Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH3:11].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[Na+].[Na+].C(OCCO)C.[OH:29][S:30]([OH:33])(=[O:32])=[O:31]>CC(O)C>[S:30]([OH:33])([OH:32])(=[O:31])=[O:29].[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:3]([CH3:11])[CH:4]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOCCO
Solvent: CC(C)O
Product: Cc1cc(N)ccc1N1CCCC1

Procedure:
15.5g (0.1 mole) 2-fluoro-5-nitrotoluene, 25 ml (0.3 mole) pyrrolidine, 11.0 g Na2CO3 were combined with 50 ml 2-ethoxyethanol and refluxed with stirring. When the TLC showed no evidence of starting material (ca. 2 hours), the mixture was poured onto ice. The precipitate was filtered, washed 5 times with cold H2O, and dried on filter paper for 2 hours. The resulting solid was mixed with 125 ml 2-propanol, 10% Pd/C, and hydrogenated at 60 psi on a Parr apparatus. The mixture was filtered through filter-aid and stirred with external cooling in an ice/acetone bath. A cold solution of 10.7 g (0.105 mole) concentrated H2SO4 in 15 ml 2-propanol was added dropwise over 15 minutes. The resultant precipitate was filtered, washed 2 times with 2-propanol and dried in vacuo at 50° C. The final yield was 24.45 g (89%) of a light grey solid. MS (solid probe): m/e 176 (free base).
Reaction SMILES: [OH-].[Br:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][N:4]=1.[CH3:10]I>CS(C)=O>[Br:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Oc1cccnc1Br
Reactant: CI
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cccnc1Br
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
5.93 g (90.0 mmol) of 85% powdered potassum [sic] hydroxide are suspended in 30 ml of DMSO and heated to 50° C. under argon as the inert gas. 2.54 g (14.6 mmol) of 2-bromo-3-hydroxypyridine dissolved in 10 ml of DMSO are added dropwise to this suspension. This solution is stirred for another 10 minutes, after which 12.3 g (5.30 ml, 33.1 mmol) of methyl iodide are added dropwise over a period of 2 minutes. The addition takes place at such a rate that the reaction temperature is always between 50°-55° C. The reaction [sic] is then stirred at this temperature for another 10 minutes. The finished reaction solution is finally poured onto 100 ml of ground ice. The crude product obtained is recrystallized from ether/petroleum ether (4:1).
Reaction SMILES: C([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10]([CH2:24][Cl:25])[CH2:9]1)=O)(C)(C)C.CCN=C=NCCCN(C)C.Cl.[C:38]([NH:41][C:42]1[CH:43]=[C:44]([CH:50]=[CH:51][CH:52]=1)/[CH:45]=[CH:46]/C(O)=O)(=[O:40])[CH3:39]>CC(N(C)C)=O>[C:38]([NH:41][C:42]1[CH:43]=[C:44]([CH:50]=[CH:51][CH:52]=1)/[CH:45]=[CH:46]/[C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10]([CH2:24][Cl:25])[CH2:9]1)=[O:5])(=[O:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc([N+](=O)[O-])c1ccccc21
Reactant: CC(=O)Nc1cccc(/C=C/C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1cccc(/C=C/C(=O)N2CC(CCl)c3c2cc([N+](=O)[O-])c2ccccc32)c1
Yield: 74.7 %

