Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:25]4[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:31])([F:30])[F:19])[CH:26]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc(C(F)(F)F)c4)cc3CC[C@@H]12
Yield: 74.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 3-trifluoromethylphenylboronic acid (148 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 180 mg (77%) of the title compound as an amorphous foam. mp 64°-87°. FDMS: m/e=373. α[D]589 =+64.42 (c=1.04, chloroform).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:28](OCC)[O:29]CC)=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][CH:21]=[CH2:22])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].Cl>CC(C)=O>[CH3:1][C:2]1[NH:3][C:4]([CH:28]=[O:29])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:20][CH:21]=[CH2:22])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C=CCOc1ccccc1C1C(C(=O)OCC)=C(C)NC(C(OCC)OCC)=C1C(=O)OCC
Agent: Cl
Solvent: CC(C)=O
Product: C=CCOc1ccccc1C1C(C(=O)OCC)=C(C)NC(C=O)=C1C(=O)OCC
Reaction time: 0.17 h

Procedure:
To a solution of diethyl 2-methyl-4-(2-allyloxyphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.5 g) in acetone (15 ml) was added 6N-hydrochloric acid (1.5 ml) with stirring and the resultant mixture was further stirred for an hour and 45 minutes at room temperature. The solvent was removed, and addition of water to the residue resulted a yellowish suspension with precipitation of an oil, which was immediately solidified. After being allowed to stand for about 10 minutes, the precipitated solids were collected by filteration and washed with water and dried. Thus obtained crude crystals were recrystallized from a mixture of diisopropyl ether and acetone to give orange-yellow granules of diethyl 2-methyl-4-(2-allyloxyphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 129° to 131° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])[C:12]2[N:17]=[CH:16][C:15]([C:18](O)=[O:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[NH2:48][CH2:49][CH2:50][NH:51][C:52](=[O:58])[O:53][C:54]([CH3:57])([CH3:56])[CH3:55]>CN(C)C1C=CN=CC=1.ClCCl.CCCCCC>[C:54]([O:53][C:52](=[O:58])[NH:51][CH2:50][CH2:49][NH:48][C:18]([C:15]1[CH:16]=[N:17][C:12]([CH:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)(=[O:10])=[O:9])[C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[F:28])=[CH:13][CH:14]=1)=[O:19])([CH3:57])([CH3:55])[CH3:56]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 42.8 %

Procedure:
To a dichloromethane (5 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]carboxylic acid (100 mg, 0.236 mmol) obtained in Example 50 were added triethylamine (40 μl, 0.283 mmol), 4-dimethylaminopyridine (14 mg, 0.118 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (54 mg, 0.283 mmol) and t-butyl N-(2-aminoethyl)carbamate (45 μl, 0.283 mmol). The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The resulting organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=1:1 eluate was concentrated under reduced pressure to give the title compound (57 mg, 0.101 mmol, 43%) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10]C)[CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1
Reactant: COc1cc(F)ccc1C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(F)cc1O
Temperature: 130 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
A mixture of 4-fluoro-2-methoxybenzonitrile, (4.53 g, 30 mmol;) and AlCl3 (5.0 g, 37.6 mmol; Aldrich) in anhydrous toluene (30 mL) was stirred at approximately 130° C. for 18 hrs. After cooling, ice water (˜50 mL)was added and the resulting mixture extracted with ether (20 mL×2). The combined extracts were washed sequentially with water and brine, then dried (MgSO4), and concentrated in vacuo to provide the title compound (3.90 g, 28.5 mmol, Yield 95%) as a white solid: 1H NMR (DMSO-d6, 300 MHz) δ ppm: 6.74-6.84 (2H, m, Ar—Hs), 7.71 (1H, dd, J=7 Hz, J=8.5 Hz, Ar—H), 11.64 (1H, s, OH); 13C NMR (DMSO-d6, 75.5 Hz) δ ppm: 95.13 102.45, 102.78, 106.53, 106.83 115.53, 134.68, 134.84, 161.41, 161.58, 163.00, 166.35. HRMS (ESI-) calcd for C7H3NOF (M−H) 136.0199, found 136.0199.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[F:13][C:14]1[C:15](/[CH:20]=[N:21]/[S@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])=[N:16][CH:17]=[CH:18][CH:19]=1.CCOC(C)=O>C1COCC1>[F:13][C:14]1[C:15]([C@H:20]([C:3]2[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=2)[NH:21][S@:22]([C:24]([CH3:27])([CH3:26])[CH3:25])=[O:23])=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CC(C)(C)[S@](=O)/N=C/c1ncccc1F
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[S@](=O)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1F
Reaction time: 4 h

