Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].Cl[C:10]([O:12][CH2:13][CH3:14])=[O:11]>[OH-].[Na+].O1CCOCC1>[CH2:13]([O:12][C:10]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:11])[CH3:14]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOC(=O)N[C@H](C(=O)O)C(C)C

Procedure:
The title compound is prepared, in analogy with Example 30a), from L-valine in 2N NaOH and dioxane using ethyl chloroformate (Fluka, Buchs, Switzerland), and subjected to further processing without purification.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[S:16](O)(=O)=O>>[O:8]=[C:1]1[CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:16][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]1=2
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)CC(=O)c1ccccc1
Product: CCOC(=O)C1Sc2ccccc2C1=O
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 114.3 %

Procedure:
Ethyl benzoylacetate (100.0 g, 0.52 mol) was added dropwise over a period of 1.5 h under vigorous mechanical stirring to fuming H2SO4 37% (500.0 g) cooled at 5° C. in an ice bath. After the addition was complete the reaction mixture was stirred for 1.5 h and then added to 1000 g of ice. The solid product was collected by filtration and washed with cold water (30 ml) to give 132.1 g (85%) of Compound X as a pale yellow solid:melting point 138°-140° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)CCCC>[CH3:13][O:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:3]=[CH:4][N:5]=2)[N:10]=1
Reactant: C1CNCCN1
Reactant: COc1ccc2nccc(Br)c2n1
Solvent: CCCCCO
Product: COc1ccc2nccc(N3CCNCC3)c2n1
Yield: 96.2 %

Procedure:
A solution of 8-bromo-2-methoxy-[1,5]naphthyridine (4.78 g, 20 mmol, prepared as in WO 2006/032466) and piperazine (8.6 g, 100 mmol) in 1-pentanol (20 mL) was heated at 80° C. over night. The mixture was cooled and the precipitate filtered off. The filtrate was diluted with EA (100 mL) and washed with water (20 mL). The aq. phase contains some product, which was extracted with DCM/MeOH 9:1 (3×30 mL). The org. phases were combined, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by CC (EA/MeOH 4:1 to MeOH) to give the desired intermediate (4.7 g, 96%) as yellow oil.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]([NH:15][NH:16][C:17](=[S:26])[NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=O)[O:4]1>[OH-].[Na+]>[CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]2[N:18]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17](=[S:26])[NH:16][N:15]=2)[O:4]1
Reactant: CO[C@@H]1O[C@H](C(=O)NNC(=S)NCc2ccccc2)[C@H]2OC(C)(C)O[C@@H]12
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H]1O[C@H](c2n[nH]c(=S)n2Cc2ccccc2)[C@H]2OC(C)(C)O[C@@H]12
Temperature: 25 °C
Yield: 39.1 %

Procedure:
A solution of 2-{[(3aS,4S,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]carbonyl}-N-benzylhydrazinecarbothioamide (Preparation 17) (5.9 g, 15.5 mmol) in 2 M aqueous sodium hydroxide (200 ml) was heated under reflux for 2 hours. The solution was allowed to cool to room temperature and extracted with dichloromethane (50 ml). The aqueous phase was then acidified to pH 4 with 2 M aqueous hydrochloric acid and extracted with ethyl acetate (300 ml). The ethyl acetate layer was dried (anhydrous magnesium sulphate) and evaporated under reduced pressure to give the title compound (2.20 g).
Reaction SMILES: [CH:1]1([C:7]2([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:13](Cl)(=[O:16])[CH:14]=[CH2:15].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:13]([O:12][C:7]1([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:8][CH2:9][CH2:10][CH2:11]1)(=[O:16])[CH:14]=[CH2:15]
Reactant: OC1(C2CCCCC2)CCCC1
Reactant: C=CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)OC1(C2CCCCC2)CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.5 %