Procedure:
Deprotection of 13 (250 mg, 0.69 mmol) as in Example C above and reaction of the product with EDCI.HCl (332 mg, 1.73 mmol), (E)-3-(acetylamino)cinnamic acid (148 mg, 0.72 mmol) and DMA (3 mL) at 20° C. for 3 h, followed by addition of dilute KHCO3, precipitated. This was collected, dissolved in warm EtOAc (180 mL) and filtered through a column of silica gel. Solvent concentration followed by addition of i-Pr2O precipitated the crude product which was recrystallised from EtOAc/i-Pr2O to give 14k (232 mg, 75%), mp 214-216° C. 1H NMR [(CD3)2SO] δ 10.07 (s, 1 H, NH), 9.22 (s, 1 H, H-4), 8.33 (dd, J=7.8, 1.9 Hz, 1 H, H-6), 8.19 (dd, J=7.3, 1.6 Hz, 1 H, H-9), 7.88 (s, 1 H, H-2'), 7.78-7.63 (m, 3 H, H-7,8,4'), 7.68 (d, J=15.3 Hz, 1 H, PhCH=CH), 7.55 (d, J=7.8 Hz, 1 H, H-6'), 7.39 (t, J=7.9 Hz, 1 H, H-5'), 7.14 (d, J=15.4 Hz, 1 H, PhCH=CH), 4.72-4.55 (m, 3 H, H-1,2), 4.12-4.05 (m, 2 H, CH2Cl), 2.08 (s, 3 H, CH3). Anal. Calculated for C24H20ClN3O4 : C, 64.1; H, 4.5; N, 9.2; Cl, 7.9. Found: C, 64.3; H, 4.4; N, 9.3; Cl, 7.8%.
Reaction SMILES: Br[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].N#N.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>O.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Oc1cccnc1Br
Agent: [Pd]
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Oc1cccnc1-c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 72 h
Yield: 45.7 %

Procedure:
2-Bromo-3-hydroxypyridine (50 g, 0.29 mol), sodium carbonate (64 g, 0.60 mol), toluene (600 ml), and water (300 ml) were combined in a 2 liter 3-necked flask with condenser and N2 bubbler. A steady stream of N2 was passed over the reaction mixture while warming to 50° C. over 30 minutes. Tetrakis(triphenylphosphine) palladium(0) (10 g) was slurried in water then added to the reaction mixture then 4-fluorobenzeneboronic acid (46 g, 0.33 mol) was slurried in ethanol (100 ml) and added. The reaction mixture was refluxed for 5 hours then cooled and stirred at room temperature for 3 days. The organic layer was decanted off and concentrated in vacuo and the aqueous layer saturated with potassium carbonate and extracted with ethyl acetate (×4). The organics were combined and concentrated in vacuo then ethyl acetate (200 ml) added and the mixture heated. A yellow powder settled in the flask which was filtered off to give the title compound (25.1 g, 46%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@:4]([N:9]=[C:10]=[O:11])([CH:6]([CH3:8])[CH3:7])N.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][OH:20]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH:9][C:10]([O:20][CH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1)=[O:11]
Reactant: COC(=O)[C@](N)(N=C=O)C(C)C
Reactant: OCc1ccccn1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](NC(=O)OCc1ccccn1)C(C)C
Yield: 54.1 %

Procedure:
A solution of 0.78 g (5.0 mmol) of α-isocyanato-valine methyl ester and 0.55 ml (5.7 mmol) of pyridine-2-methanol in 30 mL of toluene was heated at reflux under N2 atmosphere for 4 h. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography using 2% methanol in chloroform to give 0.72 g (54%) of the desired compound as an oil. 1H NMR (CDCl3) δ 0.91 (d, J=7 Hz, 3 H), 0.98 (d, J=7 Hz, 3 H), 2.19 (m, 1 H), 3.75 (s, 3 H), 4.32 (dd, J=9, 5 Hz, 1 H), 5.24 (s, 2 H), 5.39 (br d, 1 H), 7.23 (ddd, J=8, 4, 1 Hz, 1 H), 7.37 (d, J=8 Hz, 1 H), 7.70 (td, J=8, 2 Hz, 1 H), 8.60 (br d, 1 H). Mass spectrum: (M+H)+ =267.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([O:22][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CNc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1nc(OCc2ccccc2)ccc1[N+](=O)[O-]

