Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)#[N:2].S(=O)(=O)(O)[OH:16].[OH-].[NH4+]>O>[C:1]([C:3]1[C:12]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)(=[O:16])[NH2:2]
Reactant: COc1cccc2c(C#N)cccc12
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1cccc2c(C(N)=O)cccc12

Procedure:
1-Cyano-5-Methoxy-naphthalene (36 g) is stirred with concentrated sulfuric acid (250 ml) and H2O (20 ml) on a steam bath for two hours and is allowed to cool. The reaction mixture is poured into a slurry of crushed ice and concentrated ammonium hydroxide (250 ml). The mixture is extracted with methylene chloride and the organic extract dried, filtered and evaporated, yielding the desired amide as a solid.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=1.[NH2:16][C@@H:17]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=1)[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[O:28]=[C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:29])[N:19]1[CH2:18][C@@H:17]([NH:16][C:7]([C:5]1[S:6][C:2]([CH3:1])=[C:3]([C:10]2[N:14]([CH3:15])[N:13]=[CH:12][CH:11]=2)[CH:4]=1)=[O:9])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:38])[F:40])[CH:32]=1
Reactant: N[C@@H](Cc1cccc(C(F)(F)F)c1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1sc(C(=O)O)cc1-c1ccnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1sc(C(=O)N[C@@H](Cc2cccc(C(F)(F)F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1ccnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
To a 50 mL round-bottomed flask was added 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (201 mg, 0.91 mmol), 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (301 mg, 0.87 mmol) [Prepared according to Preparation 6 except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 14.95 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (519 mg, 1.11 mmol) in chloroform (9 mL). DIEA (790 μL, 4.52 mmol) was added and the mixture stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (247 mg, 45%): LC-MS (ES) m/z=553 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([NH2:22])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]=O.C[O-].[Na+].[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]1[CH:21]=[C:20]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([NH:22][CH3:23])=[CH:17][C:18]=3[NH:19]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=O
Reactant: Nc1ccc2c(c1)[nH]c1cc(OCc3ccccc3)ccc12
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNc1ccc2c(c1)[nH]c1cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Yield: 82.7 %

Procedure:
A mixture of 7-(benzyloxy)-9H-carbazol-2-amine (150 mg, 0.52 mmol), paraformaldehyde (78 mg, 2.6 mmol), and NaOMe (900 mg, 25% MeOH solution, 4.16 mmol) in 15 mL of MeOH was heated at reflux for 2 h under Ar atmosphere and cooled to rt. To this mixture was added NaBH4 (98 mg, 2.6 mmol) and the mixture was heated at reflux for 2 h. After cooling to rt, the mixture was quenched onto ice (30 g). It was extracted with EtOAc (3×50 mL) and the combined organic phase was dried over MgSO4 and concentrated. The crude product was purified with chromatography (hexane/EtOAc) to afford 7-(benzyloxy)-N-methyl-9H-carbazol-2-amine as a light-brown solid (130 mg, 82%). 1H NMR (400 MHz, acetone-d6) δ 9.78 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.49 (d, J=7.2 Hz, 2H), 7.37 (m, 2H), 7.32-7.28 (m, 1H), 6.98 (d, J=2.4 Hz, 1H), 6.78 (dd, J=8.4, 2.4 Hz, 1H), 6.56 (d, J=2.0 Hz, 1H), 6.49 (dd, J=8.4, 2.4 Hz, 1H), 5.13 (s, 2H), 4.96 (s, 1H), 2.82 (s, 3H); MS (ESI) m/z 303 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:11][N:10]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:9]1=[O:25])(C)(C)C>C(OCC)(=O)C>[NH2:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:11][N:10]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:9]1=[O:25]
Reactant: CC(C)CN1C[C@H](c2ccccc2F)C[C@H](NC(=O)OC(C)(C)C)C1=O
Solvent: CCOC(C)=O
Product: CC(C)CN1C[C@H](c2ccccc2F)C[C@H](N)C1=O
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl[(3S,5S)-5-(2-fluorophenyl)-1-(2-methylpropyl)-2-oxopiperidin-3-yl]carbamate (150 mg, 0.41 mmol) in ethyl acetate (20 mL), pre-cooled to 0° C. was sparged with HCl gas for ˜1 min. The ice-bath was removed and the acidic solution was allowed to warm to 23° C. as stirring was continued for 2 h. The mixture was then concentrated to dryness to afford the title compound as a hydrochloride salt. MS: m/z=265.1 (M+1).
Reaction SMILES: [F-].[Cs+].[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:19])=[N:14][CH:15]=[C:16](Br)[CH:17]=1.[CH3:20][C:21]1[C:25](B2OC(C)(C)C(C)(C)O2)=[C:24]([CH3:35])[NH:23][N:22]=1>CO.[Pd](Cl)Cl.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>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:19])=[N:14][CH:15]=[C:16]([C:25]2[C:21]([CH3:20])=[N:22][NH:23][C:24]=2[CH3:35])[CH:17]=1
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Nc1ncc(Br)cc1-c1nc2ccccc2o1
Agent: Cl[Pd]Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: Cc1n[nH]c(C)c1-c1cnc(N)c(-c2nc3ccccc3o2)c1
Temperature: 140 °C
Reaction time: 2 h
Yield: 16.3 %

