Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccc(C(C)=O)cc1
Yield: 50.8 %

Procedure:
A solution of 0.90 g (6.61 mmol) of 4'-hydroxyacetophenone, and 1.93 g (9.92 mmol) of ethyl 4-bromobutyrate in 1.80 mL of N,N-dimethylformamide is stirred for 48 hours, under dry conditions with 2.74 g (19.8 mmol) of potassium carbonate and 0.110 g (0.66 mmol) of potassium iodide. The reaction mixture is then evaporated under vacuum, and the residue partitioned between ether and water. The organic phase is separated, washed thrice with water, dried with magnesium sulfate, filtered, and evaporated under vacuum to give a brown solid. This is recrystallized from a warm ether-hexane mixture. The beige crystals are air dried, leaving 0.84 g (51%) of 4-(4-acetylphenoxy)-butanoic acid, ethyl ester: m.p. 59°-61° C.; IR (KBr) 1740, 1670 cm-1 ; 1H-NMR (CDCl3) is consistent with the desired product; MS (FAB) m/e 251.1285 Δ=-0.2 mmμ (M+ +H). Analysis calculated for C14H18O4 : C, 67.18; H, 7.25; O, 25.57. Found: C, 67.16; H, 7.16; O, 25.68.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.O.[NH2:17][NH2:18]>C(O)COCCO>[NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4](=[N:17][NH2:18])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccccc1C(=O)c1ccccc1
Reactant: NN
Solvent: OCCOCCO
Solvent: O
Product: NN=C(c1ccccc1)c1ccccc1N

Procedure:
In the manner given in Preparation 1, 2-aminobenzophenone is refluxed with hydrazine hydrate in diethylene glycol to give 2-aminobenzophenone hydrazone.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:14])[CH:12]=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[Mn]([O-])(=O)(=O)=[O:16].Cl[O-]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:14])[C:12]([OH:16])=[O:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)Cc1ccc(C(C)C=O)cc1
Agent: [O-]Cl
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1

Procedure:
After the hydroformylation, the obtained α-(4-isobutylphenyl)propionaldehyde is oxidized by the conventional method using, for example, permanganate or hypochlorite to obtain the ibuprofen, α-(4-isobutylphenyl)propionic acid.
Reaction SMILES: [N:1]1([C:53](OC(C)(C)C)=O)[CH2:52][CH2:51][CH2:50][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([N:16]([CH3:49])[C@H:17]([C:25]([N:27]([CH2:29][C:30]([NH:32][C@H:33]([C:38]([NH:40][C@H:41]([C:46]([NH2:48])=[O:47])[CH2:42][CH2:43][S:44][CH3:45])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:31])C)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[NH:1]1[CH2:53][CH2:52][CH2:51][CH2:50][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([N:16]([CH3:49])[C@H:17]([C:25]([NH:27][CH2:29][C:30]([NH:32][C@H:33]([C:38]([NH:40][C@H:41]([C:46]([NH2:48])=[O:47])[CH2:42][CH2:43][S:44][CH3:45])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:31])=[O:26])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CN(C)C(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCCN1)C(N)=O

Procedure:
Condensation of BocPro-Phe-MePheNHNH2 (0.86 g.) and HSar-Leu-MetNH2 (Example 3, 0.63 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-Phe-MePhe-Sar-Leu-MetNH2 in 75% yield. De-t-butoxycarbonylation of BocPro-Phe-MePhe-Sar-Leu-MetNH2 (0.90 g.) using trifluoroacetic acid in methylene dichloride gave HPro-Phe-MePhe-Gly-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (1:1) salt in 59% yield.
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[C@@H:12]([CH2:31][O:32]CC2C=CC=CC=2)[O:11][C@:10]21[C:50]1[CH:49]=[C:48]3[C:44]([CH:45]=[CH:46][N:47]3[CH2:51][C:52]3[CH:57]=[CH:56][C:55]([CH2:58][CH3:59])=[CH:54][CH:53]=3)=[CH:43][C:42]=1[CH2:41][O:40]2)C1C=CC=CC=1>CO.C1COCC1.[Pd]>[CH2:58]([C:55]1[CH:54]=[CH:53][C:52]([CH2:51][N:47]2[C:48]3[C:44](=[CH:43][C:42]4[CH2:41][O:40][C@@:10]5([C@H:9]([OH:8])[C@@H:14]([OH:15])[C@H:13]([OH:23])[C@@H:12]([CH2:31][OH:32])[O:11]5)[C:50]=4[CH:49]=3)[CH:45]=[CH:46]2)=[CH:57][CH:56]=1)[CH3:59]
Reactant: CCc1ccc(Cn2ccc3cc4c(cc32)[C@]2(OC4)O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Cn2ccc3cc4c(cc32)[C@]2(OC4)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 42.7 %

