Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:12]3[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:7][C:6]=2[N:5]=[CH:4]1)[CH3:2].C(N1C2CN(C3C([N+]([O-])=O)=CC=CN=3)CCC=2NC1)C.[CH2:41]=[O:42]>>[CH2:1]([N:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:12]3[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:7][C:6]=2[N:5]=[C:4]1[CH2:41][OH:42])[CH3:2]
Reactant: CCn1cnc2c1CCN(c1ncccc1[N+](=O)[O-])C2
Reactant: C=O
Agent: CCN1CNC2=C1CN(c1ncccc1[N+](=O)[O-])CC2
Product: CCn1c(CO)nc2c1CCN(c1ncccc1[N+](=O)[O-])C2
Temperature: 150 °C

Procedure:
A mixture of 1-ethyl-5-(3-nitro-pyridin-2-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 3-ethyl-5-(3-nitro-pyridin-2-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine in 37% formaldehyde (5 mL) in a sealed tube is heated at 150° C. overnight. The mixture is allowed to cool to ambient temperature and evaporated under reduced pressure. The resulting residue is partitioned between ethyl acetate and water and the layers are separated. The aqueous layer is further extracted with ethyl acetate and the combined organic extracts are dried over Na2SO4, filtered and the solvents removed under reduced pressure. Column chromatography of the residue on silica gel (5% MeOH in CH2Cl2 as eluent) gives [1-ethyl-5-(3-nitro-pyridin-2-yl)-4,5,6,7-tetrahydro-1H-imidazo [4,5-c]pyridin-2-yl]-methanol (80 mg). 1H NMR (CDCl3) δ: 8.33 (d, 1H), 8.15 (dd, 1H), 6.73 (q, 1H), 4.64 (s, 2H), 4.22 (s, 2H), 3.90-3.98 (m, 4H), 2.82(t, 2H) and 1.36 (t, 3H). MS: 304.2 (m+1).
Reaction SMILES: [CH2:1]([C:9]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][C:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:17][CH:18]=3)[CH:13](O)[CH2:12][C:11]=2[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CCN(S(F)(F)[F:38])CC>ClCCl>[F:38][CH:13]1[CH2:12][C:11]2[CH:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][C:16]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:17][CH:18]=2
Reactant: CCN(CC)S(F)(F)F
Reactant: CCCCCCCCc1ccc2c(c1)CC(O)c1cc(CCCCCCCC)ccc1-2
Solvent: ClCCl
Product: CCCCCCCCc1ccc2c(c1)CC(F)c1cc(CCCCCCCC)ccc1-2

Procedure:
From 2,7-dioctyl-9,10-dihydrophenanthren-9-ol by reaction with DAST in abs. dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:17][OH:18])[C:9]2[CH:14]=[CH:13][C:12](C)=[CH:11][C:10]=2O)=[CH:4][CH:3]=1.[C:19](=O)([O-])[O-].[Na+].[Na+].O1C2C=CC=CC=2C=N1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[CH:10]=[C:11]([CH3:19])[CH:12]=[CH:13][C:14]=3[O:18][N:17]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=NO)c2ccc(Cl)cc2)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc2oncc2c1
Solvent: O
Product: Cc1ccc2onc(-c3ccc(Cl)cc3)c2c1

Procedure:
4'-Chloro-2-hydroxy-4-methylbenzophenone-oxime (0.2g) and anhydrous sodium carbonate (0.2g) were heated together under reflux in triglyome (5ml) for 30 minutes. On cooling, the mixture was poured into water (50ml.) and filtered. On standing a solid separated from the filtrate and was filtered, washed, dried and examined by NMR. The NMR spectrum was consistent with the preparation of the title compound (~30%). T.L.C. also confirmed the presence of the benzisoxazole.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([C:19]3[C:20]([Cl:25])=[N:21][CH:22]=[CH:23][CH:24]=3)=[O:18])[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.C(OC(=O)C)C.Cl>C(#N)C>[O:2]=[C:3]1[C:8]([CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][C:17]([C:19]3[C:20]([Cl:25])=[N:21][CH:22]=[CH:23][CH:24]=3)=[O:18])[CH2:14][CH2:15]2)=[CH:7][CH:6]=[CH:5][NH:4]1
Reactant: COc1ncccc1CN1CCC(CC(=O)c2cccnc2Cl)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(CC1CCN(Cc2ccc[nH]c2=O)CC1)c1cccnc1Cl
Yield: 47.9 %