Procedure:
Bis(triphenylphosphine) palladium (II) chloride (85 mg) and caesium fluoride (1.1 g) were added to a degassed solution of 3-(1,3-benzoxazol-2-yl)-5-bromo-pyridin-2-amine (700 mg) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (563 mg) in Methanol (14 ml). The suspension was stirred at 140° C. for 2 hours in a 300 W microwave. The mixture was adsorbed on silica gel and purified by flash chromatography on silica gel eluting with 5 to 10% methanol in dichloromethane. The solvent was evaporated to dryness to afford 3-(1,3-benzoxazol-2-yl)-5-(3,5-dimethyl-1H-pyrazol-4-yl)pyridin-2-amine (120 mg). NMR Spectrum: (DMSOd6) 2.22 (s, 6H), 7.40-7.487 (m, 2H), 7.66 (bs, 2H), 7.76-7.81 (m, 1H), 7.82-7.87 (m, 1H), 8.13 (d, 1H), 8.18 (d, 1H); Mass spectrum: M+H+ 306
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])=[C:4]([O:17][CH2:18][CH:19]2[O:21][CH2:20]2)[CH:3]=1.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([NH:26][CH2:20][CH:19]([OH:21])[CH2:18][O:17][C:4]1[CH:3]=[C:2]([Cl:1])[CH:16]=[CH:15][C:5]=1[C:6]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)CCC(=O)c1ccc(Cl)cc1OCC1CO1
Product: CCOC(=O)CCC(=O)c1ccc(Cl)cc1OCC(O)CNC(C)(C)C
Yield: 82.4 %

Procedure:
A stirred mixture of ethyl 3-[4-chloro-2-(2,3-epoxypropoxy)benzoyl]propionate (3.0 g, 0.01 mole) methanol (28 ml) and t-butylamine (6.7 ml, 0.0625 mole) was heated under reflux for 70 minutes. The mixture was evaporated to an oily residue which was purified on a silica column by elution with mixtures of chloroform and methanol and recrystallisation from ether-petroleum ether (b.p. 40°-60°) to give ethyl 3-[2-(3-t-butylamino-2-hydroxypropoxy)-4-chlorobenzoyl]propionate (3.18 g, 88%, m.p. 70°).
Reaction SMILES: [ClH:1].[CH2:2]([O:14][C:15]1[CH:23]=[CH:22][C:18]([CH:19]([NH2:21])[CH3:20])=[CH:17][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].Cl.C[CH:26]([NH2:41])[C:27]1C=[CH:31][C:30](CCC2C=CC=CC=2)=[CH:29][CH:28]=1>>[ClH:1].[CH2:2]([O:14][C:15]1[CH:16]=[CH:17][C:18]([CH:19]([N:21]=[C:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:41]2)[CH3:20])=[CH:22][CH:23]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCOc1ccc(C(C)N)cc1
Reactant: CC(N)c1ccc(CCc2ccccc2)cc1
Agent: Cl
Product: CCCCCCCCCCCCOc1ccc(C(C)N=C2CCCCCN2)cc1

Procedure:
Following essentially the same procedure described in Example 7 above and substituting p-dodecyloxy-α-methylbenzylamine hydrochloride for the α-methyl-p-phenyethylbenzylamine hydrochloride above, results in the formation of 2-(p-dodecyloxy-α-methylbenzylimino)hexahydroazepine hydrochloride having a M.P. of 186°-8° C (dec.).
Reaction SMILES: [S:1]([CH3:13])[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].Cl[Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C1C=CN=CC=1)C.ClCCCl.ClCCl>[Si:15]([O:12][CH2:11][C@H:9]1[O:10][C@@H:2]([S:1][CH3:13])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@H:7]1[OH:8])([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CS[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CS[C@@H]1O[C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Yield: 79.6 %