Procedure:
To a solution of (3′R,4′S,5′S,6′R,7S)-3′,4′,5′-tris-benzyloxy-6′-benzyloxymethyl-1-[(4-ethylphenyl)methyl]-3′,4′,5′,6′-tetrahydro-spiro[furo[3,4,f]indole-7(5H),2′-[2H]pyran] (43 mg, 0.055 mmol) in methanol (1 mL) and THF (1 mL) was added with 10% palladium on carbon (41 mg). The resultant solution was stirred under a hydrogen atmosphere for 1 hour at room temperature, and the catalyst was then filtered off. Solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solution=dichloromethane:methanol (10:1)), to thereby obtain the titled compound (10 mg, 43%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:26]=[CH:25][C:13]([O:14][CH:15]([CH3:24])[CH2:16][NH:17][S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36]>C(Cl)Cl>[CH3:36][CH:35]([CH3:37])[C:34]([NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:26]=[CH:25][C:13]([O:14][CH:15]([CH3:24])[CH2:16][NH:17][S:18]([CH:21]([CH3:22])[CH3:23])(=[O:20])=[O:19])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=[O:38]
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CN)cc2)cc1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CNC(=O)C(C)C)cc2)cc1
Yield: 19 %

Procedure:
The final title compound (59 mg, 19%) was prepared from (2-{4-[4-(aminomethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]amine hydrochloride (250 mg, 0.717 mmol, prepared in example 32) methylene chloride (4.6 mL, absolute) triethylamine (0.07 mL, 0.8621 mmol), aind isobutyryl chloride (0.06 mL, 1.0345 mmol), in a manner analogous to Example 29.
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[F:16])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.Cl.[NH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[C:34]([CH3:43])[CH:33]=1>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[C:1]([C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][C:11]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])=[C:34]([CH3:43])[CH:33]=2)=[O:13])=[CH:7][C:6]=1[F:16])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(OCC(=O)O)cc1F
Reactant: Cc1cc(CN)ccc1NS(C)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cc(CNC(=O)COc2ccc(C(C)(C)C)c(F)c2)ccc1NS(C)(=O)=O
Yield: 16.6 %

Procedure:
(4-tert-Butyl-3-fluorophenoxy) acetic acid (339 mg, 1.5 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (518 mg, 2.7 mmol), 4-(dimethylamino)pyridine (DMAP) (55 mg, 0.45 mmol), triethylamine (0.836 ml) and N-[4-(aminomethyl)-2-methylphenyl]methanesulfonamide hydrochloride (451 mg, 1.8 mmol) were mixed in the same procedure described in Example 2(b) to give 105 mg (17% yield) of the title compound as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:9][O:10][C:11]1[CH:12]=[N:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23]CC3C=CC=CC=3)=[CH:19][CH:18]=2)=[N:15][CH:16]=1.C1COCC1>CO>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:9][O:10][C:11]1[CH:16]=[N:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)=[N:13][CH:12]=1
Reactant: CCCCC[C@H](COc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1)OC1CCCCO1
Solvent: CO
Solvent: C1CCOC1
Product: CCCCC[C@H](COc1cnc(-c2ccc(O)cc2)nc1)OC1CCCCO1
Yield: 102 %