Procedure:
To a stirred suspension of magnesium (170 g, 2365 mmol) in THF (1.35 L), was added 4-bromobenzotrifluoride (532 g, 2365 mmol). Stirring was continued for 4 h (cautious: slightly exothermic, cooled with a water bath if needed). The solution was cannulated to a stirred solution of (S,E)-N-((3-fluoro-pyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide (270 g, 1182 mmol) in THF (1.3 L) at −78° C. dropwise. Stirring was continued for 1 h. The progress of reaction was monitored by TLC (50% EtOAc in petroleum ether). After completion of the reaction, the reaction mixture was quenched with saturated aqueous NH4Cl (2.5 L), and the solution extracted with Et2O (5×500 mL). The organic layers were combined, dried over Na2SO4, concentrated, and purified by column chromatography using silica (100-200 mesh) with 25-30% EtOAc in petroleum ether as eluent to give (S)—N—((S)-(3-fluoropyridin-2-yl)(4(trifluoro-methyl)phenyl)methyl)-2-methylpropane-2-sulfinamide as a brown oil. 1H-NMR (400 MHz, CDCl3): δ ppm 8.45 (d, J=3.6 Hz, 1H), 7.73-7.78 (m, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.63 (m, 2H), 7.43-7.48 (m, 1H), 6.23 (d, J=6.8 Hz, 1H), 5.99 (d, J=6.8 Hz, 1H), 1.36 (s, 9H). MS (ESI pos. ion) m/z: 375.1 (M−O and t-Bu).
Reaction SMILES: [CH2:1]([S:5][CH:6]=[C:7]1[CH:12]([OH:13])[C:11]([CH3:15])([CH3:14])[C@@H:10]([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH2:9][CH2:8]1)[CH2:2][CH2:3][CH3:4].C([OH:25])C.C1C=CC=CC=1>C(=O)([O-])[O-].[Cd+2].[Hg](Cl)Cl.O>[CH3:14][C:11]1([CH3:15])[C@@H:10]([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH2:9][CH2:8][C:7]([CH:6]=[O:25])=[CH:12]1.[CH2:1]([S:5][CH:6]=[C:7]1[C:12](=[O:13])[C:11]([CH3:14])([CH3:15])[C@@H:10]([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH2:9][CH2:8]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCSC=C1CC[C@H](OC2CCCCO2)C(C)(C)C1O
Reactant: CCO
Agent: Cl[Hg]Cl
Agent: O=C([O-])[O-]
Agent: [Cd+2]
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)C=C(C=O)CC[C@@H]1OC1CCCCO1
Product: CCCCSC=C1CC[C@H](OC2CCCCO2)C(C)(C)C1=O
Reaction time: 0.08 h

Procedure:
The crude compound (7) (2.00 g), cadmium carbonate (1.10 g, 6.4 mmoles) and mercury dichloride (1.74 g, 6.4 mmoles) were added to 95% ethanol (45 ml), and the solution was stirred for 5 minutes under reflux. After cooling, benzene and water were added, and the mixture was filtered through Celite. The filtrate was extracted twice with benzene, washed with an aqueous solution of sodium chloride, and dried over magnesium sulfate. The product was filtered and concentrated to give 1.32 g of a crude compound (8). At the same time, a compound corresponding to the compound (8) from which the tetrahydropyranyl group was removed formed as a by-product. This by-product was tetrahydropyranylated in a conventional manner, and purified by column chromatography (50 g of silica gel; n-hexane/ethyl acetate). Finally, the compound (8) was obtained in an amount of 0.71 g (in a yield of 47% from the compound (6)).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>C(Cl)Cl.C(N(CC)CC)C.O>[CH:32]1([C:35]([NH:1][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]4[C:19](=[O:31])[N:20]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:21]([CH3:24])[C:22]=4[CH3:23])=[O:17])=[N:13][CH:14]=3)[CH:5]=[CH:4][N:3]=2)=[O:36])[CH2:34][CH2:33]1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cn2)c(=O)n(-c2ccccc2)n1C
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)C4CC4)c3)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 60.2 %