Procedure:
A mixture of methyl 1-thio-β-D-galactopyranoside (25) 5 g, 28 mmol), chloro t-butyldiphenylsilane (5.85 g, 21 mmol) and DMAP (2.63 g, 21 mmol) in dry 1,2-dichloroethane (130 mL) was left to stir at reflux for 2.5 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane (200 mL) and washed with saturated sodium chloride solution (2×250 mL). The organic phase was dried over MgSO4 and subsequently evaporated to dryness to give methyl 6-O-(t-butyldiphenylsilyl)-1-thio-β-D-galactopyranoside (26) (7.5 g, 81%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:27][C:15]3[N:16]=[CH:17][N:18]=[C:19](NCC4CCCS4)[C:14]=3[C:13]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:8][CH:7]=1.FC(F)(F)C([O-])=O.[O:42]=[S:43]1(=[O:50])[CH2:47][CH2:46][CH2:45][CH:44]1[CH2:48][NH3+:49]>>[CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[O:27][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH:49][CH2:48][CH:44]4[CH2:45][CH2:46][CH2:47][S:43]4(=[O:50])=[O:42])[C:14]=3[C:13]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:10][CH:11]=1
Reactant: CN(C)CCOc1ccc(-c2oc3ncnc(NCC4CCCS4)c3c2-c2ccccc2)cc1
Reactant: [NH3+]CC1CCCS1(=O)=O
Agent: O=C([O-])C(F)(F)F
Product: CN(C)CCOc1ccc(-c2oc3ncnc(NCC4CCCS4(=O)=O)c3c2-c2ccccc2)cc1

Procedure:
Prepared by the method of 233 using (1,1-Dioxotetrahydrothiophen-2-yl)methylammonium trifluoroacetate (229). 1H NMR (D2O): 8.28 (1H, s); 7.62 (3H, br s); 7.52-7.40 (4H, m); 6.94 (2H, d, J=10 Hz); 4.42-4.34 (2H, m); 3.84 (1H, dd, J=12, 6 Hz); 3.72 (1H, dd, J=12, 8 Hz); 3.20-3.01 (2H, m); 3.54-3.43 (1H, m); 3.35-3.23 (1H, m); 3.15-3.09 (1H, m); 3.00 (6H, s); 2.48-2.35 (1H, m), 2.30-2.15 (2H, m) and 1.90-1.78 (1H, m). LC/MS: 507 (MH+).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[CH2:19]([N:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[N:23]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[C:22]1=[O:37])[CH3:20].[H-].[Na+]>CN(C=O)C>[CH2:19]([N:21]1[C:29]2[C:24](=[N:25][CH:26]=[CH:27][CH:28]=2)[N:23]([C:30]2[CH:31]=[CH:32][C:33]([O:36][C:2]3[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]4[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=4[N:3]=3)=[CH:34][CH:35]=2)[C:22]1=[O:37])[CH3:20]
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2ncccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3COCC[Si](C)(C)C)cc2)c2ncccc21
Temperature: 200 °C
Yield: 94.5 %

Procedure:
2-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (1.861 g) was added to a solution of 1-ethyl-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.4 g) and sodium hydride (0.263 g) in DMF (dry) (10 mL) at room temperature. The mixture was heated at 200° C. for 1 h under microwave irradiation. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, eluted with 5%-50% EtOAc in hexane) to give 1-ethyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.60 g) as a colorless solid. A mixture of 1-ethyl-3-{4-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (194 mg) and 2 M HCl in EtOH (6.0 mL) was stirred at 70° C. for 4 h. After cooling to room temperature, the solvent was removed in vacuo. The residue was recrystallized from EtOH-ether to give 3-[4-(1H-benzimidazol-2-yloxy)phenyl]-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one hydrochloride (154 mg).
Reaction SMILES: [CH:1]([NH2:3])=[S:2].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH:13](Br)[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1>C(#N)C>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]2[N:3]=[CH:1][S:2][C:12]=2[C:9]2[CH:8]=[CH:7][C:6]([O:5][CH3:4])=[CH:11][CH:10]=2)=[CH:19][CH:18]=1
Reactant: NC=S
Reactant: COc1ccc(C(=O)C(Br)c2ccc(OC)cc2)cc1
Solvent: CC#N
Product: COc1ccc(-c2ncsc2-c2ccc(OC)cc2)cc1
Reaction time: 0.25 h
Yield: 59 %