Procedure:
In a 2 l four-necked flask were charged 25.3 g (51.2 mmol) of the compound obtained in step 1, 506 ml of THF, and 506 ml of methanol. After purging the flask with nitrogen, 5 g of 10% palladium-on-carbon was added thereto to conduct hydrogenation at 30° to 35° C. under atmospheric pressure for 2 hours. After completion of the reaction, the catalyst was removed by filtration in a nitrogen stream, and the solvent was recovered to afford 20.18 g of the titled compound.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([N:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:18]([F:21])([F:20])[F:19])[C:10]1=[O:22])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1.O>[CH3:7][CH:6]([CH3:8])[CH2:5][C@H:4]([N:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:18]([F:21])([F:19])[F:20])[C:10]1=[O:22])[C:3]([OH:23])=[O:2]
Reactant: COC(=O)[C@H](CC(C)C)N1Cc2c(cccc2C(F)(F)F)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)N1Cc2c(cccc2C(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
A solution of (S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic acid methyl ester (274 mg, 0.83 mmol) in tetrahydrofuran/water (12 mL, 1:1) was treated with lithium hydroxide monohydrate (70 mg, 1.66 mmol) at room temperature. The reaction mixture was then stirred at room temperature for 2 h. After this time, the reaction mixture was concentrated in vacuo to remove the tetrahydrofuran. The resulting material was then diluted with a 1N aqueous hydrochloric acid solution (10 mL) and then extracted with ethyl acetate. The organic layers were combined and then dried over magnesium sulfate, filtered to remove the drying agent, and the filtrate was concentrated in vacuo to afford (S)-4-methyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-pentanoic acid (254 mg, 97%) as a white solid.
Reaction SMILES: [C:1]([C:4]([NH:9][C:10]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=O)([CH3:8])[CH:5]([CH3:7])[CH3:6])(=[O:3])[NH2:2].[H-].[Na+].O>C1(C)C(C)=CC=CC=1>[CH:5]([C:4]1([CH3:8])[C:1](=[O:3])[NH:2][C:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[N:9]1)([CH3:7])[CH3:6]
Reactant: CC(C)C(C)(NC(=O)c1ccc2ccccc2n1)C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(C)C1(C)N=C(c2ccc3ccccc3n2)NC1=O
Yield: 78.3 %

Procedure:
To a slurry of N-(1-carbamoyl-1,2-dimethylpropyl)-2-quinolinecarboxamide (16.04 g, 0.0562 mol) in xylene (610 ml) under nitrogen is added a 50% oil dispersion of sodium hydride (2.7 g, 0.056 mol) at 20° C. The reaction is heated to reflux for 2 hours, cooled and water (50 ml) added. The aqueous layer is extracted with methylene chloride and the organic layers combined and evaporated to give a yellow oil, 17 g. Purification is accomplished by passing through a silica gel column using hexane-ethyl acetate as solvent. A pale yellow solid is obtained and is recrystalized from ethyl acetate to give 11.77 g (78%) of white product, mp 112°-117° C. Anal. calcd. for C16H17N3O: C, 71.88; H, 6.41; N, 15.72. Found: C, 71.91; H, 6.47; N, 15.70.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:16]2)=[CH:11][CH:10]=1.I[CH3:36]>>[Cl:1][C:2]1[CH:27]=[C:26]([O:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15]([CH3:36])([C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:16]2)=[CH:11][CH:10]=1
Reactant: CCOC(=O)C1CCc2ccc(OCCCOc3ccc(Oc4ccccc4)cc3Cl)cc2O1
Reactant: CI
Product: CCOC(=O)C1(C)CCc2ccc(OCCCOc3ccc(Oc4ccccc4)cc3Cl)cc2O1

Procedure:
The title compound was prepared following the procedure described in Example 2 employing ethyl 7-(3-(2-chloro-4-phenoxyphenoxy)propoxy)-chromane-2-carboxylate (Example 17) instead of ethyl 7-(3-(2-propyl-4-phenoxyphenoxy)propoxy)-chromane-2-carboxylate, and iodomethane instead of iodopropane.
Reaction SMILES: [C:1]12([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH2:16][CH2:17][C:18]([NH:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])=[O:20])=[CH:21][CH:22]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: O=C(O)CCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)CCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Yield: 92 %