Procedure:
To a suspension of N-(5-((2-aminopyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (500 mg, 1.2 mmol) in DCM (5 mL) and triethylamine (1 mL) was added cyclopropanecarbonyl chloride (377 mg, 3.6 mmol) at 0° C. slowly. The mixture was warmed up to rt and stirred for 4.5 hours, then diluted with DCM (10 mL) and water (10 mL). The organic phase was separated and concentrated in vacuo. The residue was dissolved in MeOH (30 mL), and saturated solution of Na2CO3 (30 mL). The resulted mixture was stirred at rt for 2 hours, then filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (v/v)=50/1) to give the title compound as an off-white solid (350 mg, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#N)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-:13].[K+].[OH2:15]>C(O)CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:15])=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O
Reactant: [OH-]
Reactant: N#CC1(c2ccc(Br)cc2)CC1
Agent: [K+]
Solvent: OCCO
Product: O=C(O)C1(c2ccc(Br)cc2)CC1
Temperature: 180 °C
Reaction time: 4 h

Procedure:
1-(4-Bromo-phenyl)-cyclopropanecarbonitrile (5 g, 22.5 mmol) and potassium hydroxide (5 g, 89.3 mmol) were combined in ethylene glycol (70 mL), and the reaction was stirred at 180° C. for 4 hours. The mixture was poured into H2O, acidified, and filtered to give the title compound.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([OH:24])=[O:23])=O)(C)(C)C.Cl.O1CCOCC1>CO>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([OH:24])=[O:23]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (530 mg, 1.49 mmol) in MeOH (10 mL) was added HCl in dioxane (4 M, 5 mL, 20.0 mmol). The reaction mixture was stirred at room temperature for 48 hr and the solvents removed under reduced pressure to give 5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid as the hydrochloride salt. 1H NMR (400 MHz, d6-DMSO) δ 7.57-7.45 (m, 1H), 7.29-7.18 (m, 2H), 5.30 (br s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:17][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)=[O:27]>C1COCC1.CCOC(C)=O>[C:26](=[O:27])([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([B:9]2[O:17][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:10]2)=[CH:7][CH:8]=1)[O:28][C:29]1[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)OB(c2ccc(CO)cc2)OC1(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(COC(=O)Oc3ccc([N+](=O)[O-])cc3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
4-(Hydroxymethyl)phenylboronic acid pinacol ester (0.5 g, 2.1 mmol) was dissolved in 20 mL of dry THF. Triethylamine (0.6 mL, 4.3 mmol) was added followed by 4-nitrophenyl chloroformate (0.47 g, 2.3 mmol) and the reaction was allowed to stir at room temperature for 1 h. The reaction was diluted with EtOAc and washed with 1.0 M HCl followed by saturated NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated. Compound B2a was purified on a silica gel column eluting with 5% EtOAc in hexanes to give 0.51 g (1.3 mmol, 60% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ=8.25 (d, J=9.2 Hz, 2H), 7.85 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 7.36 (d, J=9.2 Hz, 2H), 5.31 (s, 2H), 1.35 (s, 12H). 13C NMR (100 MHz, CDCl3) δ=155.7, 152.7, 145.6, 137.2, 135.4, 127.9, 125.5, 122.0, 84.2, 71.0, 25.1. ESI-MS(+): m/z 417.19 [M+NH4]+, 422.20 [M+Na]+.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([C:21]3[CH:30]=[CH:29][C:24]([O:25][CH2:26][C:27]#[N:28])=[CH:23][CH:22]=3)=[CH:16][C:15]=2[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:31]=[N+:32]=[N-:33].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([N:8]1[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[C:15]2[C:20]1=[CH:19][CH:18]=[C:17]([C:21]1[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]3[NH:33][N:32]=[N:31][N:28]=3)=[CH:29][CH:30]=1)[CH:16]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCOc1ccc(-c2ccc3c(c2)c2c(n3Cc3ccccc3)CCCC2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(Cn2c3c(c4cc(-c5ccc(OCc6nnn[nH]6)cc5)ccc42)CCCC3)cc1

