The mixture is hydrogenated at 1 atm for 2 h then the catalyst is filtered and the solvent removed under reduced pressure. The residue is purified by preparative HPLC to give the title compound as a white solid: (M−1)−=311. HPLC retention time: 1.31 min (Method A).
Reaction SMILES: [C:1]([NH:9][CH:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:11]([OH:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:26][CH:27](OCC)OCC)[CH3:25].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C1C=CC=CC=1>[C:1]([N:9]1[C@@H:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[O:17][CH:27]1[O:26][CH2:24][CH3:25])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)C(O)C(NC(=O)c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccccc1
Product: CCOC(=O)[C@@H]1OC(OCC)N(C(=O)c2ccccc2)[C@H]1c1ccccc1

Procedure:
[R-(R*,S*)]-β-(Benzoylamino)-α-hydroxybenzenepropanoic acid, ethyl ester (1.16 mmol) is suspended in benzene (10 ml), and triethoxymethane (3.44 mmol) and PPTS (72 mg) are added. Heating to reflux provides the title compound.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[Si:24]([O:31][C:32]([CH3:45])([CH3:44])[CH2:33][N:34]1[CH:38]=[C:37]([Sn](C)(C)C)[N:36]=[C:35]1[CH3:43])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>O1CCOCC1.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>[Si:24]([O:31][C:32]([CH3:45])([CH3:44])[CH2:33][N:34]1[CH:38]=[C:37]([C:2]2[CH:23]=[CH:22][C:5]3[C:6]4[N:7]([CH:11]=[C:12]([C:14]5[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:16][N:15]=5)[N:13]=4)[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)[N:36]=[C:35]1[CH3:43])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: Cc1nc([Sn](C)(C)C)cn1CC(C)(C)O[Si](C)(C)C(C)(C)C
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)cn1CC(C)(C)O[Si](C)(C)C(C)(C)C
Temperature: 120 °C
Reaction time: 0.58 h
Yield: 35.6 %

Procedure:
To a mixture of 9-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (300 mg, 0.8 mmol), Pd(PPh3)4 (93 mg, 0.08 mmol), 1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-2-methyl-4-(trimethylstannyl)-1H-imidazole (690 mg, 1.6 mmol) in dioxane (2 mL) was bubbled with N2 for about 2 min and then stirred at 120° C. for 35 min under the irradition of microwave. Filtered, concentrated and purified by pre-TLC (pure EtOAc) to give 160 mg of 9-(1-(2-(tert-butyldimethylsilyloxy)-2-methylpropyl)-2-methyl-1H-imidazol-4-yl)-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine. Yield=46%. LC-MS: m/z=548 [M+H+]
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[NH:21][CH:22]=3)[C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:25]=1)[CH3:2].[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[CH:30]=1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH:16]([C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[N:21]([CH2:35][C:31]4[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=4)[C:28]([O:27][CH3:26])=[O:37])[CH:22]=3)[C:11]3[N:12]=[C:13]([CH3:15])[O:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH:25]=1)[CH3:2]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CCc1ccc2c(c1)C=Cc1oc(C)nc1C2c1c[nH]c(=O)[nH]c1=O
Product: CCc1ccc2c(c1)C=Cc1oc(C)nc1C2c1cn(Cc2cccc(C(=O)OC)c2)c(=O)[nH]c1=O

Procedure:
The subtitle compound was prepared from the product of example 3 step (vii) (2. g) and 3-bromomethyl benzoic acid methyl ester (0.5 g) using the method of example 1 step (viii). Purification was by chromatography eluting with 60% ethyl acetate in toluene.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]([O:20]C)=[O:19])[CH:13]=2)=[CH:8][C:7]=1[CH:22]1[C:35]2[C:34](=[O:36])[CH2:33][C:32]([CH3:38])([CH3:37])[CH2:31][C:30]=2[O:29][C:28]2[CH2:27][C:26]([CH3:40])([CH3:39])[CH2:25][C:24](=[O:41])[C:23]1=2>O.C1COCC1>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([C:18]([OH:20])=[O:19])[CH:13]=2)=[CH:8][C:7]=1[CH:22]1[C:35]2[C:34](=[O:36])[CH2:33][C:32]([CH3:37])([CH3:38])[CH2:31][C:30]=2[O:29][C:28]2[CH2:27][C:26]([CH3:40])([CH3:39])[CH2:25][C:24](=[O:41])[C:23]1=2
Reactant: COC(=O)c1cc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2)ccn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccnc(C(=O)O)c2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reaction time: 1 h
Yield: 73.2 %

