Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][NH:28][CH2:27]2>>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28]([CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]1)[CH2:27]2
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Reactant: Fc1ccc2c(c1)CNC2
Product: O=C(O)c1ccnc(-c2cn(CCN3Cc4ccc(F)cc4C3)cn2)c1
Yield: 76 %

Procedure:
The title compound was prepared in 76% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 5-fluoro-2,3-dihydro-1H-isoindole according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 3.08 (2H, t, J=6.0 Hz), 3.88 (2H, s), 3.92 (2H, s), 4.19 (2H, t, J=6.0 Hz), 6.98 (1H, td, J=9.6 and 2.5 Hz), 7.08 (1H, dd, J=5.5 and 2.0 Hz), 7.24 (1H, dd, J=6.7 and 3.0 Hz), 7.52 (1H, d, J=3.8 Hz), 7.80 (1H, s), 7.84 (1H, s), 8.26 (1H, s), 8.53 (1H, d, J=5.0 Hz). [M+H] Calc'd for C19H17FN4O2, 353. Found, 353.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[Br:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[CH3:32].O>C(Cl)(Cl)Cl>[Br:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][C:23]=1[CH2:32][Br:8]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(Br)c(CBr)c1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
NBS (46.6 g, 262 mmol) and AIBN (0.72 g, 4.4 mmol) were added in one portion into a solution of methyl 4-bromo-3-methylbenzoate (50.0 g, 218 mmol) in CHCl3 (1 L) under N2. The mixture was stirred at 70° C. for 2 days. The reaction mixture was cooled to RT and water (500 mL) was added. The organic layer was washed with a saturated solution of NaHCO3 (50 mL), water (350 mL) and brine (500 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was washed with pentane (2×500 mL) affording the title compound as a yellow solid. HPLC (Method A), Rt 4.9 min (Purity: 98.2%). 1H NMR (DMSO-d6, 300 MHz) δ 8.24 (d, J=1.9 Hz, 1H), 7.85 (m, 2H), 4.87 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[C:19]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:18]=[C:17]([CH3:32])[C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][CH2:14][O:15][CH3:16])=[C:9]([CH:12]=1)C=O.C1C=C(Cl)C=C(C(OO)=[O:41])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:32][C:17]1[CH:18]=[C:19]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:23]([CH3:25])[CH3:24])[CH:26]([CH3:27])[CH3:28])[CH:20]=[C:2]([CH3:1])[C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][CH2:14][O:15][CH3:16])=[C:9]([OH:41])[CH:12]=1
Reactant: COCOc1ccc(Cc2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1C=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCOc1ccc(Cc2c(C)cc(O[Si](C(C)C)(C(C)C)C(C)C)cc2C)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To 5-(2,6-dimethyl-4-triisopropylsilanyloxybenzyl)-2-methoxymethoxy-benzaldehyde (compound 15, step e; 0.460 g, 1.01 mmol) in dichloromethane 30 mL was add mCPBA (0.870 g, 2.52 mmol) and saturated sodium bicarbonate solution (2 mL). After stirring at rt overnight, the reaction mixture was poured into dichloromethane 50 mL and washed 3× with 10 mL of saturated aqueous sodium bicarbonate. The dichloromethane was dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was combined with methanol (10 mL) and 2 mL of 1 N NaOH and stirred for 1.5 hours at room temperature. The reaction was acidified with 12 N HCl (pH<3) and poured into 50 mL ethyl acetate. The layers were separated and the organics were dried over sodium sulfate, filtered and concentrated. Flash column chromatography using silica and a step gradient of hexane/ethyl acetate [20:1], hexane/ethyl acetate [9:1] provided 5-(2,6-dimethyl-4-triisopropylsilanyloxybenzyl)-2-methoxymethoxy-phenol (0.189 g, 42%): 1H NMR (300 MHz, DMSO-d6): δ 8.95 (s, 1H), 6.86 (d, 1H, J=8.1 Hz), 6.56 (s, 2H), 6.41 (d, 1H, J=2.1 Hz), 6.34 (dd, 1H, J=2.1 Hz and J=8.7 Hz), 5.05 (s, 2H), 3.78 (s, 2H), 3.38 (s, 3H), 2.13 (s, 6H), 1.11 (m, 3H), 1.00 (m, 18H); Uniplate silica gel, 250 microns; Mobile phase=10% ethyl acetate in hexane: Rf=0.15
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[C:7]([Cl:22])[C:6]=1[CH3:23])(=[O:3])[CH3:2]>C(OCC)(=O)C.O.[Pt](=O)=O>[C:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[C:7]([Cl:22])[C:6]=1[CH3:23])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(Cl)c(Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1C
Agent: O=[Pt]=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cc(Cl)c(Oc2ccc(N)cc2)c(Cl)c1C
Reaction time: 6 h
Yield: 54.6 %