Procedure:
An ethereal solution of thioformamide (0.153 mole) was concentrated in vacuo at less than 25°. The residue was slurried with acetonitrile (10 ml.) and cooled in an ice water bath. p-Methoxy-2-bromo-2-(p-methoxyphenyl)acetophenone (4.27 g.; 0.0128 mole) was dissolved in acetonitrile (50 ml.) and added via syringe to the above slurry. After stirring for 15 minutes in ice, the flask was refrigerated at 5°-10° for 16 hours. The solution was then stirred at ambient temperature for 70 hours before work up. The solvent was removed in vacuo and the residue was partitioned with ether and saturated sodium bicarbonate solution. The ether layer was washed with saturated sodium bicarbonate solution, water, and saturated sodium chloride solution, dried (sodium sulfate), and concentrated in vacuo. The residue was chromatographed on silica gel 60 at low pressure with 5% ethyl acetate in benzene. Recrystallization from hexane:benzene (11:1) afforded 2.25 g. (59% yield) of 4,5-bis(p-methoxyphenyl)thiazole.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([N+:30]([O-])=O)[CH:29]=1)[C:6]([NH:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]([F:25])([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[CH:11][C:10]=1[CH3:26])=[O:7])#[N:2].[Sn](Cl)(Cl)(Cl)Cl.Cl>C(O)(C)C>[NH2:30][C:28]1[CH:29]=[C:3]([C:1]#[N:2])[CH:4]=[C:5]([CH:27]=1)[C:6]([NH:8][C:9]1[C:10]([CH3:26])=[CH:11][C:12]([C:16]([F:25])([C:17]([F:18])([F:19])[F:20])[C:21]([F:22])([F:23])[F:24])=[CH:13][C:14]=1[CH3:15])=[O:7]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(C#N)cc([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC(C)O
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(N)cc(C#N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
3-Cyano-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-5-nitro-benzamide (12.0 g, 25.9 mmol) (Example I5) was dissolved in isopropanol (200 ml) and tin chloride (14.73 g, 77.7 mmol) was added. The mixture was cooled to 0° C. and aqueous hydrochloric acid (concentrated) (30 ml) was added slowly. The reaction mixture was stirred at 80° C. for 0.5 hours. ⅓ of the total volume of isopropanol was evaporated. Water (100 ml) was added to the concentrated mixture and aqueous sodium hydroxide (4N) was added to adjust the pH to 7-8. The aqueous phase was extracted three times with ethyl acetate (3×200 ml). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 4:1 to 0:1) to give 5-amino-3-cyano-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide (10.6 g, 94.4% yield). 1H-NMR (400 MHz, CDCl3): 7.47 (s, 1H), 7.44 (s, 2H), 7.36 (s, 2H), 7.07 (s, 1H), 4.11 (bs, 2H), 2.32 (s, 6H) ppm.
Reaction SMILES: O.[NH2:2][NH2:3].[OH:4][N:5]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]2[C:11]([C:19]#[N:20])=[C:10](SC)[N:9]=[C:8]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:7]=2[C:6]1=[O:31]>C(O)CCC.CS(C)=O>[NH2:20][C:19]1[C:11]2[C:12]3[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[N:5]([OH:4])[C:6](=[O:31])[C:7]=3[C:8]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[N:9][C:10]=2[NH:3][N:2]=1
Reactant: NN
Reactant: COc1ccc(-c2nc(SC)c(C#N)c3c2c(=O)n(O)c2ccccc32)cc1
Solvent: O
Solvent: CCCCO
Solvent: CS(C)=O
Product: COc1ccc(-c2nc3[nH]nc(N)c3c3c2c(=O)n(O)c2ccccc32)cc1
Reaction time: 3 h
Yield: 39.7 %