Procedure:
In acetonitrile (4 ml) were dissolved 100 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(2-chloro-3-pyridyl)-2-oxoethyl)piperidine obtained in Example 62 and 0.35 ml of a 4 M hydrogen chloride ethyl acetate solution, followed by heating under reflux for 1 hour. The solvent was evaporated, and then the residue was dissolved in ethyl acetate and a 1N sodium hydroxide aqueous solution. The organic layer was separated, washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was recrystallized from ethanol, to give 46 mg of the title compound as colorless crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][C:11]([OH:13])=O)=[O:5])C.[NH2:17][CH2:18][CH:19]([OH:22])[CH2:20][NH2:21]>>[OH:22][CH:19]([CH2:20][NH:21][C:11](=[O:13])[CH2:10][O:9][C:8]1[CH:7]=[C:6]([CH:16]=[CH:15][CH:14]=1)[C:4]([OH:3])=[O:5])[CH2:18][NH:17][C:11](=[O:13])[CH2:10][O:9][C:8]1[CH:7]=[C:6]([CH:16]=[CH:15][CH:14]=1)[C:4]([OH:5])=[O:3]
Reactant: NCC(O)CN
Reactant: CCOC(=O)c1cccc(OCC(=O)O)c1
Product: O=C(COc1cccc(C(=O)O)c1)NCC(O)CNC(=O)COc1cccc(C(=O)O)c1

Procedure:
By following the processes described in stages A to C of Example R13, Example R15 is prepared by dimerization of [3-(ethoxycarbonyl)phenoxy]acetic acid with 1,3-diaminopropan-2-ol. A white powder is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:15]=[CH:14][N:13]([CH2:16][C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=4)[N:12]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[CH3:35][S:36]([NH:39][C:40]1[CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:43]=[CH:42][C:41]=1[N:55]1[CH2:60][CH2:59][N:58]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:57][CH2:56]1)(=[O:38])=[O:37].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.C(OCC)(=O)C.CCCCCC.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>[F:23][C:21]1[CH:22]=[C:17]([CH:18]=[C:19]([F:24])[CH:20]=1)[CH2:16][N:13]1[CH:14]=[CH:15][C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:44]4[CH:43]=[CH:42][C:41]([N:55]5[CH2:56][CH2:57][N:58]([C:61]([O:63][C:64]([CH3:65])([CH3:66])[CH3:67])=[O:62])[CH2:59][CH2:60]5)=[C:40]([NH:39][S:36]([CH3:35])(=[O:37])=[O:38])[CH:45]=4)[CH:3]=3)[N:8]([S:25]([C:28]3[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=3)(=[O:26])=[O:27])[CH:9]=2)=[N:12]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccn(Cc4cc(F)cc(F)c4)n3)c3cc(Br)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2NS(C)(=O)=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccn(Cc4cc(F)cc(F)c4)n3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)c(NS(C)(=O)=O)c4)cnc32)cc1
Yield: 39.9 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3,5-difluorobenzyl)-1H-pyrazol-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (intermediate 63) (100 mg, 0.184 mmol) was coupled with tert-butyl 4-(2-(methylsulfonamido)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (intermediate 69G) (106 mg, 0.22 mmol) using sodium carbonate (58 mg, 0.552 mmol) and Pd(PPh3)4 (10 mg, 0.009 mmol) in toluene/ethanol/water (2/2/1 ml). This afforded 60 mg (39.9% yield) after preparative TLC (Silicagel-1000 micron) using 40% ethyl acetate in hexane as eluent. MS: m/z=818.6 (M+1).
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[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].C1([C@@H]2[O:40][CH:39]([CH2:41][O:42][NH2:43])[CH2:38][CH2:37][O:36]2)C=CC=CC=1>>[OH:40][C@@H:39]([CH2:38][CH2:37][OH:36])[CH2:41][O:42][NH:43][C:20]([C:11]1[C:12](=[O:19])[N:13]([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:10]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1])=[O:21]
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Reactant: NOCC1CCO[C@H](c2ccccc2)O1
Product: Cn1c(Nc2ccc(I)cc2F)c(C(=O)NOC[C@@H](O)CCO)c(=O)n(C)c1=O
Yield: 87 %