Procedure:
In 1 liter of methylene chloride was dissolved 92.4 g of 1-cyclohexylcyclopentanol. To the solution below −20° C., 74.3 g of acrylic chloride was added dropwise over 10 minutes. To the reaction mixture, 1.0 g of 4-(N,N-dimethylamino)pyridine was added and then, 125.0 g of triethylamine was added dropwise over one hour and below −20° C. This reaction mixture was agitated for 15 hours at room temperature and subjected to conventional post-treatment, obtaining an oily substance. Vacuum distillation yielded 110.5 g of 1-cyclohexylcyclopentyl acrylate (designated Monomer 1). The yield was 90.5%. Boiling point: 83-85° C./53.3 Pa
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[CH3:7][C:8]1[CH:9]=[C:10]([OH:15])[CH:11]=[CH:12][C:13]=1[CH3:14]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][O:15][C:10]1[CH:11]=[CH:12][C:13]([CH3:14])=[C:8]([CH3:7])[CH:9]=1
Reactant: Cc1ccc(O)cc1C
Reactant: BrCCCCBr
Product: Cc1ccc(OCCCCBr)cc1C
Yield: 86 %

Procedure:
1,4-Dibromobutane, condensed with 3,4-dimethylphenol according to Ismaïel et al. (J. Med. Chem., 1993, 36, 2519-25), gives 1-[4-bromobutoxy]-3,4-dimethylbenzene with a yield of 86%. The condensation of this compound (according to the same authors) with 1,4-dioxa-8-azaspiro[4.5]decane gives, after deprotection, 1-[4-(3,4-dimethylphenoxy)butyl]-4-piperidone in the form of an orangey oil with a yield of 61%. The reductive amination of this ketone (4.33 g or 15.7 mmol) with methylamine hydrochloride (1.06 g; 15.7 mmol) in the presence of sodium triacetoxyborohydride (4.33 g; 20.5 mmol) according to the protocol of Example 3.1 makes it possible to prepare 5.95 g (Yd: 63%) of the compound of formula 10:
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[C:5]([O:10][CH2:11][O:12][CH2:13][CH3:14])=[CH:4][C:3]=1[CH:15]([OH:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].Br[CH2:23]Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:13]([O:12][CH2:11][O:10][C:5]1[CH:4]=[C:3]([CH:15]([OH:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:2]2[O:1][CH2:23][O:8][C:7]=2[C:6]=1[CH3:9])[CH3:14]
Reactant: CCOCOc1cc(C(O)C(=O)OCC)c(O)c(O)c1C
Reactant: ClCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOCOc1cc(C(O)C(=O)OCC)c2c(c1C)OCO2
Yield: 43.5 %

Procedure:
By following Example 9 procedure, 0.19 g of ethyl 2-(2,3-dihydroxy-5-(ethoxymethoxy)-4-methylphenyl)-2-hydroxyacetate is reacted with 1.0 g of bromochloromethane and 0.65 g of cesium carbonate in DMF medium to get 0.086 g of title compound as syrup. IR (neat): 3481, 2978, 2928, 1739, 1492, 1435, 1397, 1365, 1255, 1209, 1117, 1058, 984, 936, 847, and 718 cm−1. 1H-NMR (CDCl3, 400 MHz): δ 6.51 (s, 1H, Ar. H), 5.96 (d, J=1.2 Hz, 1H, OCH2O), 5.92 (d, J=1.2 Hz, 1H, OCH2O), 5.17 (br. s., exch. with D2O, 1H, OH), 5.15 (d, J=1.6 Hz, 2H, ArOCH2O), 4.19-4.30 (m, 2H, OCH2OCH2CH3), 3.72 (q, J=6.8 Hz, 2H, COOCH2CH3), 2.10 (s, 3H, ArCH3), 1.25 (t, J=7.2 Hz, 3H, OCH2CH3), 1.23 (t, J=7.2 Hz, 3H, OCH2CH3). 13C NMR (CDCl3, 100 MHz): δ 173.04 (CO), 151.26 (C-6), 146.70 (C-1a), 139.58 (C-3a), 116.38 (C-4), 110.94 (C-7), 105.55 (C-5), 101.30 (C-2), 94.43 (OCH2O), 68.83 (CHOH), 64.29 (OCH2CH3), 62.17 (OCH2CH3), 15.09 (OCH2CH3), 14.04 (OCH2CH3), 8.96 (ArCH3)
Reaction SMILES: C([NH:4][C:5]1[C:6]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]2=[C:9]([CH:20]=1)[C:10](=[O:19])[N:11]([OH:18])[C:12]3=[O:17])(=O)C.Cl>CCO>[NH2:4][C:5]1[C:6]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]2=[C:9]([CH:20]=1)[C:10](=[O:19])[N:11]([OH:18])[C:12]3=[O:17]
Reactant: CC(=O)Nc1cc2c3c(cccc3c1N1CCCC1)C(=O)N(O)C2=O
Agent: Cl
Solvent: CCO
Product: Nc1cc2c3c(cccc3c1N1CCCC1)C(=O)N(O)C2=O