Procedure:
The title compound was prepared from 3-(4-(adamantan-1-yl)phenoxy)propanoic acid (0.2 g, 0.66 mmol) and N,N-dimethylethane-1,2-diamine (0.058 g, 0.66 mmol) according to the example 1, which was given 3-(4-(adamantan-1-yl)phenoxy)-N-(2-(dimethylamino)ethyl)propanamide as a white solid (0.225 g, 91.4% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:23][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:12][CH2:11][CH2:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCc2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 500 mL round-bottomed flask was charged with 2-(3-nitrophenyl)ethanol (1.0235 g, 6.12 mmol), 4-dimethylaminopyridine (0.075 g, 0.612 mmol) and p-toluenesulfonyl chloride (1.401 g, 7.35 mmol) in CH2Cl2 (61.2 ml). Triethylamine (1.707 ml, 12.25 mmol) was added, and the mixture stirred at ambient temperature for 3 hours. The reaction mixture was washed with water and brine, dried (MgSO4), filtered and concentrated onto silica gel. The crude product was purified by flash chromatography using an Argonaut Flashmaster Solo 25 g column (100% hexanes to 30% ethyl acetate:hexanes over 25 minutes, then to 100% ethyl acetate over 10 minutes) to provide the title compound. MS (ESI(+)) m/e 338.9 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:42]I>C1(C)C=CC=CC=1>[I:42][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: II
Reactant: COc1ccc(CCCCCCCCO)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CCCCCCCCI)cc1
Temperature: 65 °C

Procedure:
To a stirred solution of 8-(4-methoxyphenyl)octan-1-ol (12.3 g, 52 mmol) in dry toluene (200 mL) under an argon atmosphere was added triphenylphosphine (17.8 g, 67.6 mmol) and imidazole (10.6 g, 156 mmol). After the imidazole had dissolved I2 (17.1 g, 67.6 mmol) was added. The reaction was then heated at 65° C. for 30 minutes. Upon cooling to room temperature the reaction was concentrated to 1/4 volume. The remaining solution was diluted with Et2O and washed with H2O and brine and dried. (MgSO4). The solvent was removed and the resulting residue was dissolved in CH2Cl2 and applied to a flash chromatography column (silica). Elution with 2 % EtOAc in hexane provided a colorless oil. (slight contamination with triphenylphosphine): 1H NMR (250 MHz, CDCl3) δ7.08 (d, J=8.6 Hz, 2H, aryl), 6.82 (d, J=8.6 Hz., 2H, aryl), 3.78 (s, 3H, OMe), 3.t7 (t, J=7.4 Hz, 2H, I-CH2), 2.54 (t, J=7.6 Hz, 2H, benzylic), 1.85 (m, 2H, CH2), 1.60 (m, 2H, CH2), 1.31 (m, 8H, aliphatic); MS (CI): 364.2 (M+NH4).
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.C[O:20][C:21](=[O:25])[CH2:22][CH2:23][NH2:24].[OH-].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:24][CH2:23][CH2:22][C:21]([OH:25])=[O:20])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Oc2nc3ncccc3s2)cc1
Reactant: COC(=O)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCNCc1ccc(Oc2nc3ncccc3s2)cc1
Reaction time: 4 h
Yield: 31.1 %

Procedure:
To a mixture of 4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)-benzaldehyde (100 mg, 0.39 mmol) and β-alanine methyl ester (54 mg, 0.39 mmol, 1 equiv.) was added methanol (2 mL) followed by 1N NaOH (430 μL). The reaction was allowed to stir at rt for 1 h before the addition of sodium triacetoxyborohydride (95 mg, 0.39 mmol, 1 equiv.). Stirring was allowed to continue for 4 h before the reaction was concentrated and purified using preparative reversed phase HPLC to afford the product as white powder (40 mg, 31%). 1H NMR (400 MHz, CD3OD): 8.49 (d, J=4.8, 1H), 8.33 (d, J=7.9, 1H), 8.27 (s, 1H), 7.65 (d, J=8.2, 2H), 7.55 (d, J=8.2, 2H), 7.38-7.33 (m, 1H), 4.28 (s, 2H), 3.24 (t, J=6.4, 2H), 2.58 (t, J=6.4, 2H). MS (ESI): Mass calcd for C16H16N3O3S, 329.08; m/z found, 330.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[N:38]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>>[F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:27][CH2:28][N:29]([C:44]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:45])[CH2:30][CH2:31]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCNCC4)c3F)s2)c1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCN(C(=O)N5CCOCC5)CC4)c3F)s2)c1