Procedure:
37.4 ml (770 mmol) of hydrazine hydrate is added to a solution of 3 g (7.7 mmol) of 6-hydroxy-4-(4-methoxyphenyl)-2-(methylthio)-5-oxo-5,6-dihydrobenzo[c][2,7]-naphthyridine-1-carbonitrile dissolved in 80 ml of butan-1-ol and 32 ml of dimethylsulfoxide. The reaction medium is carried at 150° C. for 3 hours and then is allowed to rest at room temperature overnight. The precipitate obtained is filtered and then rinsed with methanol to yield 1.14 g (39%) of 1-amino-7-hydroxy-5-(4-methoxyphenyl)-3H-benzo[f]pyrazolo[3,4-c][2,7]naphthyridin-6(7H)-one in the form of a yellow solid.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH3:4].C([O:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:40]2[C:48]3[C:43](=[CH:44][C:45]([C:49](O)=[O:50])=[CH:46][CH:47]=3)[C:42]([CH3:52])=[C:41]2[CH3:53])=[CH:35][CH:34]=1)=[O:26])(C)(C)C>>[CH2:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][CH2:9][C@@H:5]1[C@@H:3]([NH:2][C:49]([C:45]1[CH:44]=[C:43]2[C:48](=[CH:47][CH:46]=1)[N:40]([CH2:39][C:36]1[CH:35]=[CH:34][C:33]([C:28]3[C:27]([C:25]([OH:26])=[O:24])=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:38][CH:37]=1)[C:41]([CH3:53])=[C:42]2[CH3:52])=[O:50])[CH3:4])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C[C@H](N)[C@H]1CCCN1C(=O)OCc1ccccc1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)[C@H]3CCCN3C(=O)OCc3ccccc3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-benzyl 2-((S)-1-aminoethyl)pyrrolidine-1-carboxylate hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 630 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:32](OCC)=[O:33].[O-]CC.[Na+].Cl>C(O)C>[OH:33][CH:32]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[N:23]([C:28]([CH3:31])([CH3:30])[CH3:29])[N:24]=[C:25]([CH3:27])[CH:26]=4)=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)n(C(C)(C)C)n1
Reactant: CCOC=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C(C)(C)C)n1
Temperature: 78 °C
Yield: 54 %

Procedure:
2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.715 g, 1.717 mmol) and ethyl formate (0.43 mL, 5.32 mmol) were dissolved in anhydrous ethanol (5.00 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (2 mL, 5.357 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure 2-tert-Butyl-5-methyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.412 g, 0.927 mmol, 54%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:6](=[O:17])[CH:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH3:8])[OH:5].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:29]=2[N:30]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:6](=[O:17])[CH:7]([O:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:26]2[O:27][C:28]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:29]=3[N:30]=2)=[CH:14][CH:15]=1)[CH3:8])[OH:5]
Reactant: Clc1ccc2oc(Cl)nc2c1
Reactant: COC(=O)C(O)C(=O)C(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(O)C(=O)C(C)Oc1ccc(Oc2nc3cc(Cl)ccc3o2)cc1
Yield: 83.9 %

Procedure:
25.4 g of 2-(4-hydroxyphenoxy)-propionyl-glycolic acid methyl ester and 16.6 g of potassium carbonate in 180 cc of acetonitrile are refluxed for 1 hour to form a salt. After addition of 20 g of 2,5-dichlorobenzoxazole, the mixture is refluxed for 10 hours. The salt is filtered off at 60° C. and the acetonitrile is distilled off. The residue is freed in vacuo from volatile residues. 34 g (84.8% of theory) of 2-[4-(5-chloro-2-benzoxazolyloxy)-phenoxy]-propionyl-glycolic acid methyl ester are obtained as a brownish viscous oil, nD23 =1.5587. ##STR12##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11]3[C:7](=[C:8]([CH2:19][OH:20])[S:9][CH:10]=3)[C:6]=2[CH:21]=1.Cl.Cl[CH2:24][CH2:25][CH2:26][NH2:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11]3[C:7](=[C:8]([CH2:19][O:20][CH2:24][CH2:25][CH2:26][NH2:27])[S:9][CH:10]=3)[C:6]=2[CH:21]=1
Reactant: OCc1scc2c1-c1cc(Cl)ccc1Oc1ccccc1-2
Reactant: NCCCCl
Agent: Cl
Product: NCCCOCc1scc2c1-c1cc(Cl)ccc1Oc1ccccc1-2

Procedure:
Starting from the alcohol 14 (0.18 mmole) and 3-chloropropylamine-hydrochloride (1.8 mmoles), an oily product was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:10]1[CH2:13][N:12](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C.C(O)(=O)C>[C:31]([O:30][C:28]([NH:27][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:10]1[CH2:11][NH:12][CH2:13]1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC(NC(=O)OC(C)(C)C)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(NC(=O)OC(C)(C)C)C1CNC1
Reaction time: 8 h
Yield: 97 %

Procedure:
A mixture of 3-[bis-(tert-butoxycarbonylamino)methyl]-1-(diphenylmethyl)azetidine (Intermediate 152, 6.4 g) and 10% palladium on carbon (3 g) in ethanol (100 mL) and acetic acid (2 mL) was stirred under an atmosphere of hydrogen overnight. The solid was filtered off and the filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium carbonate, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM (10%) to give 3-[bis-(tert-butoxycarbonylamino)methyl]azetidine (4.0 g) as a colourless liquid, which was used without further characterisation.