Procedure:
To 5-acetamido-2-hydroxy-6-(pyrrolidin-1-yl)-benzo[de]isoquinoline-1,3-dione (200 mg, 0.59 mmol, from Example 64) was added 40% HCl in EtOH (5.0 mL) at 60° C. overnight, followed by cooling, concentrating, and recrystallization of the residue from ethanol/water solution to give the title compound mp 253-256° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:35])=[C:5]([C:26]([O:33][CH3:34])=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13].Cl>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:35])=[C:5]([C:26]([O:33][CH3:34])=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)=[C:11]([CH:16]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1Oc1cccc(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(Oc2ccc(Cc3c(C)c(OC)c(OC)c(OC)c3OC)cc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.6 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-(3-methoxyphenoxy)benzoate (0.200 g, 0.414 mmol) was dissolved in a mixed solution of an aqueous 1N NaOH solution (3 ml) and 1,4-dioxane (3 ml) and the resulting solution was stirred at room temperature for 6 hours. The reaction solution was diluted with water, rendered acidic with concentrated hydrochloric acid and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was recrystallized from ether to obtain the titled compound (0.190 g, 0.408 mmol, 99%).
Reaction SMILES: O[CH2:2][CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[Br:18][CH2:2][CH:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC(=CCO)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(=CCBr)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 15.292 g (67.277 mM) of tert-butyl 4-(2-hydroxyethylidene)piperidine-1-carboxylate and 24.5 g (74.0 mM) of carbon tetrabromide in 150 ml of acetonitrile was added 19.4 g (74.0 mM) of triphenylphosphine at −78° C. Then, at room temperature, the mixture was stirred for 2 hours. This reaction mixture was distilled under reduced pressure to remove the solvent. To the residue was added diethyl ether, followed by stirring, and the resulting precipitate was filtered off and washed with diethyl ether. The filtrate and washes were pooled and the solvent was distilled under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=30/1 to 9/1) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[CH:6]=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:8]=[C:9]([NH2:12])[C:10]=2[CH:11]=1.[F:17][C:18]([F:30])([F:29])[C:19]1[CH:28]=[CH:27][C:22]([CH2:23][N:24]=[C:25]=[O:26])=[CH:21][CH:20]=1>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([NH:12][C:25]([NH:24][CH2:23][C:22]1[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:30])[F:29])=[CH:28][CH:27]=1)=[O:26])[CH:8]=[C:7]([C:13]([F:14])([F:16])[F:15])[CH:6]=2
Reactant: Cc1cc2c(N)cc(C(F)(F)F)cc2cn1
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Product: Cc1cc2c(NC(=O)NCc3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)cc2cn1

Procedure:
Prepared from 3-methyl-7-(trifluoromethyl)isoquinolin-5-amine (Description 74) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 428 (M+H)+.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH2:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[Na+].[BH4-].[Na+]>CN(C)C=O>[CH3:8][CH:9]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=CCCCCCCC
Reactant: OCCCCCO
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCCCCC(C)OCCCCCO
Temperature: 25 °C