Procedure:
The title compound was synthesized following a similar procedure described in the synthesis of Example 2 by treatment of compound 2A with O—((S)-2-Phenyl-[1,3]dioxan-4-ylmethyl)-hydroxylamine, followed by acid hydrolysis of the resulting material (total yield 87%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.32 (s, 1H) 11.97 (s, 1H) 7.80 (dd, J=10.11, 1.77 Hz, 1H) 7.58 (d, J=8.84 Hz, 1H) 7.15 (t, J=8.59 Hz, 1H) 4.90 (d, J=4.29 Hz, 1H) 4.38 (t, J=5.05 Hz, 1H) 3.74-3.86 (m, 2H) 3.56-3.66 (m, 1H) 3.45-3.53 (m, 2H) 3.21 (s, 3H) 2.96 (s, 3H) 1.35-1.56 (m, 2H). [M+H] calc'd for C17H20FIN4O6, 523. found, 523.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4](=[O:12])[CH2:3]1.[CH3:13]C1C=C(C)C=C2C=1CCC(=O)C2>>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4](=[O:12])[CH2:3]1
Reactant: CC1CC(=O)Cc2ccccc21
Reactant: Cc1cc(C)c2c(c1)CC(=O)CC2
Product: CC1(C)CC(=O)Cc2ccccc21

Procedure:
Using method A, 4-methyl-2-tetralone and 5,7-dimethyl-2-tetralone were also prepared.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([OH:17])=O)[N:12]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:25][C:26]1[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1>>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]([N:36]3[CH2:37][CH2:38][N:33]([C:27]4[C:26]([Br:25])=[CH:31][CH:30]=[C:29]([CH3:32])[N:28]=4)[CH2:34][CH2:35]3)=[O:17])[N:12]([CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)[C:11]2=[O:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(Br)c(N2CCNCC2)n1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2)C(=O)N1C1CCCCC1
Product: Cc1ccc(Br)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3C3CCCCC3)CC2)n1

Procedure:
In analogy to example 1, (RS)-1-benzenesulfonyl-3-cyclohexyl-2-oxo-imidazolidine-4-carboxylic acid (example 39, step 4) was coupled with 1-(3-bromo-6-methyl-pyridin-2-yl)-piperazine to give the title compound as a colorless solid. MS: 591.7 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=2)[C:10]=1[C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1)=[O:22].B(Br)(Br)Br.C(#N)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[C:10]=1[C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1)=[O:22]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3cc(F)ccc3F)ccc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2cc(F)ccc2F)ccc2cc(O)ccc12
Reaction time: 2 h
Yield: 87.9 %

Procedure:
Convert [2-(2,5-difluoro-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (1.8 g, 3.5 mmol) to the hydrochloride salt and dissolve it in 300 mL methylene chloride. Chill the mixture in ice and slowly add boron tribromide (5.0 mL, 53.0 mmol) with swirling. Allow the mixture to come to room temperature and stir for two hours. Add to this mixture acetonitrile (15 mL) slowly and with stirring which produces an orange precipitate. Pour the mixture into saturated sodium bicarbonate with stirring, separate the organic layer and dry with molecular sieves to give 1.5 g of the title compound (86%).
Reaction SMILES: [CH2:1]([C@H:8]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9](=[O:15])[NH:10][CH2:11][CH2:12][CH:13]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][C@@H:28]([C@H:36]([C@@H:38]1[C@@H:42]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[C@@H:41]([O:51][Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53])[C@H:40]([N:59]2[CH:64]=[CH:63][C:62](=[O:65])[N:61]([CH2:66][C:67]3[CH:72]=[CH:71][C:70]([O:73][CH3:74])=[CH:69][CH:68]=3)[C:60]2=[O:75])[O:39]1)[OH:37])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.O1CCCC1>[CH2:1]([C@@H:8]([C:9](=[O:15])[NH:10][CH2:11][CH2:12][CH2:13][NH:27][C@@H:28]([C@H:36]([CH:38]1[C@@H:42]([O:43][Si:44]([C:47]([CH3:48])([CH3:49])[CH3:50])([CH3:46])[CH3:45])[C@@H:41]([O:51][Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:53])[CH3:54])[C@H:40]([N:59]2[CH:64]=[CH:63][C:62](=[O:65])[N:61]([CH2:66][C:67]3[CH:72]=[CH:71][C:70]([O:73][CH3:74])=[CH:69][CH:68]=3)[C:60]2=[O:75])[O:39]1)[OH:37])[C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3O[C@H]([C@H](O)[C@H](N)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Reactant: O=CCCNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@H](Cc4ccccc4)NC(=O)OCc4ccccc4)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 21 %