Procedure:
A procedure similar to that described in Preparation 88 was repeated, except that 7.00 g of 6-chloro-2-methylamino-3-nitropyridine (prepared as described in Preparation 66), 1.79 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 4.3 ml of benzyl alcohol and 150 ml of dimethylformamide were used. After working up the product as described in Preparation 88, the resulting crude product was crystallized by trituration with isopropanol, to give 9.02 g of the title compound, melting at 149° C.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:19])=[CH:9][C:10]([O:17][CH3:18])=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.[CH3:20][Mg]Cl>C1COCC1>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:19])=[CH:9][C:10]([O:17][CH3:18])=[CH:11][C:12]=3[C:13]2([CH3:20])[OH:16])=[CH:4][CH:3]=1
Reactant: C[Mg]Cl
Reactant: COc1cc(F)c2oc3ccc(Br)cc3c(=O)c2c1
Solvent: C1CCOC1
Product: COc1cc(F)c2c(c1)C(C)(O)c1cc(Br)ccc1O2
Temperature: -30 °C

Procedure:
7-bromo-4-fluoro-2-methoxy-9H-xanthen-9-one (22 g, 68.1 mmol) was dissolved in 300 ml of THF and cooled to −30° C. in a dry ice ACN bath. Methylmagnesium chloride (34.0 mL, 102 mmol) (3M in THF) was added to the slurry maintaining temperature less than −15° C. The solution was allowed to warm to RT (undissolved solids went into solution), then quenched with saturated NH4Cl (250 mL). The aqueous layer was extracted with EtOAc (3×200 mL) and the combined organic layers were washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated to afford 7-bromo-4-fluoro-2-methoxy-9-methyl-9H-xanthen-9-ol as a brown liquid that was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[NH:15][CH:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:33][C:34]([F:37])([F:36])[F:35]>>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:33][C:34]([F:37])([F:36])[F:35])[CH:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)OCCc1sc(-c3ncc[nH]3)nc1-2
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cn1ccnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reaction time: 0.75 h

Procedure:
To a solution of 8-Bromo-2-(1H-imidazol-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene (0.430 g, 1.23 mmol) in N,N-Dimethylformamide (17.2 mL, 222 mmol) was added Cesium Carbonate (0.805 g, 2.47 mmol). After 45 min. 2-iodo-1,1,1-trifluoro-ethane (0.241 mL, 2.47 mmol) was added to the reaction mixture. The reaction mixture was stirred at 50 C 4 h. The reaction was quenched with water then extracted with EtOAc 2×. The organic layers was combined, dried Na2SO4, concentrated and purified by chromatography (EtOAc/Hex) (eluted at 35%) to give 8-Bromo-2-[1-(2,2,2-trifluoro-ethyl)-1H-imidazol-2-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene. MS: (ESI+)=330.1.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:8][CH2:9][CH:10]([NH2:12])N)[CH:5]=[CH:6][N:7]=1)[CH3:2].[OH-].[Na+].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>C(Cl)Cl>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:12][CH2:10][CH2:9][CH2:8][N:4]2[CH:5]=[CH:6][N:7]=[C:3]2[CH2:1][CH3:2])=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCc1nccn1CCC(N)N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCc1nccn1CCCNC(=O)c1ccc(Cl)cc1
Reaction time: 18 h

