Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:23])=[C:11]([CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([C:20](O)=[O:21])[CH2:16][CH2:15]3)[N:12]=2)=[CH:4][CH:3]=1.[N:24]1([CH2:31][CH2:32][CH2:33][NH2:34])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C.C(Cl)CCl>CN(C=O)C>[N:24]1([CH2:31][CH2:32][CH2:33][NH:34][C:20]([CH:17]2[CH2:16][CH2:15][N:14]([CH2:13][C:11]3[N:12]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[O:9][C:10]=3[CH3:23])[CH2:19][CH2:18]2)=[O:21])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NCCCN1CCCCCC1
Reactant: Cc1oc(-c2ccc(Cl)cc2)nc1CN1CCC(C(=O)O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1oc(-c2ccc(Cl)cc2)nc1CN1CCC(C(=O)NCCCN2CCCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of 1-((2-(4-chlorophenyl)-5-methyloxazol-4-yl)methyl)piperidine-4-carboxylic acid (0.25 g, 0.75 mmole), 3-(Azepan-1-yl)propan-1-amine (0.33 g) and DIPEA (0.32 mL) in DMF (5 mL) was added EDC (0.153 g). The reaction solution was stirred at room temperature overnight. The solvent removed and EtOAc (100 mL) was added. The organic layer was washed with saturated sodium bicarbonate (50 mL), water (50 mL) and dried over anhydrous magnesium sulfate. After filtration, the residue after concentration of the filtrate was crystallized from EtOAc/Hexane to provide the N-(3-(azepan-1-yl)propyl)-1-((2-(4-chlorophenyl)-5-methyloxazol-4-yl)methyl)piperidine-4-carboxamide as white solid (0.30 g, 85%). H1NMR (300 MHz, CDCl3), ppm: 7.94 (d, 2H), 7.49 (m, 1H), 7.39 (d, 2H), 3.44 (s, 2H), 3.36 (m, 2H), 2.99 (d, 2H), 2.67 (m, 4H), 2.60 (t, 2H), 2.39 (s, 3H), 2.07 (m, 3H), 1.83 (m, 4H), 1.65 (m, 10H). MS (ESI+) M/z: 473, 475 (M+H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C:13]([O-])(C)C.[K+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])(C)C)=[O:21]>CC(O)(C)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][O:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:26][CH2:12][CH3:13]
Reactant: OCCOCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCCCOC(=O)COCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 58.8 %

Procedure:
To a stirred solution of 2-(benzyloxy)ethanol 8 (1.7 g, 11.17 mmol) in t-BuOH (25 ml) was added at room temperature t-BuOK (1.38 g, 12.29 mmol). Mixture was stirred at room temperature for 2.5 hrs. t-butyl bromoacetate (2.7 ml, 20.11 mmol) was then added while mixture was cooled with a water bath. Mixture was stirred overnight at room temperature and concentrated. Water was added and aqueous layer was extracted with dichloromethane. Combined organic layers were dried over MgSO4, filtered and concentrated. Flash chromatography on silica gel (EtOAc/pentane 1/4) afforded ester 9 as an oil (1.749 g, 59%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:22][C:23]([C:25]2[C:26](=[O:38])[N:27]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:28]([CH3:31])[C:29]=2[CH3:30])=[O:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1.CS(O[CH2:44][CH2:45][CH2:46][N:47]1[CH2:53][CH:52]([OH:54])[C:49]2([CH2:51][CH2:50]2)[CH2:48]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[OH:54][CH:52]1[C:49]2([CH2:51][CH2:50]2)[CH2:48][N:47]([CH2:46][CH2:45][CH2:44][O:21][C:15]2[CH:14]=[C:13]3[C:18]([C:9]([O:8][C:7]4[CH:6]=[CH:5][C:4]([NH:22][C:23]([C:25]5[C:26](=[O:38])[N:27]([C:32]6[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=6)[N:28]([CH3:31])[C:29]=5[CH3:30])=[O:24])=[CH:3][C:2]=4[F:1])=[CH:10][CH:11]=[N:12]3)=[CH:17][C:16]=2[O:19][CH3:20])[CH2:53]1
Reactant: CS(=O)(=O)OCCCN1CC(O)C2(CC2)C1
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3F)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3F)ccnc2cc1OCCCN1CC(O)C2(CC2)C1
Temperature: 25 °C
Reaction time: 40 h
Yield: 65.8 %

Procedure:
To a solution of N-(3-fluoro-4-(7-hydroxy-6-methoxyquinolin-4-yloxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (200 mg, 0.389 mmol) in DMA (2 mL) was added 3-(7-hydroxy-5-azaspiro[2.4]heptane-5-yl)propyl methanesulfonate (193 mg, 0.778 mmol) and Cs2CO3 (379 mg, 1.167 mmol). The reaction was then stirred at rt for 40 hrs. The solvent was removed and the residue was partioned between saturated NaHCO3 aqueous solution (10 mL) and CHCl3 (30 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated in vacuo and the residue was purified by a silica gel column chromatography (100:15:1 (v/v/v) EtOAc/CH3OH/Et3N) to afford the desired compound as a pale yellow solid (171 mg, 66%).