Procedure:
To a solution of methyl[3,5-dichloro-4-(4-nitrophenoxy)phenyl] acetate (14 g) in ethyl acetate (90 mL) was added platinum(IV) oxide monohydrate (0.48 g) and the mixture was stirred vigorously under hydrogen gas (1 atmospheres) for 6 hours. The suspension was filtered and the filtrate concentrated. The residue was purified on column (silica gel, n-heptane/ethyl acetate, 1:1) to give 7.0 g of methyl[3,5-dichloro-4-(4-aminophenoxy)-phenyl] acetate as orange crystals.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]1=[O:10].[CH3:11][CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[CH2:31]Cl)[CH2:23][CH2:22]1)[CH3:13]>CN(C=O)C>[CH3:13][CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:29]=[C:30]([CH2:31][N:3]3[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]3=[O:10])[CH:33]=[CH:34][CH:35]=2)[CH2:23][CH2:22]1)[CH3:11]
Reactant: CC(C)Oc1ccccc1N1CCN(Cc2cccc(CCl)c2)CC1
Reactant: O=C1CCCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccccc1N1CCN(Cc2cccc(CN3C(=O)CCCC3=O)c2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of NaH (0.224 g, 7.48 mmol) and DMF (10 mL) was treated slowly with 2,6-piperidinedione (0.846 g, 7.48 mmol) at room temperature. After the addition was complete, the mixture was cooled to 0° C. and a solution of 3-[3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]benzyl chloride (2.46 g, 7.12 mmol) and DMF (10 mL) was added dropwise. The cooling bath was removed and the reaction was stirred at room temperature overnight. A small portion of water was added and the reaction was concentrated under vacuum. The residue was partitioned between CH2Cl2 /water and the organic layer was separated, dried, and evaporated to give 1-[[3-[[1-[2-(1-methylethoxy)phenyl]- 4-piperazinyl]methyl]phenyl]methyl]-piperidine-2,6-dione as an oil, 3.25 g. This material was dissolved in i-PrOH (13 mL) and treated with maleic acid (0.83 g, 7.15 mmol). Trituration with ether, filtration, and drying afforded 1-[[3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]-piperidine-2,6-dione (Z)-2-butenedioate (1:1) as a white solid (2.73 g, 70%), m.p. 103°-105° C. 1H NMR and mass spectral analysis supported the assigned structure.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH2:15])=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH2:3]1.Cl.[NH2:21][OH:22].N1C=CC=CC=1>>[OH:22][N:21]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([C:13]([NH2:15])=[O:14])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[CH2:3]1
Reactant: NO
Reactant: NC(=O)N1c2ccccc2CC(=O)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Product: NC(=O)N1c2ccccc2CC(=NO)c2ccccc21

Procedure:
A suspension of 4.0 g (15.86 mmol) of 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide and 3.86 g (55.49 mmol) of hydroxylamine hydrochloride in 100 mL of absolute alcohol was treated with 3.76 g (47.57 mmol) of pyridine. The mixture was heated at reflux for 1 hour and then the ethanol was removed by evaporation under reduced pressure. The residue was partitioned between 150 mL of water and 150 mL of dichloromethane. The organic layer was separated and washed with 50 mL of 1M aqueous HCl, a saturated solution of NaHCO3 and brine, then dried by sodium sulphate. Filtration and evaporation of the solvent under reduced pressure gave an off-white solid which was triturated with hot ethanol to give the desired compound as a white powder of m.p. 230.4° to 231.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][Si](C(C)C)(C(C)C)C(C)C)[C:14]=3[O:30][CH3:31])[N:10]([C:32]([C:34]3[C:39]([F:40])=[CH:38][C:37]([F:41])=[CH:36][C:35]=3[F:42])=[O:33])[N:9]=2)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:61][O:62][C:63](=[O:72])[C:64]1[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70]Br)[CH:65]=1>C(#N)C>[CH3:61][O:62][C:63](=[O:72])[C:64]1[CH:69]=[CH:68][CH:67]=[C:66]([CH2:70][O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([CH:11]3[N:10]([C:32](=[O:33])[C:34]4[C:35]([F:42])=[CH:36][C:37]([F:41])=[CH:38][C:39]=4[F:40])[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[S:12]3)[C:14]=2[O:30][CH3:31])[CH:65]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: COc1c(O[Si](C(C)C)(C(C)C)C(C)C)cccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: COC(=O)c1cccc(COc2cccc(C3SC(c4ccc(F)cc4)=NN3C(=O)c3c(F)cc(F)cc3F)c2OC)c1
Reaction time: 0.5 h