Procedure:
The desired product was prepared using a procedure similar to step 6 of example 3. Thus, [4-(9-benzyl-6,7,8,9-tetrahydro-5H-carbazol-3-yl)-phenoxy]-acetonitrile (0.357 g, 0.910 mmol) was reacted with NaN3 (0.296 g, 4.548 mmol) and NH4Cl (0.243 g, 4.548 mmol) in DMF (10 ml) to give the product (0.329 g, 0.755 mmol, 83%) as a white solid, dec. 228-230° C. 1H NMR (DMSO-d6) δ 1.79-1.85 (m, 4H), 2.64-2.71 (m, 4H), 5.33 (s, 2H), 5.50 (s, 2H), 7.03 (d, J=7.6 Hz, 2H), 7.11 (d, J=8.7 Hz, 2H), 7.21 (t, J=7.2 Hz, 1H), 7.27-7.30 (m, 3H), 7.39 (d, J=8.6 Hz, 1H), 7.59-7.61 (m, 3H), 16.80 (broad s, 1H); IR (solid) 3030, 2920, 2590, 1520, 1470 and 1240 cm−1; [ESI(+)], m/z 436 (M+H)+; Anal. Calcd. for C27H25N5O: C, 74.46; H, 5.79; N, 16.08; Found: C, 74.34; H, 5.46; N, 16.26.
Reaction SMILES: [CH2:1]([O:3]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:2].Br[C:20]1[CH:45]=[CH:44][C:23]2[O:24][C:25]3[CH:43]=[CH:42][CH:41]=[CH:40][C:26]=3[C@@H:27]3[C@H:32]([NH:33][C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])[CH2:31][CH2:30][CH2:29][N:28]3[C:22]=2[CH:21]=1.Cl>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:20]1[CH:45]=[CH:44][C:23]2[O:24][C:25]3[CH:43]=[CH:42][CH:41]=[CH:40][C:26]=3[C@@H:27]3[C@H:32]([NH:33][C:34](=[O:39])[C:35]([F:36])([F:38])[F:37])[CH2:31][CH2:30][CH2:29][N:28]3[C:22]=2[CH:21]=1)(=[O:3])[CH3:2]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(N[C@@H]1CCCN2c3cc(Br)ccc3Oc3ccccc3[C@H]12)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc2c(c1)N1CCC[C@@H](NC(=O)C(F)(F)F)[C@H]1c1ccccc1O2
Temperature: 140 °C
Reaction time: 3 h
Yield: 46.2 %

Procedure:
(1-Ethoxyvinyl)tributyl tin (90 μl, 0.23 mmol) was added to a solution of trans-N-(7-bromo-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (100 mg, 0.23 mmol) and PdCl2(PPh3)2 (3 mg, 4.3 μmol) in toluene (6 mL) under N2. The reaction mixture was heated to 140° C. and stirred for 3 h. After cooling to room temperature, 2N (aq) HCl (450 ul) was added and the reaction mixture was stirred for 1 h. The reaction was quenched with sat NaHCO3 (aq) and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and evaporated. The crude compound was chromatographed with heptane/ethyl acetate 1:1. Purifcation by HPLC gave the title compound (43 mg, 47%). Data: 1H-NMR (400 MHz, DMSO) 1.60-2.09 (m, 4H), 3.21 (t, J=11.2, 1H), 3.90 (d, J=14.0, 1H), 4.16 (d, J=10.4, 1H), 4.44 (m, 1H), 7.04-7.54 (m, 10H), 9.20 (d, J=10.0, 1H). (m/z)=405 (M+H)+.
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3](O)[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6].C(O)CCC.S(=O)(=O)(O)O.ClC(Cl)=C(Cl)Cl.Cl>O>[O:8]=[C:7]1[O:9][C@H:3]([C@H:2]([CH2:1][OH:13])[OH:12])[C:4]([OH:10])=[C:5]1[OH:6]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)=C(Cl)Cl
Solvent: CCCCO
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Temperature: 85 °C
Reaction time: 17 h