Procedure:
A solution of lithium hydroxide monohydrate (21.7 mg, 0.52 mmol) in water (2.4 ml) was added to a solution of the methyl 4-[4-methoxy-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridine-2-carboxylate produced in Example 2-1 (121 mg, 0.23 mmol) in THF (4.8 ml) at room temperature, and the mixed solution was then stirred at the same temperature as above for 1 hour. Thereafter, water was added to the reaction solution, and the mixed solution was then washed with diethyl ether. A 1 N aqueous solution of hydrochloric acid (0.52 ml) was added to the water layer, and the mixed solution was then extracted with dichloromethane four times. The organic layer thus obtained was dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure, and the residue thus obtained was then washed with a mixed solution of diethyl ether and hexane, followed by collection by filtration and drying, to obtain the title compound (84.5 mg, yield: 72%).
Reaction SMILES: Cl.[N:2]1([CH2:7][CH2:8]Cl)[CH2:6][CH2:5][CH2:4][CH2:3]1.[SH:10][CH2:11][C:12]1[NH:13][C:14]([CH3:37])=[C:15]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=2)[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[O-]CC.[Na+].CC(O)=O>C(O)C>[N:2]1([CH2:7][CH2:8][S:10][CH2:11][C:12]2[NH:13][C:14]([CH3:37])=[C:15]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)[C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)C1=C(C)NC(CS)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: ClCCN1CCCC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(CSCCN2CCCC2)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Yield: 41.8 %

Procedure:
A solution of 2-(pyrrolidin-1-yl)-1-chloroethane hydrochloride (2.8 g), 2-mercaptomethyl-3,5-dicarboethoxy-4-(m-nitrophenyl) -6-methyl-1,4-dihydropyridine (5.4 g) and sodium ethoxide (2 g) in ethanol (70 ml) is heated to the reflux temperature for 6 hours, then it is neutralized with AcOH and evaporated under reduced pressure. The residue, after the usual work-up, is purified by column-chromatography (SiO2 ; 210 g; eluent AcOH/MeOH 99/1) to give 2.8 g of 2-[2-(pyrrolidin-1-yl)ethylthio]methyl-3,5-dicarboethoxy-4-(m-nitrophenyl) -6-methyl-1,4-dihydropyridine, as an oil, that upon treatment with fumaric acid gives the corresponding salt, m.p. 192°-194° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8](OC)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].O.[NH2:15][NH2:16]>CCO>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([NH:15][NH2:16])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 4-nitrobenzoate (5.42 g; 29.92 mmol; 1 eq.) is dissolved in EtOH (120 ml). Hydrazine hydrate (7.27 ml; 149.60 mmol; 5 eq.) is added and the mixture is stirred 1 hour at rt. It is stirred at 60° C. for 6 hours and rt overnight. The precipitate formed is filtrated and dried under vacuo, affording 4-nitrobenzohydrazide as white-off solid (4.31 g; 79%). 1H NMR (DMSO-d6) δ: 4.63 (s, 2H), 8.03 (d, J=9 Hz, 2H), 8.23 (d, J=9 Hz, 2H), 10.12 (s, 1H). HPLC (method A), Rt: 0.78 min (purity: 100.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[S:7].[CH2:12]([O:14][C:15](=[O:21])[CH:16](Cl)[C:17](=O)[CH3:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[S:7][C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:8][C:17]=1[CH3:18])=[O:21])[CH3:13]
Reactant: COc1cccc(C(N)=S)c1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1sc(-c2cccc(OC)c2)nc1C
Temperature: 25 °C
Yield: 91.7 %