Procedure:
[5-(4-fluoro-phenyl)-2-(2-methoxy-3-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone (0.02 mmol) is treated with tetrabutylammonium fluoride (1 M in THF) (0.04 mmol) at room temperature for 30 minutes. 3-Bromomethyl-benzoic acid methyl ester (0.04 mmol) is then added. After 30 minutes, the reaction is complete as determined by LC/MS. The mixture is diluted with acetonitrile and purified by preparative LC/MS (20-100% MeCN/H2O) to give 3-{3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxymethyl}-benzoic acid methyl ester as white solid after evaporation of solvent: 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 8.02 (d, J=7.8 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.47-7.55 (m, 4H), 7.01-7.07 (m, 3H), 6.94 (t, J=8.3 Hz, 2H), 6.77 (t, J=8.5 Hz, 2H), 5.16 (s, 2H), 4.07 (s, 3H), 3.94 (s, 3H). LC/MS (ES+: (M+1) 610.9.
Reaction SMILES: [C:1]([C:5]1[CH:23]=[CH:22][C:8]([CH2:9][NH:10][CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[CH2:30](Cl)[CH:31]=[CH2:32]>CN(C)C=O>[CH2:32]([N:10]([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[CH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:23][CH:22]=1)[CH:31]=[CH2:30]
Reactant: CC(C)(C)c1ccc(CNCc2cccc3ccccc23)cc1
Reactant: C=CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(Cc1ccc(C(C)(C)C)cc1)Cc1cccc2ccccc12
Temperature: 25 °C
Yield: 95 %

Procedure:
3.03 g (0.01 mole) of N-(4'-t-butylbenzyl)-1-naphthylmethylamine was dissolved in 50 ml of dry dimethylformamide, and 1.6 g (0.015 mole) of anhydrous sodium carbonate was added. With continued stirring at room temperature, 0.84 g (0.011 mole) of allyl chloride was added, and the mixture was reacted at 30° to 40° C. for 5 hours. The reaction mixture was mixed with ice water and extracted with toluene. The organic layer was washed with water, and toluene was evaporated. The residue was chromatographed on a silica gel column, and eluted with 5% ethyl acetate/n-hexane. The eluate was concentrated to give 3.26 g (yield 95%) of an oily substance.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([OH:12])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:14](OC(=O)C)(=[O:16])[CH3:15]>N1C=CC=CC=1>[C:14]([O:12][C:9]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([CH3:13])[C:2]([Br:1])=[CH:11][CH:10]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1c(O)ccc(Br)c1C
Solvent: c1ccncc1
Product: COC(=O)c1c(OC(C)=O)ccc(Br)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
A solution of Example 106B (1.05 g, 4.3 mmol) in pyridine (3 mL) was treated with acetic anhydride (0.82 mL, 8.6 mmol), stirred at room temperature for 2 hours, and partitioned between ethyl acetate and 2N HCl. The organic phase was washed sequentially with aqueous NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated to give 1.19 g (97% yield) of the desired product. MS (ESI(+)) m/e 304, 306 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([C:26]#[C:27][Si](C)(C)C)=[CH:25][C:19]=2[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]1[C:17]1[NH:21][C:20]2[CH:22]=[CH:23][C:24]([C:26]#[CH:27])=[CH:25][C:19]=2[N:18]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C#Cc1ccc2[nH]c([C@@H]3CCCCN3C(=O)OCc3ccccc3)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2[nH]c([C@@H]3CCCCN3C(=O)OCc3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring solution of compound (S)-2-(5-trimethylsilanylethynyl-1H-benzoimidazol-2-yl)-piperidine-1-carboxylic acid benzyl ester (85.3 mg, 0.197 mmol) in MeOH (2 mL) is added potassium carbonate (27.3 mg, 0.197 mmol). The reaction mixture is stirred at room temperature for 3 hours and concentrated in vacuum to dryness. The residue obtained is used directly in the next step.
Reaction SMILES: CCOCC.[F:6][C:7]1[CH:33]=[C:32]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:31]=[CH:30][C:8]=1[O:9][CH2:10][CH2:11][C@@H:12]1[CH2:14][C@@H:13]1[CH:15]1[CH2:20][CH2:19][N:18](CC(C2C=CC=CC=2)=O)[CH2:17][CH2:16]1>C(O)C.[Pd]>[F:6][C:7]1[CH:33]=[C:32]([S:34]([CH3:37])(=[O:35])=[O:36])[CH:31]=[CH:30][C:8]=1[O:9][CH2:10][CH2:11][C@@H:12]1[CH2:14][C@@H:13]1[CH:15]1[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]1
Reactant: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCN(CC(=O)c3ccccc3)CC2)c(F)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(OCC[C@@H]2C[C@@H]2C2CCNCC2)c(F)c1
Reaction time: 64 h