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH2:15][C:16]#[N:17])=[CH:9][NH:10]2.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]=O)[CH:19]=1.C(OCC)C>C(O)C.C(Cl)Cl>[CH3:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8](/[C:15](=[CH:24]/[C:20]1[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=1)/[C:16]#[N:17])=[CH:9][NH:10]2
Reactant: O=Cc1cccnc1
Reactant: COc1cccc2[nH]cc(CC#N)c12
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: CCOCC
Product: COc1cccc2[nH]cc(/C(C#N)=C/c3cccnc3)c12
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To a solution of sodium methanolate (261 mg, 4.8 mmol, 1.5 eq.) in anhydrous ethanol (40 mL) were added, under an argon atmosphere, of (4-methoxy-1H-indol-3-yl)-acetonitrile (600 mg, 3.2 mmol, 1.0 eq.) and, after 30 minutes stirring, pyridine-3-carbaldehyde (908 μL, 9.7 mmol, 3.0 eq.). The reaction apparatus was protected from light and the mixture heated at 60° C. Several amounts of sodium methanolate (4×1.0 eq.) and pyridine-3-carbaldehyde (4×1.0 eq.) were added after stirring for 24, 48, 72 and 96 hours respectively. The reaction was pursued for 2 days (6 days overall) at 60° C. and then, the solvent was removed under reduced pressure and the crude taken up in ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4 and then, evaporated. The residue was purified by silica gel flash-column chromatography (eluent: CH2Cl2/EtOH, 98:2 to 97:3) to afford, after trituration with diethyl ether, the compound (27) as a yellow powder (510 mg, 58%). TLC: Rf=0.30 (CH2Cl2 96/EtOH 4); mp: 177° C.; 1H NMR (DMSO, 500 MHz): δ (ppm): 3.90 (3H, s, 4′-methoxy), 6.66 (1H, d, J5′-6′=7.9 Hz, H5′), 7.07 (1H, d, J7′-6′=7.9 Hz, H7′), 7.14 (1H, t, J6′-5′=J6′-7′=7.9 Hz, H6′), 7.55 (1H, dd, J5″-4″=7.9 Hz, J5″-6″=4.9 Hz, H5″), 7.62 (1H, s, H2′), 7.78 (1H, s, H3), 8.31 (1H, d, J4″-5″=7.9 Hz, H4″), 8.59 (1H, d, J6″-5″=4.9 Hz, H6″), 8.91 (1H, s, H2″), 11.67 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz): δ (ppm): 55.6 (4′-methoxy), 101.4 (C5′), 106.0 (C7′), 108.6 (C2), 111.9 (C3′), 114.7 (C3a′), 119.1 (C1), 124.1 (C5″), 124.3 (C6′), 126.6 (C2′), 131.1 (C3″), 134.9 (C4″), 138.0 (C3), 139.0 (C7a′), 150.3 (C6″), 150.4 (C2″), 153.7 (C4′); ESI-MS: m/z 276.1 ([M+H]+), 298.1 ([M+Na]+); HRESI-MS: m/z 276.1137 (calcd for C17H14N3O, 276.1137).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=5)[CH:19]=4)[CH2:13][CH2:12]3)=[CH:4][C:3]=2[O:2]1.[Cl:36][CH2:37][C:38]1[CH:43]=[CH:42][N:41]=[C:40]([C:44]2[CH:49]=[C:48]([O:50][CH3:51])[C:47]([O:52][CH3:53])=[C:46]([O:54][CH3:55])[CH:45]=2)[CH:39]=1>>[ClH:36].[ClH:36].[ClH:36].[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:25]=[C:26]([O:34][CH3:35])[C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=5)[CH:19]=4)[CH2:13][CH2:12]3)[CH2:37][C:38]3[CH:43]=[CH:42][N:41]=[C:40]([C:44]4[CH:49]=[C:48]([O:50][CH3:51])[C:47]([O:52][CH3:53])=[C:46]([O:54][CH3:55])[CH:45]=4)[CH:39]=3)=[CH:4][C:3]=2[O:2]1
Reactant: COc1cc(-c2cc(CN3CCC(Nc4ccc5c(c4)OCO5)CC3)ccn2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCC(N(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)c4ccc5c(c4)OCO5)CC3)ccn2)cc(OC)c1OC
Product: Cl

Procedure:
4-(3,4-Methylenedioxyphenylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (119 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl) pyridine (114 mg) were condensed by the same manner as described in Example 9. Yellow oil of a free base was converted to a trihydrochloride which gave the title compound as yellow powder.