Procedure:
A mixture of 2.3 g. of 2-ethyl-1H-imidazole-1-propanediamine, 15 ml. of 2N sodium hydroxide and 150 ml. of methylene chloride was stirred at room temperature and 4.0 ml. of 4-chlorobenzoyl chloride was added. The reaction mixture was stirred for 18 hours, then methylene chloride and 15 ml. of 1N sodium hydroxide were added and the layers were separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The crystalline residue was washed onto a filter with ether and melted at 120°-122° C.
Reaction SMILES: [O-:1][N+:2]1[C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:6]=2[N:5]=[C:4]([CH2:15][CH2:16][CH2:17][OH:18])[N:3]=1)[CH2:12][CH2:11][CH2:10]3.[C:19]([NH:26][C@H:27]([C:31](O)=[O:32])[CH:28]([CH3:30])[CH3:29])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:22]([O:21][C:19]([NH:26][CH:27]([CH:28]([CH3:30])[CH3:29])[C:31]([O:18][CH2:17][CH2:16][CH2:15][C:4]1[N:3]=[N+:2]([O-:1])[C:7]2[CH:8]=[C:9]3[C:13]([CH2:12][CH2:11][CH2:10]3)=[CH:14][C:6]=2[N:5]=1)=[O:32])=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: [O-][n+]1nc(CCCO)nc2cc3c(cc21)CCC3
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)OCCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Temperature: 20 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
A mixture of alcohol 70 (50 mg, 0.20 mmol), N-Boc Valine (44 mg, 0.20 mmol), DCC (46 mg, 0.22 mmol) and DMAP (2.5 mg, 0.02 mmol) in DCM (10 mL) was stirred at 20° C. for 1 h. The solvent was evaporated and the residue purified by chromatography, eluting with a gradient (0-5%) of MeOH/DCM, to give the crude ester, which was suspended in DCM (2 mL) and filtered to remove urea by-products. The filtrate was concentrated to give crude ester 310 (84 mg, 93%) as a pale-brown gum: 1H NMR δ 8.27 (s, 1H, H-9); 7.76 (s, 1H, H-5), 4.96-5.03 (m, 1H, CH), 4.28 (t, J=6.5 Hz, 2H, CH2O), 3.08-3.16 (m, 6H, H-6, H-8, CH2), 2.21-2.31 (m, 4H, H-7, CH2), 2.08-2.17 (br m, 1H, CH), 1.46 [s, 9H, C(CH3)3], 0.97 (d, J=6.9 Hz, 3H, CH3), 0.91 (d, J=6.9 Hz, 3H, CH3), NH not observed; HRMS calcd for C23H32N4O5 (M+) m/z 444.2373, found 444.2382.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=[O:15])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:19]OC(OC)(C)C>CO.Cl.O1CCOCC1>[CH3:19][O:15][C:14]([CH:10]1[CH2:11][CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:18][CH:17]=2)[CH2:9]1)=[O:16]
Reactant: COC(C)(C)OC
Reactant: O=C(O)[C@H]1CCC[C@H](C(=O)c2ccc(Br)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)C1CCCC(C(=O)c2ccc(Br)cc2)C1
Temperature: 50 °C
Yield: 95.5 %

Procedure:
To a solution of trans-3-(4-bromobenzoyl)cyclohexane-1-carboxylic acid (500 mg, 1.61 mmol, obtained from Rieke Metals Inc., Lincoln, Nebr., USA) and 2,2-dimethoxypropane (669 mg, 6.43 mmol) in methanol (20 mL), 5 drops of 4 M HCl in dioxane was added, and this reaction mixture was heated at 50° C. overnight. The solvent was removed by rotary evaporation to give the product 3-(4-bromo-benzoyl)-cyclohexanecarboxylic acid methyl ester as a brown oil (500 mg, yield 95.7%). 1H NMR (300 MHz, DMSO) δ 7.80 (d, 2 H), 7.60 (d, 2 H), 3.70 (s, 3 H), 3.25 (m, 1 H), 2.50 (m, 1 H), 2.20–1.90 (m, 4 H), 1.70–1.50 (m, 4 H); LC-MS ret. time 3.30 min, m/z 324.9 (MH+).
Reaction SMILES: [C:1]([C:9]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])=[CH:10]OCC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][N:26]=1>CC(N(C)C)=O>[C:1]([C:9]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:15])=[O:16])=[CH:10][NH:24][C:25]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][N:26]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CCOC=C(C(=O)c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Solvent: CC(=O)N(C)C
Product: Cc1ccc(S(=O)(=O)C(=CNc2ccc(Br)cn2)C(=O)c2ccccc2)cc1
Yield: 34 %