Procedure:
The ether, 2-[4-((1R,2S)-2-{2-{2-fluoro-4-(methylsulfonyl)phenoxy]ethyl}cyclopropyl)piperidine-1-yl]-1-phenylethanone (740 mg, 1.62 mmol) in ethanol (25 mL) was added Palladium on carbon (10 wt. %, wet, 0.200 g), degassed (3× vacuum/H2) again and stirred under H2 at 1 atm for 64 h. The reaction mixture was filtered through a plug of celite, and the filter cake rinsed with ethanol (150 mL), ethyl acetate (150 mL), and the filtrate was concentrated under reduced pressure to provide the piperidine as a yellow oil. MS (ESI): 342 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:17]=1)=[C:7]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[O:8][N:9]=2.O>C(O)(=O)C.[Fe]>[NH2:9][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][C:6]=1[C:7]([C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)=[O:8]
Reactant: Oc1ccc(-c2onc3ccc(Cl)cc23)cc1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(Cl)cc1C(=O)c1ccc(O)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 83.7 g (0.34 mole) of 5-chloro-3-(4-hydroxyphenyl)-2,1-benzisoxazole in 1500 ml of glacial acetic acid was added 45 g of iron filings. The mixture was stirred and heated on the steam bath for 20 min. Every 30 min. an additional 20 g of iron filings and 100 ml of water was added for 2.5 hr. After 30 min. more, the reaction mixture was filtered while hot. The collected precipitate was heated with acetic acid and filtered. The combined filtrates were diluted with ice water to precipitate 39.8 g (47%) of product, mp 170°-175°. Recrystallization from methanol-water gave yellow rods, mp 173°-178°.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[N:7][C:6]=1[CH3:28])C.[Li+].[OH-].Cl>C1COCC1.O>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]2[C:8]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=3)=[N:7][C:6]([CH3:28])=[C:5]([CH:10]=2)[C:4]([OH:29])=[O:3])=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)c(-c2ccc(Cl)cc2)cc1C(=O)O
Reaction time: 16 h

Procedure:
A solution of 1.6 g of 5-(4-Chloro-phenyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid ethyl ester and 136 mg of LiOH in 5 ml of THF and 5 ml of water was stirred at room temperature for 16 h. After 16 h, the mixture was brought to pH 2 by addition of 1 M hydrochloric acid. The reaction mixture was concentrated under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The residue was codistilled twice with dichloromethane and twice with toluene The isolated crude product was used in the next reaction step. Yield: 1.6 g.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])[CH:15]=NO)=[CH:9][CH:8]=1>C(OCC)(=O)C>[F:6][C:7]1[CH:12]=[C:11]2[C:10](=[CH:9][CH:8]=1)[NH:13][C:14](=[O:18])[C:15]2=[O:2]
Reactant: O=C(C=NO)Nc1ccc(F)cc1
Reactant: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(F)cc2C1=O
Temperature: 90 °C