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:17][CH:16]=[N:15][CH:14]=2)=[CH:9][CH:8]=1.CN([CH:21]=[O:22])C.Cl>C1COCC1.CCOCC>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[O:17][C:16]([CH:21]=[O:22])=[N:15][CH:14]=2)=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(-c2cnco2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1ncc(-c2ccc(F)cc2)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
A solution of nBuLi (1.6 M in hexane, 3.45 ml, 5.53 mmol) was added dropwise at −78° C. to a stirred solution of 5-(4-fluorophenyl)-1,3-oxazole (0.82 g, 5.03 mmol) in THF (10 ml) (Organic Letters (2001),(3)2, 271-273). The mixture was stirred at −78° C. for 30 minutes and then quenched with DMF (0.43 ml, 5.53 mmol). It was gradually warmed to room temperature, stirred for further 30 minutes, diluted with Et2O (30 ml), then neutralised with 1N HCl. The organic layer was separated, washed with brine (20 ml), dried over MgSO4 and concentrated in vacuo. Purification by chromatography on silica gel eluting with DCM afforded 5-(4-fluorophenyl)-1,3-oxazole-2-carbaldehyde (0.58 g, 60%): δH (360 MHz, CDCl3) 7.18 (2H, t, J 8.6 ), 7.58 (1H, s), 7.77-7.81 (2H, m), 9.76 (1H, s); m/z (ES+) 192 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH2:17][C:18]([O:20]C)=[O:19])[CH:12]=2)[CH:7]=1)[CH3:5].Cl>[OH-].[Na+]>[C:18]([CH2:17][O:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[C:6]([CH:4]([CH3:5])[C:3]([OH:22])=[O:2])[CH:15]=[CH:14]2)([OH:20])=[O:19]
Reactant: COC(=O)COc1ccc2cc(C(C)C(=O)OC)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C(=O)O)c1ccc2cc(OCC(=O)O)ccc2c1
Temperature: 90 °C
Yield: 71.8 %

Procedure:
A mixture of 2-(6-Methoxycarbonylmethoxy-naphthalen-2-yl)-propionic acid methyl ester 31 (23 grams, 76.16 mmol) in 4 N—NaOH solutions (230 mL) was heated on a water bath at 90° C. for 8 hours. The reaction mass was cooled to room temperature and the pH adjusted to 2 with concentrated hydrochloric acid. Crude 89 was filtered, dried, and recrystallized from a mixture of ethyl acetate:hexane (1:6) to give pure 89 (15 grams, 71.9%) as a white powder. Mp: 185-188° C. IH NMR (DMSO-d6) δ 1.54(d,3H,CH3), 3.80(q,1H,CH), 4.74(s,2H,OCH2), 7.08(s,1H,Ar), 7.22(m,1H,Ar), 7.42(m,1H,Ar), 7.66(m,3H,Ar).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[N+:7]([O-:9])=[O:8].[N+:16]([O-])([OH:18])=[O:17].S(=O)(=O)(O)O>C(Cl)Cl>[O:1]([CH2:2][CH2:3][O:4][CH2:5][C:6]([N+:13]([O-:15])=[O:14])([N+:7]([O-:9])=[O:8])[N+:10]([O-:12])=[O:11])[N+:16]([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])C(COCCO)([N+](=O)[O-])[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=[N+]([O-])OCCOCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The dried solution of 2,2,2-trinitroethyl 2-hydroxyethyl ether produced in example 3 was diluted to 200 ml with methylene chloride and this solution was slowly added with cooling below 5° C. (ice bath) to a vigorously stirred nitrating solution (prepared by slowly adding 136 ml of 90% nitric acid to 272 ml of concentrated sulfuric acid with cooling). The nitration mixture was vigorously stirred at room temperature for 3 hours before it was poured onto ice. The organic layer was separated, washed with 3×100 ml of water, dried over magnesium sulfate and allowed to stand in a hood to evaporate volatiles to give 75 g (65%) of essentially pure 2,2,2-trinitroethyl 2-nitroxyethyl