Procedure:
By using an analogous procedure to that described for Example 1, a solution of benzyl (1S)-1-benzyl-2-oxo-2-[(3-oxopropyl)amino]ethylcarbamate (61 mg, 0.173 mmol, obtained from Reference Example 22), tert-butyl (2S,3R)-2-amino-3-[(2R,3R,4R,5R)-3,4-bis{[tert-butyl-(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)-tetrahydro-2-furanyl]-3-hydroxypropanoate (100 mg, 0.139 mmol, obtained from Reference Example 6), acetic acid (1 drop), and sodium triacetoxyborohydride (59 mg, 0.277 mmol) in anhydrous tetrahydrofuran (4 ml) was stirred at room temperature under nitrogen for 5 hours. The product was purified by chromatography (flash column, silica gel, 2.5% methanol in methylene chloride) to provide tert-butyl (5S,12S)-5-benzyl-12-[(R)-[(3R,4R,5R)-3,4-bis{[tertbutyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (31 mg, 21%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:7]([CH:10]=1)[CH:8]=O.[CH2:21]([NH2:29])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:7]([CH:8]=[N:29][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:10]=1
Reactant: NCCc1ccccc1
Reactant: COc1ccc(OCCCN2CCOCC2)c(C=O)c1
Solvent: Cc1ccccc1
Product: COc1ccc(OCCCN2CCOCC2)c(C=NCCc2ccccc2)c1
Temperature: 50 °C
Yield: 92.1 %

Procedure:
5-Methoxy-2-[3-(4-morpholinyl)propoxy]benzaldehyde (33.4 g) and 14.5 g of phenethylamine are refluxed in 120 ml of toluene for about 1 hour. After cooling to about 50° C., the solvent is removed using a rotary evaporator and the oily residue is distilled to give 42.1 g of the title compound, boiling point 240°-245° C. at 0.2-0.3 mm of Hg.
Reaction SMILES: [CH2:1]([CH:3]([O:6][CH2:7][C:8]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][C:13]2=[O:19])[CH2:4][CH3:5])[CH3:2].[N:20]1([CH2:25][C@@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)O)[CH:24]=[CH:23][N:22]=[CH:21]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>O1CCCC1>[CH2:1]([CH:3]([O:6][CH2:7][C:8]1[C:17]([O:18][C@@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:25][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][CH2:12][C:13]2=[O:19])[CH2:4][CH3:5])[CH3:2]
Reactant: O[C@@H](Cn1ccnc1)c1ccccc1
Reactant: CCC(CC)OCc1c(O)ccc2c1CCCC2=O
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(CC)OCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 60.6 %

Procedure:
According to step 2 in the method of example 19, 5-(1-Ethyl-propoxymethyl)-6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (0.123 g, 0.53 mmol), (R)-2-Imidazol-1-yl-1-phenyl-ethanol (0.131 g, 0.7 mmol), triphenylphosphine resin (0.620 g, loading 1.24 mmol/g, Argonaut Technologies), diethyl diazodicarboxylate (0.121 ml, 0.77 mmol, Aldrich Chemical) and freshly distilled tetrahydrofuran (5 ml, Aldrich Chemical) were combined in a 2 dram screw topped vial with a teflon lined cap. After mixing on an inverting mixer at 25° C. for 16 hrs., the resin was removed by gravity filtration and mixture concentrated in vacuo to a yellow-brown syrup. The residue was dissolved in methanol (5 ml) and macroporous polystyrene sulfonic acid resin (0.583 g, loading 1.5 mmol/g, Argonaut Technologies) added. After mixing for 2 hrs. at 25° C., the resin was collected by gravity filtration, washed with methanol (2×5 ml). Elution of product from the resin with 2.0 M ammonia in methanol (5 ml, Aldrich) and concentration in vacuo yielded 139 mg brown glass compound. Low resolution mass spectroscopy m/z (APCI) 433 [M+H]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][C:29]([O:37][CH2:38][CH2:39]O)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30]>C(Cl)Cl.[Al]>[Br:1][CH2:39][CH2:38][O:37][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:30])[CH3:28]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(OCCO)c1ccccc1
Agent: [Al]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(OCCBr)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 42 %