Procedure:
A solution of 1-benzoyl-2-ethoxy-1-(4-methylphenylsulphonyl)ethene (0.85 g) and 2-amino-5-bromopyridine (0.45 g) in dimethylacetamide (30 ml) was heated at reflux for 2 hours. It was then cooled and poured onto ice (60 g). The resulting off-white precipitate was filtered off, washed with water, dried, and recrystallised from ethyl acetate, to give 1-benzoyl-2-(5-bromopyrid-2-ylamino)-1-(4-methylphenylsulphonyl)ethene (0.4 g), m.p. 205° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Br.C(=O)([O-])[O-].[K+].[K+]>>[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([F:9])[CH:4]=1
Reactant: Oc1ccc(Br)c(F)c1
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1cc(OCc2ccccc2F)ccc1Br
Yield: 108.5 %

Procedure:
A solution of 4-bromo-3-fluorophenol (5 g, 25 mmol), 2-fluorobenzylbromide (4.94 g, 26 mmol) and potassium carbonate (5.39 g, 39 mmol) was stirred at room temperature for 6 h. The solvent was evaporated, the residue taken up in water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure, affording the title compound (8.11 g) as a white solid; Rt (HPLC) 6.31 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])([O-])=[O:2]>CN1CCOCC1.[Pt]>[C:5]1([CH3:10])[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH:1][OH:2]
Reactant: Cc1ccccc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CN1CCOCC1
Product: Cc1ccccc1NO
Reaction time: 13 h
Yield: 82.6 %

Procedure:
A suspension of 411 g (3 mol) of 2-nitrotoluene and 15 g of platinum on active carbon (F 105 XRS/W 5% from Degussa) in 2.8 l of 4-methylmorpholine was flushed at 0° C. with nitrogen and then with hydrogen. The reaction was carried out at 100 mbar gauge pressure. The reaction was completed after 13 hours. The mixture was flushed with nitrogen and the catalyst was filtered off, after which the solvent was very substantially distilled off at from 45 to 50° C. under reduced pressure. The residue was taken up in 1 l of 1:1 methylene chloride/water and the aqueous phase was acidified with hydrochloric acid and then extracted with methylene chloride. The organic phases were dried and the solvent was distilled off, after which the residue was digested in pentane and the product was filtered off and washed. 305 g of the title compound were obtained as (according to HPLC analysis) 89% strength by weight product.
Reaction SMILES: [Na+].[I-].C[Si](Cl)(C)C.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)O)=[CH:11][CH:10]=1.O>CC#N>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)=[CH:11][CH:10]=1
Reactant: OC(c1ccc(F)cc1)c1cccs1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Fc1ccc(Cc2cccs2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a suspension of NaI (8 g, 53 mmol) in CH3CN (100 mL) was added TMSCl (6.8 mL, 54 mmol). The resulting mixture was cooled to 0° C. and treated with (4-fluorophenyl)-2-thienylmethan-1-ol, allowed to warm to room temperature, stirred overnight, then cooled to 0° C. and treated with water. The resulting mixture was extracted with EtOAc. The organic layer was washed with a saturated Na2S2O3 solution, water and a saturated NaCl solution, then concentrated under reduced pressure. The crude product was purified by flash chromatography (hex) to give 2-(4-fluorobenzyl)thiophene (1.89 g, 40% overall yield) as a pink oil: TLC (hex) Rf 0.69; 1H NMR (CDCl3) δ 4.14 (s, 2H), 6.80-6.82 (m, 1H), 6.93-7.04 (s, 3H), 7.16-7.28 (m, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH:11]([C:13]1[CH:21]=[C:20]2[C:16]([C:17](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])=[N:18][NH:19]2)=[CH:15][CH:14]=1)=O>>[O:10]=[C:2]1[NH:1][C:9]2[C:4](/[C:3]/1=[CH:11]\[C:13]1[CH:21]=[C:20]3[C:16]([C:17](/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25])=[N:18][NH:19]3)=[CH:15][CH:14]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1ccc2c(/C=C/C(=O)O)n[nH]c2c1
Product: O=C(O)/C=C/c1n[nH]c2cc(/C=C3/C(=O)Nc4ccccc43)ccc12
Yield: 21.1 %