Procedure:
A mixture of 3-methoxy-thiobenzamide (1.99 g, 11.88 mmole) and 2-chloro-3-oxo-butyric acid ethyl ester (1.7 ml, 12.11 mmole) in ethanol (20 ml) was refluxed for 18 h before it was cooled to room temperature and concentrated in vacuo. It was partitioned between ethyl acetate and saturated sodium bicarbonate, the organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as a yellow solid (3.02 g). MS: (+) m/z 277.93 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@H:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][C@H:9]1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([O:30]C)=[O:29])=[N:26][CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@H:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][C@H:9]1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[N:26][CH:27]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O)c3ccccc3)N2C(=O)OC(C)(C)C)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)nc2)CC[C@@H]1[C@H](O)c1ccccc1
Temperature: 60 °C

Procedure:
To a solution of methyl 5-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)pyridine-2-carboxylate (330 mg, 0.77 mmol) in THF (4 mL) and methanol (4 mL) was added 1N NaOH solution (4 mL, 4.0 mmol) and the resulting solution heated at 60° C. for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure to remove the organic solvents. The aqueous layer was adjusted to pH of 6.5 (using 2.0M aqueous HCl) and extracted with ethyl acetate (2×10 mL) and dichloromethane (10 mL). The organics were combined, dried over sodium sulfate, filtered, and concentrated to dryness under vacuum. The product (304 mg, 96%) did not require any further purification and was of reagent grade quality for analog syntheses. LC-MS: C23H28N2O5 calculated 412.20 found m/z (ES) 413.1 (MH)+ and 313.2 (M-Boc)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])[C:10]3[N:14]=[C:13]([O:15]CC)[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[CH:28]1([Mg]Cl)[CH2:32][CH2:31][CH2:30][CH2:29]1>C1COCC1>[CH:28]1([C:19]([OH:20])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[C:9]2[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:18]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:27])[CH:8]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOc1nc2c(C(=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Reactant: Cl[Mg]C1CCCC1
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1cc(C(O)(c2ccccn2)C2CCCC2)c2[nH]c(=O)[nH]c2c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (50 mg, 0.14 mmol) was dissolved in dry THF (1.4 mL) under argon and cooled to 0° C. Cyclopentylmagnesium chloride (2.0 M, 0.14 mL, 0.28 mmol) was added dropwise and reaction was allowed to stir for 10 minutes then quenched with water. Reaction mixture was extracted three times with EtOAc and combined organic layers were washed once with water and concentrated. Residue was taken up in EtOH (1.5 mL) and 4.0M HCl/dioxane (0.75 mL) and heated to 65° C. for 2 hours. Reaction was concentrated and purified by reverse-phase HPLC to afford the desired product as a white powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([S:49][CH2:50][CH2:51][OH:52])[CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C@@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([S:49][CH2:50][CH2:51][OH:52])[CH:44]=2)[N:36]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(SCCO)c2)n1
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(SCCO)c4)c4ccccc43)cn12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of Intermediate 5c (109 mg, 0.3 mmol) and Intermediate 35c (140 mg, 0.3 mmol) in 1,4-dioxane (3 mL) and DIPEA (78 μL, 0.45 mmol) was stirred at 90° C. for 4 h. The cooled mixture was concentrated in vacuo. The residue was purified by FCC, using 0-14% MeOH in DCM, to give the title compound as an off-white powder after freeze-drying (115 mg, 56%). LCMS (Method 5): Rt 3.47 min, m/z 681 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.28 (9H, s), 1.83-2.26 (11H, m), 2.31-2.39 (1H, m), 3.04 (2H, t, J 6.8), 3.09 (1H, m), 3.59 (2H, q, J 6.0), 3.99 (1H, t, J 8.2), 4.78-4.86 (1H, m), 4.95 (1H, t, J 5.6), 5.36-5.41 (1H, m), 6.33 (1H, s), 7.08 (1H, d, J 8.4), 7.24-7.46 (9H, m), 7.75 (1H, d, J 9.6), 8.12 (1H, s), 8.25 (1H, br d).
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][C:41]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(=O)=O.[H-].[Na+]>CN(C)C=O>[C:42]1([C:41]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[O:40][CH2:39][CH2:38][O:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: OCCOCCOCCOCCOCCOCCOCc1ccccc1
Reactant: CS(=O)(=O)OCCOCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COCCOCCOCCOCCOCCOCCOCCOCCOCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 73.8 %