Procedure:
N-bromosuccinimide (119 mg, 0.666 mmol) was added to resin-bound triphenylphosphine (222 mg, 0.666 mEquiv, Fluka) and 2-[(1-methyl-1-phenylethyl)oxy]ethanol (60 mg, 0.333 mmol) in DCM (4 mL). The reaction vial was sealed with a Teflon-lined cap, wrapped in aluminum foil, and shaken at rt for 17 h. The reaction was filtered through a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and 50% EtOAc/hexanes (fraction 3) to give the title compound (34 mg, 42%). The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: [OH-:1].[K+].C[CH:4]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:5]CS([O-])(=O)=O>C1(C)C(C)=CC=CC=1>[CH2:5]([O:1][CH2:5][CH2:4][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:4][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: [OH-]
Reactant: CCCCC(C)CCS(=O)(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Product: CCCCCCOCCCCCC
Yield: 14.3 %

Procedure:
A mixture of 0.67 g (120 mmol) of powdered KOH in 20 ml of dry xylene was heated to reflux and ~10 ml of xylene was removed by distillation. To this stirred mixture was added a solution of 400 mg (1.49 mmol) of [1α,2β(Z),3β,4α]-7-[3-(hydroxymethyl)-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid, methyl ester prepared as described in U.S. Pat. No. 4,143,054 in 6 ml of xylene. Approximately 10 ml of xylene was removed by distillation to afford a clear solution with a gummy precipitate adhering to the magnetic stirring bar. To this mixture was added a solution of 1.45 g (7.5 mmol) of crude 2-methyl-hexylmesylate in 4 ml of xylene. This caused the gummy precipitate to break up to form a somewhat gelatinous reaction mixture. The mixture was refluxed for 21/4 hour. The cooled reaction mixture was partitioned between 20 ml each saturated NH4Cl and EtOAc. The aqueous layer was acidified to pH=3.5 and then extracted with three 20 ml portions of EtOAc. The combined EtOAc extracts were dried (MgSO4), filtered and concentrated in vacuo to give the crude product which was treated with excess ethereal CH2N2. The crude product was purified by flash chromatography on 35 g of silica gel using 4:1 hexane/ether as eluant. Fractions 15-20 were concentrated to give 320 mg of title ether (58%). Fractions 23-27 afforded 100 mg of the n-hexyl ether related to title ether (19%). (Apparently, the commercial 2-methyl-hexanoic acid which was the precursor to the mesylate employed was contaminated with ~10% hexanoic acid) and fractions 21-22 gave 70 mg (13%) of a mixture of these two ethers.
Reaction SMILES: [Na+].[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([P:9]([C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:11])[O-:10])=[C:5]([CH3:20])[C:4]=1[CH3:21].S(=O)(=O)(O)O>O>[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([P:9]([C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:10])[OH:11])=[C:5]([CH3:20])[C:4]=1[CH3:21]
Reactant: Cc1ccc(P(=O)([O-])C(=O)c2ccccc2)c(C)c1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1ccc(P(=O)(O)C(=O)c2ccccc2)c(C)c1C
Reaction time: 1 h

Procedure:
401.55 g of the sodium salt from Example 1 were dissolved in 1500 ml of water acidified to pH 1 with 1300 ml of 0.5 molar sulfuric acid. After 1 hour, the crystal batch which had precipitated was filtered off with suction, washed twice with 700 ml of water each time and sucked dry. The filter cake was dried azeotropically with 1500 ml of toluene in a water separator. The clear, pale-yellow toluene solution was evaporated at 50° C., and the acid was recrystallized from 2150 ml of ethyl acetate. The crystals were filtered off with suction at 0°, washed with ethyl acetate and dried at 60° C. under reduced pressure. Weight: 300 g (80% of theory) of pale-yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([C:23]3[O:24][CH:25]=[CH:26][C:27]=3[CH3:28])=[O:22])[CH:15]=2)=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][N:3]=1.[OH-].[K+]>CO.O>[NH2:1][C:2]1[C:11]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([C:23]3[O:24][CH:25]=[CH:26][C:27]=3[CH3:28])=[O:22])[CH:15]=2)=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3occc3C)c2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cc(C(=O)O)cnc2N)c1
Temperature: 65 °C
Yield: 99.9 %

Procedure:
To a solution of methyl 6-amino-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinate, (1.82 g, 4.85 mmol, 1 eq) in MeOH—H2O (100 mL, 3:1) at RT was added potassium hydroxide (2.72 g, 10 eq) with stirring. The mixture was heated at 65° C. for 2 hours and a brown solution was observed at this time. The reaction mixture was concentrated to remove most of the methanol. The resulting solution was cooled to 0° C. and concentrated HCl was added until the pH was around 3 at which time a white precipitates formed. The solid which had formed was collected by filtration, rinsed with water, and dried to give the title compound as a white solid (1.75 g).