Procedure:
To a mixture of 12.6 grams of mercuric acetate and 8.3 grams of 1,5-pentanediol in 100 ml of dimethylformamide is added 5.0 grams of 1-nonene. The mixture is stirred at room temperature for ten minutes and 40 ml of an aqueous NaOH solution (3 Molar) is added followed by 40 ml of an aqueous NaBH4 solution (0.5 Molar in 3 Molar NaOH). The solution is decanted from the mercuric salts and concentrated. The residue is partitioned between ethyl acetate and water and the organic layer is washed with brine, dried over sodium sulfate, filtered, and concentrated under vacuum to give a clear liquid. This liquid is flash chromatographed, initially with a 19 to 1 ratio of hexane to ethyl acetate and, subsequently, with a 9 to 1 ratio, to give 5-(2-nonyloxy)pentanol as a clear liquid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH:9]([CH3:11])C)[O:4][N:3]=1.CC1C=C(C(=CCCC)CC)[O:15]N=1>>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[O:15][CH:11]=[CH:9][CH:8]=2)[O:4][N:3]=1
Reactant: Cc1cc(CCC(C)C)on1
Reactant: CCCC=C(CC)c1cc(C)no1
Product: Cc1cc(-c2ccco2)on1

Procedure:
MS: M+ =149 (100); m/e: 120 (2), 106 (4), 95 (43), 82 (32), 66 (18), 52 (15), 39 (18).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26](OCC)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:34][CH:35]([O:37][CH2:38][CH2:39][CH2:40][NH2:41])[CH3:36]>>[F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([NH:41][CH2:40][CH2:39][CH2:38][O:37][CH:35]([CH3:36])[CH3:34])=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Reactant: CC(C)OCCCN
Product: CC(C)OCCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-[(1-methylethyl)oxy]-1-propanamine using conditions similar to those employed in Example 563 to provide a white solid: ES+ MS: 525 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:20](=[O:22])[CH2:19][CH:18]([CH2:23][CH2:24][CH3:25])[CH2:17][C:16]=3[NH:15][C:14]([CH3:26])=[C:13]2[C:27]#[N:28])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].C(N(CC)C(C)C)(C)C.[CH3:38][O:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](Cl)=[O:43]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:20](=[O:22])[CH2:19][CH:18]([CH2:23][CH2:24][CH3:25])[CH2:17][C:16]=3[NH:15][C:14]([CH3:26])=[C:13]2[C:27]#[N:28])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[O:8][C:42](=[O:43])[C:41]1[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=1[O:39][CH3:38]
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(O)c([N+](=O)[O-])c1
Reactant: COc1ccccc1C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OC(=O)c2ccccc2OC)c([N+](=O)[O-])c1
Reaction time: 4 h

Procedure:
A mixture of 4-(3-bromo-4-hydroxy-5-nitro-phenyl)-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (200 mg), N,N-diisopropylethylamine (390 μl) and 2-methoxy-benzoyl chloride (53 μl) in dichloromethane (4 ml) was stirred for 4 h. The mixture was diluted with dichloromethane and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]1([O:15][C:16]2[CH:17]=[C:18](Br)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:14][CH2:13][CH2:12][CH2:11]1>>[CH:10]1([O:15][C:16]2[CH:17]=[C:18]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1ccc(Br)cc1OC1CCCC1
Reactant: OB(O)c1ccccc1
Product: COc1ccc(-c2ccccc2)cc1OC1CCCC1
Yield: 46 %