Procedure:
The title compound (7 mg, 21%) was synthesized as an orange solid according to the method described for Example A67 using oxindole (13.3 mg, 0.1 mmol) and (E)-3-(6-formyl-1H-indazol-3-yl)acrylic acid (21.6 mg, 0.1 mmol). NMR (400 MHz, DMSO-d6) δ 13.80 (br. s, 1H, NH), 10.64 (s, 1H, CO2H), 8.20 (d, J=8.4 Hz, 1H), 7.94 (s, 1H), 7.85 (d, J=16.4 Hz, 1H), 7.78 (s, 1H), 7.58-7.53 (m, 2H), 7.24 (t, J=7.6 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H), 6.84 (t, J=7.8 Hz, 1H), 6.75 (d, J=16.0 Hz, 1H); MS ESI 332.1 [M+H]+, calcd for [C19H13N3O3+H]+ 322.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[N:10]=[N:9][C:8]=1[C:19]([N:21]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25][C@H:24]([C:35]([O:37]C)=[O:36])[CH2:23]1)=[O:20].[OH-].[Na+]>CO>[C:31]([O:30][C:28]([N:26]1[CH2:27][C@@H:22]([N:21]([C:19]([C:8]2[N:9]=[N:10][N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[O:20])[CH2:39][CH:40]([CH3:41])[CH3:42])[CH2:23][C@@H:24]([C:35]([OH:37])=[O:36])[CH2:25]1)=[O:29])([CH3:32])([CH3:34])[CH3:33]
Reactant: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
To a solution of 1-tert-butyl 3-methyl(3R,5S)-5-[{[5-(4 methoxybutyl)-1-(2-methylphenyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (1.47 g) in methanol (10 ml) was added 4N aqueous sodium hydroxide solution (5 ml), and the mixture was stirred at 50° C. for 30 min. The solvent was concentrated under reduced pressure, and the residue was neutralized with 10% aqueous citric acid solution, extracted with ethyl acetate (30 ml×2) and the extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object product (1.3 g) as an amorphous compound.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)=[O:4].Cl.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([NH:27]N)=[CH:23][CH:22]=1)#[N:20].CC([O-])=O.[Na+]>CC(O)=O.OS(O)(=O)=O>[CH3:1][N:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]([CH:5]1[CH2:10][C:9]2[C:25]3[C:24](=[CH:23][CH:22]=[C:21]([C:19]#[N:20])[CH:26]=3)[NH:27][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CN(C(=O)C1CCC(=O)CC1)c1ccccc1
Reactant: N#Cc1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CN(C(=O)C1CCc2[nH]c3ccc(C#N)cc3c2C1)c1ccccc1
Temperature: 25 °C
Yield: 48.3 %

Procedure:
A stirred solution of 4-oxo-cyclohexanecarboxylic acid methyl-phenyl-amide (50 mg, 0.22 mmol) and (4-cyanophenyl)-hydrazine hydrochloric acid salt (36.5 mg, 0.22 mmol) in glacial AcOH (1 ml) is heated to reflux for 1 h. At rt, two drops of conc. H2SO4 are added and the reaction mixture is again heated to reflux for another 1 h, then cooled to rt and poured into 5% aqueous NaOAc. The resulting precipitate is filtered, rinsed several times with H2O and dried under high vacuum providing pure subtitle compound (35 mg) in 49% yield as a white solid. tR (LC-4) 1.06 min; ESI-MS (positive ion): m/z 329.96 [M]+ (calcd 329.40 for C21H19N3O). 1H-NMR (CDCl3): 2.12 (m, 2H); 2.53 (m, 1H); 2.73 (m, 3H); 2.93 (m, 1H); 3.34 (s, 3H); 7.25 (m, 3H); 7.32 (m, 2H); 7.41 (m, 2H), 7.71 (s, 1H); 8.04 (br s, 1H).