ether (TNEN). The TNEN can be further purified by dissolving it in 300 ml of diethyl ether, adding 300 ml of hexanes, cooling the solution in a dry ice-acetone bath until it begins to cloud, adding seed crystals, continuing cooling in the dry ice-acetone bath for 20 minutes, removing the crystals by filtration through a precooled filter funnel, washing the crystals with cold (-40° C.) hexanes and quickly redissolving the cold crystals into methylene chloride. The pure product has mp 10°-11° C.; 1H NMR (CDCl3): δ4.10 (m,2H), 4.70 (m,2H) 4.88 (s,2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH2:38]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[CH3:39]>>[CH2:38]([N:40]1[CH2:45][CH2:44][N:43]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:42][CH2:41]1)[CH3:39]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and N-ethylpiperazine according to conditions described in general procedure C. Mp: 86-87° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.96 (s, 3 H), 1.58-1.59 (m, 6 H), 2.26 (bs, 4 H), 3.26-3.31 (m, 8H), 3.46 (bs, 2 H), 6.21 (d, J=5.8 Hz, 1 H), 6.95 (d, J=12.4 Hz, 1 H), 7.15 (d, J=8.8 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.45 (s, 1 H), 7.55-7.61 (m, 3 H), 7.81-7.83 (m, 1 H), 7.97 (d, J=7.7 Hz, 1 H), 8.25 (d, J=5.5 Hz, 1 H), 10.43 (s, 1 H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11](=O)[CH3:12]>CO.[Pd]>[CH2:11]([C:3]1[C:2]([OH:1])=[C:7]2[CH2:8][CH2:9][O:10][C:6]2=[CH:5][CH:4]=1)[CH3:12]
Reactant: CC(=O)c1ccc2occc2c1O
Agent: [Pd]
Solvent: CO
Product: CCc1ccc2c(c1O)CCO2
Reaction time: 24 h

Procedure:
A mixture of 1-(4-Hydroxy-benzofuran-5-yl)-ethanone (1.37 g, 7.8 mmol) and 10 wt % Pd/C (0.7 g, Degussa type) in MeOH (20 mL) was stirred under a balloon of H2 for 24 hours. The reaction mixture was filtered through a pad of celite washing with EtOAc. The filtrate was concentrated to an oil (0.9 g, 70%). 1H NMR (400 MHz, CDCl3): δ 1.21 (t, J=7.6 Hz, 3 H), 2.56 (q, J=7.6 Hz, 2 H), 3.14 (t, J=8.6 Hz, 2 H), 4.59 (t, J=8.6 Hz, 2 H), 4.68 (s, 1H), 6.37 (d, J=8.1 Hz, 1 H), 6.37 (d, J=8.1 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH2:16]1[O:24][CH:17]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:25]([N:32]1C=CN=C1)(N1C=CN=C1)=[O:26].[OH-].[NH4+]>C(O)(C)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:16][CH:17]([O:24][C:25](=[O:26])[NH2:32])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:10][CH2:9]2)=[O:7])=[CH:14][CH:15]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: c1ccc(C2CO2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: NC(=O)OC(CN1CCC(C(=O)c2ccc(F)cc2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-(4-fluorobenzoyl)piperidine (5 mmol) and styrene oxide(5 mmol) was refluxed in 30 ml of isopropanol for 4 h. This solution was then concentrated on a rotary evaporator and diluted with ethyl acetate. This mixture was then washed with brine, the resulting organic layer was dried and concentrated in vacuo. The crude product was dissolved in THF(50 ml) and was added with 1,1′-carbonyl diimidazole (2 mmol) at 0° C. The reaction mixture was stirred at room temperature for 4 h, followed by the addition of excess ammonium hydroxide (10 ml) at 0° C. After 5 h stirring at room temperature, water was added to terminate the reaction. The organic layer was extracted 3 times with dichloromethane, dried and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:hexane=1:2). The resulting carbamic acid 2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-1-phenyl-ethyl ester was dissolved in THF and the solution was treated with a solution of HCl in ethyl ether. The resulting precipitate was filtered to give carbamic acid 2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-1-phenyl-ethyl ester; hydrochloride.