Procedure:
Concentrated sulfuric acid (200 mL) was heated at 50° C., and N-(4-fluorophenyl)-2-hydroxyiminoacetamide was slowly added. The black solution was carefully heated at 90° C. At this temperature, some slight cooling was necessary to keep the temperature at 90° C. When no more heat had developed, the reaction mixture was heated at 90° C. for an additional half hour. The dark-red solution was cooled to room temperature and poured onto 3 L ice water and 1 L ethyl acetate with vigorous stirring. The layers were separated, and the aqueous layer was extracted with ethyl acetate (1×1 L, 1×0.5 L). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to dryness. Yield: 35.3 g (52%) of a dark red solid, 5-fluoro-1H-indole-2,3-dione.
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][CH2:32][C:33]([O:35][C:36]([CH3:39])(C)C)=[O:34])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:40].C(=O)([O-])[O-].[NH4+:45].[NH4+]>C(O)C>[ClH:40].[ClH:40].[C:1]1([N:7]([CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:39])=[O:34])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH2:45])=[CH:23][CH:24]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCCC(=O)OC(C)(C)C)c3ccccc3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 68 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-tert.butyloxycarbonylpropyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 68% of theory, Rf value: 0.12 (silica gel; dichloromethane/ethanol=4:1) C29H32N6O3 (512.6) ##EQU17##
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[C:5](Cl)(=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1C=CC=CC=1>C1C=CC=CC=1>[C:5]([O:4][CH2:3][CH2:2][Br:1])(=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCC(=O)Cl
Reactant: OCCBr
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCC(=O)OCCBr
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.9 %

Procedure:
2-Bromoethanol (4 g, 32 mmol) was added dropwise to a solution of octanoyl chloride (7.8 g, 48 mmol) and pyridine (5 mL) in benzene (50 mL). The reaction mixture was stirred at room temperature for 24 hours. After evaporation of benzene and pyridine under high vacuum, the residue was redissolved in benzene (100 mL). The solution was washed with water (50 mL), sulfuric acid solution (3×25 mL, 0.5 N), sodium bicarbonate solution (25 mL, 1N), and water (2×75 mL). The benzene layer was dried over Na2SO4. The drying agent was suction filtered, and the benzene was evaporated. The resulting oil was purified by silica gel chromatography using chloroform/methanol (9:1) to give 6.5 g of pure product. Yield 81%; liquid; IR (neat) 2930 and 2850 (aliphatic CH), 1730 (CO ester) cm-1 ; 1H NMR (CDCl3) 0.85-0.95 (t, CH3 (CH2)4), 1.20-1.40 (m, CH3 (CH2)4), 1.55-1.70 (m, CH2 CH2 CO), 2.25-2.40 (t, CH2 CH2 CO), 3.50-3.60 (t, O CH2 CH2 Br), 4.35-4.40 (t, O CH2 CH2 Br).
Reaction SMILES: C([Sn]([N:14]=[N+:15]=[N-:16])(CCCC)CCCC)CCC.[C:17]([C:19]1[C:20](=[O:48])[N:21]([CH2:25][C@H:26]2[C@H:32]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=3)[O:31][CH2:30][CH2:29][N:28]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:27]2)[CH:22]=[CH:23][CH:24]=1)#[N:18]>C1(C)C=CC=CC=1>[Cl:40][C:35]1[CH:34]=[C:33]([C@@H:32]2[O:31][CH2:30][CH2:29][N:28]([C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])[CH2:27][C@H:26]2[CH2:25][N:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:17]3[NH:16][N:15]=[N:14][N:18]=3)[C:20]2=[O:48])[CH:38]=[CH:37][C:36]=1[Cl:39]
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](Cn2cccc(C#N)c2=O)C1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](Cn2cccc(-c3nnn[nH]3)c2=O)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
Tributyltin azide (0.340 mL, 1.24 mmol) was added to a solution of tert-butyl (6R,7R)-6-[(3-cyano-2-oxopyridin-1(2H)-yl)methyl]-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (198 mg, 0.41 mmol) in toluene (5 mL). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (148 mg, 0.284 mmol, 68.6%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=[CH:7]3)[CH2:24][CH2:23]2)=[CH:20][CH:21]=1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: ClCCCCn1cnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCCn3cnc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
1-(4-chlorobutyl)-1H-benzimidazole (7.51 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-methylphenyl piperazine (5.3 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 10-15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 6.4 g compound (I-11) with a yield of 60.7%. ESI-MS [M+H]+: m/z 349.2.