Procedure:
Following the procedure of Example 1, phenylboronic acid and 3-cyclopentyloxy-4-methoxybromobenzene yielded 46% of the title compound as white needles: mp 62°-64° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([OH:21])[CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20]>N1C=CC=CC=1>[S:7]([O:21][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20])([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCCOCCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCCOCCO)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
p-Toluenesulfonyl chloride (17.1 g) was added portionwise to triethylene glycol (15 g) in pyridine (600 ml) at 0° C. The solution was allowed to warm to room temperature and stirring continued for 16 h. The solvent was removed under reduced pressure to approximately 50 ml and the residue diluted with hydrochloric acid (100 ml, 3M), extracted with dichloromethane (3×100 ml), washed with brine (150 ml), dried (Na2SO4), and the solvent removed under reduced pressure. The resulting pale orange oil was purified by flash chromatography (ethyl acetate) to give triethylene glycol mono tosylate from the most polar fractions as a clear oil (6.94 g, 23%). 1H nmr (CDCl3) δ2.44 (s, 3H), 2.56 (br s, 1H OH), 3.56-3.73 (m, 10H), 4.16 (m, 2H), 7.38 and 7.78 (AB quartet, 2H each); 13C nmr (CDCl3) δ21.33, 42.52, 61.25, 68.31, 69.00, 69.86, 70.36, 72.25, 127.64, 129.63, 144.71; m/z (CI) 305 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=O)=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:33][CH2:34][CH:35]([OH:37])[CH3:36]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH:33][CH2:34][CH:35]([OH:37])[CH3:36])=[O:15])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(I)cc2F)cc1=O
Reactant: CC(O)CN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(O)CNC(=O)c1cn(C)c(=O)cc1Nc1ccc(I)cc1F
Yield: 36 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and CDI were dissolved in anhydrous THF/DMF (4:1) and treated with 1-amino-2-propanol as for example 34. After workup, the residue was triturated with hexane then dried, affording 4-(2-fluoro-4-iodoanilino)-N-(2-hydroxypropyl)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (36%) as a white solid; m.p. (EtOAc/Hexane) 161-166° C. (glue-liquid). 1H NMR [400 MHz, (CD3)2CO] δ 10.13 (br s, 1H), 8.31 (t, J=1.7 Hz, 1H), 7.73 (br s, 1H), 7.66-7.58 (m, 2H), 7.37-7.31 (m, 1H), 5.75 (dd, J=5.2, 0.9 Hz, 1H), 3.96-3.88 (m, 1H), 3.46-3.39 (m, 1H), 3.42 (s, 3H), 3.25-3.17 (m, 1H), 1.15 (d, J=6.2 Hz, 3H). HRMS (FAB+) calcd for C16H18FIN3O3 446.0377 (M+), found 446.0371. HPLC 96.8% (254 nm).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][Br:22])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C(=O)OC(C)(C)C)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1cccc(CBr)c1

Procedure:
The crude 3-methyl-benzoic acid tert-butyl ester was reacted with NBS (0.31 g, 1.726 mmol), AIBN (0.28 g, 1.726 mmol) in CCl4 (30 mL) according to the procedure for the preparation of compound 55 in example 1. After separation by chromatography eluted with CHCl3—MeOH (50:1), a mixture of two products was obtained. One of them was the product (61% pure) with MS (ESI) 272.76 (M+H+). This mixture was not further separated and directly used in the next step reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[N:7][CH:8]=1>Cl.CO.[Pt](=O)=O>[CH3:1][O:2][CH:3]1[CH2:8][NH:7][CH2:6][CH:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]1
Reactant: COC(=O)c1cncc(OC)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1CNCC(OC)C1

Procedure:
Methyl 5-methoxypyridine 3-carboxylate (1 g, 6.02 mmol) and platinum (IV) oxide (50 mg) suspended in 1.25 M HCl in methyl alcohol (10 mL) were hydrogenated in Parr shaker under 40 psi overnight. The reaction mixture was filtered through a pad of celite, washed with MeOH and concentrated to give crude product.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([CH:12]3[CH2:14][CH2:13]3)=[O:11])[S:8][C:4]=2[CH:3]=1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[F:27].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[F:27][C:19]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=1[O:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([CH:12]3[CH2:13][CH2:14]3)=[O:11])[S:8][C:4]=2[CH:3]=1
Reactant: O=C(Nc1nc2ccc(O)cc2s1)C1CC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1nc2ccc(Oc3ccc([N+](=O)[O-])cc3F)cc2s1)C1CC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 65.4 %