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([CH3:19])([CH3:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N+:31]([O-:33])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N+:31]([C:22]1[CH:23]=[C:24]([C:27]([F:28])([F:29])[F:30])[CH:25]=[CH:26][C:21]=1[O:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([CH3:19])([CH3:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])([O-:33])=[O:32]
Reactant: COC(=O)c1cc(C(C)(C)CC(C)(C)C)ccc1O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(C)(C)CC(C)(C)C)ccc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
Methyl 2-hydroxy-5-(1,1,3,3-tetramethylbutyl)benzoate (520 mg, 0.002 mol), 4-chloro-3-nitrobenzotrifluoride (442 μL, 0.003 mol) and potassium carbonate were mixed in dimethylformamide (20 mL) at 150° C., under argon, for 16 h. The mixture was filtered, the solvent was evaporated and the residue flash chromatographed (silica gel, ethyl acetate/hexane) to yield the title compound. 1H NMR (250 MHz, (CD3)2SO) δ8.38 (d, 1H), 7.98 (d, 1H), 7.89 (dd, 1H), 7.78 (dd, 1H), 7.28 (d, 1H), 6.87 (d, 1H) 3.65 (s, 3H), 3.29 (s, 2H), 1.79 (s, 3H), 1.38 (s, 6H), 0.68 (s, 6H).
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([OH:5])=O.C(N1CCOCC1)C.[CH2:24]([O:28][C:29](=[O:37])[NH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH2:25][CH2:26][CH3:27].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:24]([O:28][C:29](=[O:37])[NH:30][CH:31]1[CH2:36][CH2:35][N:34]([C:3](=[O:5])[CH2:2][NH:1][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:33][CH2:32]1)[CH2:25][CH2:26][CH3:27]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCCCOC(=O)NC1CCNCC1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOC(=O)NC1CCN(C(=O)CNC(=O)OCc2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 150 mg Z-Gly-OH in 5 ml DMF were added 0.4 ml N-ethylmorpholine, 144 mg piperidin-4-yl-carbamic acid butyl ester and 236 mg TOTU. After stirring for 12 h it was diluted with ethyl acetate and subsequently washed with aqueous LiCl (4%), saturated NaHCO3 and 0.1 M HCl. The crude product thus obtained after evaporation of the solvent was directly used in the next step. Yield: 287 mg.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18].[OH-].[Na+]>C(#N)C.O>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:21]([NH:20][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)(=[O:18])=[O:19])=[O:22])[N:7]=1
Reactant: COc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2ccccn2)n1

Procedure:
To a stirred suspension of 1.4 g of 2-amino-4-methoxy-6-methylpyrimidine in 20 ml of dry acetonitrile at room temperature is added 2.2 g of 2-pyridinesulfonylisocyanate. The mixture is stirred for several hours and filtered. Evaporation of the filtrate yields a solid residue which is stirred in approximately 30 ml of water while adjusting the pH of this mixture to 11 by the addition of 10% NaOH. This solution is filtered, the filtrate pH adjusted to pH 7 by adding 10% hydrochloric acid and the resulting neutral solution again filtered. The desired product is then precipitated from this filtrate by adjusting the pH to 2, collecting in a sintered funnel and drying in a vacuum oven at room temperature.