Procedure:
742 g (3.75 mol) of anhydrous 2-keto-L-gulonic acid were suspended in 1.5 l (17 mol) of n-butanol and, after addition of 8 g of concentrated sulfuric acid, the mixture was evacuated to 200 mbar. After heating to 85° C., 1.1 l of water-containing n-butanol were distilled off after 2 hours. The viscous, golden-yellow-colored melt was mixed with 906 ml (8.9 mol) of perchloroethylene and rearranged at 72 to 75° C. for 17 hours after addition of 84 ml of conc. hydrochloric acid. The precipitated L-ascorbic acid was filtered off with suction, washed with n-butanol and dried in vacuo. 588 g (88%) of a pale gray crude product having a purity of 98.5% were obtained. The crude product dissolved in water. After clarifying filtration, a colorless solution was obtained from which it was possible to isolate L-ascorbic acid in a manner known from the literature. The residue (0.9%) consisted mainly of carbon.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.Cl[CH2:21][C:22]1[C:23]([CH3:39])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1.O>CN(C)C=O>[CH3:39][C:23]1[C:22]([CH2:21][O:19][C:6]2[CH:7]=[CH:8][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[N:15]3)=[C:4]([CH3:3])[CH:5]=2)=[CH:27][CH:26]=[C:25]([C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]([F:37])([F:38])[F:36])=[CH:32][CH:33]=2)[N:24]=1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: Cc1nc(-c2ccc(OC(F)(F)F)cc2)ccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(OCc2ccc(-c3ccc(OC(F)(F)F)cc3)nc2C)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
26 mg (0.66 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 153 mg (0.66 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 8.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 200 mg (0.66 mmol) 3-chloromethyl-2-methyl-6-(4-trifluoromethoxy-phenyl)-pyridine were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 16 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, n-heptane, and ether. The residue was dried at 40° C. in vacuum to give 300 mg (91%) of the title compound as white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)([O-])=O.[Cl-].[NH4+]>[Fe].C(O)C.O>[N:15]1([CH2:14][CH2:13][N:8]2[C:9]3[C:5](=[C:4]([NH2:1])[CH:12]=[CH:11][CH:10]=3)[CH:6]=[N:7]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1cccc2c1cnn2CCN1CCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc2c1cnn2CCN1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-indazole (1.90 g, 7.30 mmol), iron powder (4.10 g, 73.4 mmol), and ammonium chloride (0.200 g, 3.65 mmol) were suspended in a 4:1 solution of ethanol/H2O. The mixture was heated to reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was taken up and stirred in triethylamine/ethyl acetate (1/4, 30 mL) for 15 minutes and filtered through a plug of silica gel. The silica gel was rinsing with triethylamine/ethyl acetate (1/4) and combined filtrate concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.62 (m, 4H), 2.44 (m, 4H), 2.81 (t, 2H, J=6.78), 4.34 (t, 2H, J=6.78), 5.73 (s, 2H), 6.13 (m, 1H), 6.66 (m, 1H), 7.01 (m, 1H), 8.05 (s, 1H); MS (DCI/NH3) m/z 231 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:29])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[N:5][CH:4]=1.[ClH:30].CO>C(Cl)(Cl)Cl.O1CCOCC1>[ClH:30].[ClH:30].[NH2:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[N:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:29])[CH2:20][CH2:19]1
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Reaction time: 1 h

Procedure:
A solution of 1,1-dimethylethyl (1-{2-[7-(methyloxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]ethyl}-4-piperidinyl)carbamate (5.453 g, 13.565 mmol) in chloroform (30 ml) was added 4M HCl in 1,4-dioxane (30 ml) and the reaction was stirred at rt for 0.5 h before addition of MeOH (30 ml). The reaction was stirred for a further 1 h before evaporation to provide the desired compound as a slightly impure white solid (5.323 g, 105%), which was used without further purification.