Procedure:
A suspension of N-(6-hydroxy-1,3-benzothiazol-2-yl)cyclopropanecarboxamide (1.17 g, 5.00 mmol), 1,2-difluoro-4-nitrobenzene (0.96 g, 6.00 mmol) and cesium carbonate (3.26 g, 10.0 mmol) in dimethyl sulfoxide (10 mL) was stirred at 50° C. for 5 hr. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate/tetrahydrofuran. The organic layer was washed with water, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate and collected by filtration to give the title compound (1.22 g, 65%) as a pale-yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:4][C:3]1([CH3:18])[CH3:17]>[Pd].CO>[CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[CH2:4][C:3]1([CH3:18])[CH3:17]
Reactant: CN1C(C)(C)C=C(c2ccc(O)cc2)CC1(C)C
Agent: [Pd]
Solvent: CO
Product: CN1C(C)(C)CC(c2ccc(O)cc2)CC1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To 0.33 g of palladium on activated carbon (10%) was added a solution of 4-(1,2,2,6,6-pentamethyl-1,2,3,6-tetrahydro-pyridin-4-yl)-phenol (3.27 g, 13.3 mmol) in methanol (100 mL). This mixture was stirred at room temperature under H2 (1 atm) for 2 hours. The catalyst was filtered and the filtrate concentrated. The residue was purified by chromatography on silica gel (eluting with 7N NH3 in methanol/dichloromethane) to give 4-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-phenol (2 g 60%) as a white foam.
Reaction SMILES: Cl.O1CCOCC1.[CH3:8][C:9]1[CH:53]=[CH:52][CH:51]=[CH:50][C:10]=1[CH2:11][NH:12][C:13]([C@@H:15]1[C:19]([CH3:21])([CH3:20])[S:18][CH2:17][N:16]1[C:22](=[O:49])[C@@H:23]([OH:48])[C@@H:24]([NH:32][C:33](=[O:47])[C@H:34]([CH2:43][C:44](=[O:46])[NH2:45])[NH:35][C:36]([O:38][C:39](C)(C)C)=[O:37])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:14]>>[CH3:8][C:9]1[CH:53]=[CH:52][CH:51]=[CH:50][C:10]=1[CH2:11][NH:12][C:13]([C@@H:15]1[C:19]([CH3:21])([CH3:20])[S:18][CH2:17][N:16]1[C:22](=[O:49])[C@@H:23]([OH:48])[C@@H:24]([NH:32][C:33](=[O:47])[C@H:34]([CH2:43][C:44](=[O:46])[NH2:45])[NH:35][C:36]([O:38][CH3:39])=[O:37])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:14]
Reactant: Cc1ccccc1CNC(=O)[C@H]1N(C(=O)[C@@H](O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)CSC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)N1CSC(C)(C)[C@H]1C(=O)NCc1ccccc1C
Reaction time: 2 h
Yield: 22.9 %

Procedure:
4N HCl/dioxane (2 ml) was added to the compound Boc-Asn-Apns-Dmt-NHBzl(2-Me) (70 mg) obtained in the step 1 of Example 6 and the mixture was stirred for two hours. After concentration, the reaction mixture was dissolved in DMF (1 ml) and neutralized with triethylamine (15 μl). After the addition of methyl chloroformate (9 μl ) and triethylamine (16 μl), the mixture was stirred for two hours. After the addition of ethyl acetate, the reaction mixture was washed with 3% Na2CO3, 1N HCl, and 5% NaCl and dried over MgSO4. After filtration and concentration, the residue was purified using silica gel column chromatography to obtain the title compound (15 mg).