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]=1[OH:14])[N:10]=[C:9]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=[C:7]2[Cl:22])(=[O:3])[CH3:2].[C:23](OCC)(=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25].[CH3:33]COCC>CN(C)C=O>[Cl:22][C:7]1[C:6]2[C:11](=[C:12]([CH2:15][CH2:16][CH3:17])[C:13]3[O:14][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:2][C:1](=[O:3])[C:4]=3[CH:5]=2)[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:33])=[O:19])[CH:8]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCc1c(O)c(C(C)=O)cc2c(Cl)cc(C(=O)OC)nc12
Reactant: CCOCC
Solvent: CN(C)C=O
Product: CCCc1c2nc(C(=O)OCC)cc(Cl)c2cc2c(=O)cc(C(=O)OCC)oc12
Reaction time: 0.33 h

Procedure:
Methyl 6-acetyl-4-chloro-7-hydroxy-8-propyl-quinoline-2-carboxylate (1.0 g) and diethyl oxalate (3.7 mls) in dry dimethylformamide (25 mls) was added to ether washed 50% sodium hydride (0.65 g) suspended in dry dimethyl formamide (25 mls) under nitrogen with stirring. The reaction mixture was stirred for 5 hours at room temperature, poured into ethyl acetate, aqueous acetic acid was added and the organic layer separated, washed well with water and dried. The solvent was evaporated, the residue dissolved in dry dioxan (100 mls) and dry hydrogen chloride gas passed through the solution for 20 minutes. The reaction mixture was poured into ethyl acetate, washed well with water, saturated sodium bicarbonate solution then water again and dried. The solvent was evaporated and the residue triturated with 40-60 petroleum ether to give 0.9 g of the title product. The structure was confirmed by NMR and MS evidence. The product was converted to the free acid and the disodium salt using the techniques of Example 1(b) and (c).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([CH2:30][CH2:31][OH:32])[CH:29]=1)[CH2:5][N:6]1[CH2:26][CH2:25][C:9]2([O:14][CH2:13][CH2:12][N:11]([C:15]([C:17]3[N:18]=[C:19]([CH:22]([CH3:24])[CH3:23])[S:20][CH:21]=3)=[O:16])[CH2:10]2)[CH2:8][CH2:7]1.FC(F)(F)C(O)=O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:29]=[C:28]([CH2:30][CH:31]=[O:32])[CH:27]=[C:4]([CH2:5][N:6]2[CH2:26][CH2:25][C:9]3([O:14][CH2:13][CH2:12][N:11]([C:15]([C:17]4[N:18]=[C:19]([CH:22]([CH3:23])[CH3:24])[S:20][CH:21]=4)=[O:16])[CH2:10]3)[CH2:8][CH2:7]2)[CH:3]=1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(Cl)cc(CCO)c4)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(Cl)cc(CC=O)c4)CC3)C2)cs1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of (9-(3-chloro-5-(2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 52, step c) (0.242 g) in DCM (5 mL) was cooled in ice-water, treated with trifluoroacetic acid (0.059 mL) and stirred for 5 minutes. Dess-Martin periodinane (0.323 g) was added, then the mixture was removed from the cooling bath and stirred at room temperature for 30 minutes. The solution was diluted with saturated sodium thiosulphate solution (5 mL), saturated sodium bicarbonate solution (5 mL) and ethyl acetate (5 mL) and the resulting mixture was stirred vigorously for 10 minutes. The mixture was then extracted twice with ethyl acetate, the combined organic phases were washed with brine, acidified with acetic acid (0.1 mL), dried over anhydrous magnesium sulphate and concentrated in vacuo to give the crude subtitled compound as a yellow foam. Yield 0.297 g.