Procedure:
Following the procedure given for example 81, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-phenylpiperidin-4-yl)methyl)picolinamide (compound example 11) was reacted with morpholine-4-carbonyl chloride to give the title compound. LC/MS (M+H)+: 648. Ret. time: 1.48 min. (Condition G); analytical HPLC Ret. time: 7.35 min (Condition H).
Reaction SMILES: [I:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]2[C@@H:13]3[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]3[C@@H:11]([CH2:19][OH:20])[CH2:10]2)[CH:3]=1.N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C=O)C.O>[Si:26]([O:20][CH2:19][C@@H:11]1[C@H:12]2[O:16][C:15]([CH3:17])([CH3:18])[O:14][C@H:13]2[C@H:9]([NH:8][C:4]2[CH:3]=[C:2]([I:1])[N:7]=[CH:6][N:5]=2)[CH2:10]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](Nc3cc(I)ncn3)[C@@H]2O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)O[C@@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@@H](Nc3cc(I)ncn3)[C@@H]2O1
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution of {(3aR,4R,6R,6aS)-6-[(6-iodopyrimidin-4-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol (1.321 g, 3.38 mmol) and 1H-imidazole (0.552 g, 8.10 mmol) in DMF (16.9 mL) was added tert-butyldimethylsilyl chloride (0.534 g, 3.54 mmol) and the reaction was stirred overnight. The solution was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude mixture was purified by flash chromatography (10 to 40% EtOAc/hexanes) to afford the title compound (1.465 g, 86%). LC/MS: Rt=2.47 min ES+ 506 (FA Standard).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][CH2:12][NH2:13])=[C:9]([Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[NH:8][C:5]2=[N:6][CH:7]=1.[F:21][C:22]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:23]=1[CH2:24][C:25]1[O:29][N:28]=[C:27]([C:30](O)=[O:31])[CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][CH2:12][NH:13][C:30]([C:27]3[CH:26]=[C:25]([CH2:24][C:23]4[CH:33]=[C:34]([F:37])[CH:35]=[CH:36][C:22]=4[F:21])[O:29][N:28]=3)=[O:31])=[C:9]([Si:14]([CH2:15][CH3:16])([CH2:19][CH3:20])[CH2:17][CH3:18])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1cc(Cc2cc(F)ccc2F)on1
Reactant: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCN
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: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCNC(=O)c1cc(Cc2cc(F)ccc2F)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A mixture of 2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanamine (0.128 g; 0.413 mmol), 5-(2,5-difluorobenzyl)isoxazole-3-carboxylic acid intermediate 74 (0.104 g; 0.434 mmol), HATU (N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate) (0.165 g: 0.434 mmol) and N,N-diisopropylethylamine (0.108 mL; 0.619 mmol) in DMF (3 mL) was stirred overnight at room temperature and concentrated under reduced pressure. The crude material was dissolved in dichloromethane and the organic layer was washed with water and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent: 1 to 10% of ethyl acetate in dichloromethane) to give 0.108 g (49%) of N-(2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](=[O:15])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[CH:4]=[C:3]1[C:16]([OH:18])=[O:17].[OH-].[Na+].[BH4-].[Na+].C(O)(=O)C>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH:7]([OH:15])[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[CH:4]=[C:3]1[C:16]([OH:18])=[O:17]
Reactant: Cn1cc(C(=O)c2cccc(Cl)c2)cc1C(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1cc(C(O)c2cccc(Cl)c2)cc1C(=O)O
Reaction time: 24 h

Procedure:
5 g 1-methyl-4-(3-chloro-benzoyl)pyrrole-2-carboxylic acid (obtained in Example 2) are dissolved in 40 ml aqueous ethanol (96%). 4 ml aqueous sodium hydroxide (d=1.33) and 0.7 g sodium borohydride are added thereto. After 24 hours at room temperature, the solution is made acidic by addition of acetic acid. 3 g of hydroxylated acid precipitate out; m.p.=180° C.