Procedure:
To 17-phenylmethyloxy-3,6,9,12,15-pentaoxaheptadecan-1-ol (15) (16.38 g, 43.9 mmol) in dry dimethylformamide (250 ml) was added 8-triphenylmethyloxy-3,6-dioxaoctyl methanesulfonate (13) (28.23 g, 60 mmol, 1.35 eq.) and sodium hydride (4.0 g, 100 mmol, 2.3 eq., 60% w/w in mineral oil). The reaction was left to stir for four days at room temperature after which time it was concentrated in vacuo. The reaction mixture was re-dissolved in diethyl ether (400 ml) and cooled in an ice bath to 0° C. Water was then slowly added until hydrogen was no longer evolved. The organic phase was ten partitioned twice with aq. sat. NaCl with a little NaHCO3 (2×300 ml), dried over anhydrous sodium sulphate and concentrated in vacuo to give a viscous dark brown oil. The product was isolated by N.P.S.G. chromatography, eluting with ethyl acetate only to yield (16) as a yellow oil (24.2 g, 75.0%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24].C(=O)([O-])O.[Na+]>CN(C)C=O>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:17][CH2:18][CH2:19][CH2:20][O:21][Si:22]([CH:26]([CH3:27])[CH3:28])([CH:23]([CH3:25])[CH3:24])[CH:29]([CH3:30])[CH3:31])[C:7]=2[CH:13]=1
Reactant: CC(C)[Si](OCCCCBr)(C(C)C)C(C)C
Reactant: O=C1COc2ccc(CO)cc2N1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[Si](OCCCCN1C(=O)COc2ccc(CO)cc21)(C(C)C)C(C)C
Reaction time: 1 h

Procedure:
The stirred solution of 3.70 g of 6-hydroxymethyl-4H-benzo[1,4]oxazin-3-one (Example 2d) and 95 ml of N,N-dimethylformamide is cooled to 0° C., admixed with 0.808 g of sodium hydride (60% dispersion) and stirred over 1 hour. After 7.57 g of (4-bromobutoxy)triisopropylsilane have been added, the mixture is stirred at 0° C. over a further 18 hours and the resulting reaction mixture is poured onto aqueous 1M sodium hydrogencarbonate solution (200 ml). The mixture is extracted with tert-butyl methyl ether (2×200 ml). The organic phases are washed successively with water (3×200 ml) and brine (200 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.43 (1:1 EtOAc-heptane); Rt=5.86.
Reaction SMILES: [F:1][C:2]1[C:8](F)=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.CCN(CC)CC>CS(C)=O.II>[F:1][C:2]1[C:3]([NH2:4])=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1[NH:19][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1
Reactant: Nc1c([N+](=O)[O-])ccc(F)c1F
Reactant: NCc1ccc(F)cc1
Agent: II
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1c([N+](=O)[O-])ccc(NCc2ccc(F)cc2)c1F
Temperature: 120 °C
Reaction time: 24 h
Yield: 62.8 %

Procedure:
To a stirred suspension of compound 2 (0.100 g, 0.570 mmol, 1.00 equiv) in dry DMSO (4.6 mL) were added 4-fluorobenzylamine (0.210 g, 1.72 mmol, 3.00 equiv) followed by Et3N (69.6 mg, 0.690 mmol, 1.20 equiv) and I2 (catalytic, 1.00 mg). The reaction mixture was heated to 120° C. and stirred at 120° C. for 24 h. After consumption of the starting material (by TLC), the reaction mixture was cooled to RT, diluted with water (25 mL) and extracted with EtOAc (2×25 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude; which was purified by silica gel column chromatography (EtOAc/Hexane 2:23) to afford compound 3 (0.100 g, 62.5%) as yellow solid. TLC: 20% EtOAc/Hexane (Rf: 0.20); 1H NMR (400 MHz, CDCl3): δ 7.87 (dd, J=1.60, 9.60 Hz, 1H), 7.31-7.28 (m, 2H), 7.08-7.03 (m, 2H), 6.11-6.03 (m, 3H, 2Exc), 4.82 (br s, 1H, Exc), 4.44 (d, J=5.2 Hz, 2H); LC-MS: m/z=278 (M+-1) at RT 3.64 (91.7% purity)