Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14](O)[CH2:15][OH:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:9][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[O:16][CH2:15][CH2:14][O:10]1
Reactant: OCCO
Reactant: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(c2ccc(O)c([N+](=O)[O-])c2)OCCO1

Procedure:
A stirred mixture of 1-(4-hydroxy-3-nitrophenyl)ethanone (3.00 g, 16.56 mmol), ethylene glycol (1.385 mL, 24.84 mmol) and p-toluenesulfonic acid monohydrate (0.158 g, 0.828 mmol) in toluene (60 mL) was heated to reflux for 18 hr in a 250 mL round bottom flask fitted with a Dean-Stark apparatus. The mixture was cooled and diluted with EtOAc (80 mL) and then washed with water (3×30 mL) and brine (20 mL), dried (Na2SO4) and concentrated to dryness in vacuo to afford a thick brown oily residue. This was purified by silica gel chromatography eluting with 5-50% Et2O in isohexane. The title product was isolated as a yellow oil (2.41 g, 64.6%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=1>C(#N)C>[I:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][N:3]2[CH2:4][CH2:5][CH2:6][C@H:2]2[CH3:1])=[CH:18][CH:19]=1
Reactant: ClCCOc1ccc(I)cc1
Reactant: C[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCOc1ccc(I)cc1
Temperature: 100 °C
Reaction time: 9 h
Yield: 78 %

Procedure:
To a suspension of (2R)-2-methylpyrrolidine (0.60 g) and cesium carbonate (1.2 g) in acetonitrile (3 mL), 1-(2-chloroethoxy)-4-iodobenzene obtained in Example 60-(1) (0.87 g) was added and the mixture was heated to 100° C., at which it was stirred for 9 hours. The reaction mixture was cooled to room temperature and filtered to remove insoluble materials, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by NH-type silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=9:1 to 1:1) to give the titled compound (0.80 g, 78%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@:5]([CH3:39])([C:14](=O)[NH:15][CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:21]([C:34]([F:37])([F:36])[F:35])[CH:20]=2)=O)[CH2:4][O:3]1.[S:41]1C=CN=C1>>[CH3:1][C:2]1([CH3:40])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@:5]([CH3:39])([C:14]2[S:41][C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[C:21]([C:34]([F:37])([F:36])[F:35])[CH:20]=3)=[CH:16][N:15]=2)[CH2:4][O:3]1
Reactant: CCCCCCCCOc1ccc(C(=O)CNC(=O)[C@@]2(C)COC(C)(C)N2C(=O)OC(C)(C)C)cc1C(F)(F)F
Reactant: c1cscn1
Product: CCCCCCCCOc1ccc(-c2cnc([C@@]3(C)COC(C)(C)N3C(=O)OC(C)(C)C)s2)cc1C(F)(F)F

Procedure:
The synthesis of 2,5-substituted thiazoles is described in Scheme 9. Reaction of the desired alcohol para-methoxybenzyl alcohol (PMB-OH) with substituted 4-fluoroacetophenone 1 afforded the acetophenone intermediate 2. Acetophenone intermediate 2 was then converted to the corresponding bromo-acetophenone using Bu4NBr3 which, upon reaction with NaN3, provided the azido-acetophenone intermediate. Hydrogenation of the azido-acetophenone intermediate afforded amine 3, followed by coupling with orthogonally protected amino acid 4 gave amide 5. Removal of PMB group under hydrogenation gave phenol 6. Mitsunobu reaction of the phenol 6 with the desired alcohol followed by thiazole formation under Lawesson's reagent conditions afforded intermediate 7 in good yield. Removal of the protecting group from intermediate 7 afforded the final amino-alcohol 8.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1([CH:26]2[S:30][CH2:29][N:28]([C:31]([CH3:36])([CH3:35])[C:32]([OH:34])=O)[C:27]2=[O:37])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[F:38][C:39]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:40]=1[NH2:41].C(N(CC)CC)C>C(Cl)(Cl)(Cl)Cl.ClCCl.C(Cl)(Cl)Cl>[F:38][C:39]1[CH:45]=[CH:44][C:43]([F:46])=[CH:42][C:40]=1[NH:41][C:32](=[O:34])[C:31]([N:28]1[C:27](=[O:37])[CH:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[S:30][CH2:29]1)([CH3:36])[CH3:35]
Reactant: CC(C)(C(=O)O)N1CSC(c2ccccc2)C1=O
Reactant: Nc1cc(F)ccc1F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C(=O)Nc1cc(F)ccc1F)N1CSC(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 43.2 %

Procedure:
Triphenylphosphine (1.93 g) was added to a suspension of 2-(5-phenylthiazolidin-4-on-3-yl)isobutyric acid (1.5 g) prepared according to Example 12 in carbon tetrachloride (15 mL) and dichloromethane (15 mL), and the mixture was heated for 40 minutes at 70° C. The reaction mixture was cooled with ice-water, to which 2,5-difluoroaniline (0.73 g) and then triethylamine (0.57 g) were added, and the mixture was stirred for 3 days at room temperature. The reaction mixture was diluted with chloroform, and then sequentially washed with water, diluted hydrochloric acid and a saturated sodium hydrogencarbonate aqueous solution, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the resulting crude product was purified by preparative thin-layer chromatography (developing solvent: chloroform/ethyl acetate=10/1) to give 0.92 g of the title compound as viscous oil.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:17]=[C:18]([CH:31]([OH:45])[C:32]4[CH:37]=[C:36]([Br:38])[CH:35]=[CH:34][C:33]=4[S:39]([N:42]([CH3:44])[CH3:43])(=[O:41])=[O:40])[CH:19]=[N:20][C:21]=3[NH:22][C:23]3[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[N:10]=2)=CC=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[CH:17]=[C:18]([CH:31]([OH:45])[C:32]3[CH:37]=[C:36]([Br:38])[CH:35]=[CH:34][C:33]=3[S:39]([N:42]([CH3:43])[CH3:44])(=[O:41])=[O:40])[CH:19]=[N:20][C:21]=2[NH:22][C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(O)c4cc(Br)ccc4S(=O)(=O)N(C)C)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Nc2ncc(C(O)c3cc(Br)ccc3S(=O)(=O)N(C)C)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 72 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
A solution of 2-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)(hydroxy)methyl)-4-bromo-N,N-dimethylbenzenesulfonamide (30.0 mg, 0.036 mmol) in DCM (0.5 mL) was treated with TFA (0.5 mL) followed by triethylsilane (0.3 mL). The mixture was stirred at 72° C. for 16 h. An additional 1 mL of TFA was added, the mixture was placed in a sealed tube, and heated at 100° C. for 4 h to give a much darker orange solution. The mixture was concentrated, neutralized with 2N NH3/MeOH, concentrated and purified by prep HPLC to give 2-((5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)(hydroxy)methyl)-4-bromo-N,N-dimethylbenzenesulfonamide (20 mg, 0.033 mmol, 93% yield) as a yellow solid. m/z (ESI, +ve ion) 601/603 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:6]=[CH:5]2.[F:17][C:18]([F:30])([F:29])[O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH2:13]([CH:12]([CH2:15][CH3:16])[CH2:11][N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:23]3[CH:22]=[CH:21][C:20]([O:19][C:18]([F:17])([F:29])[F:30])=[CH:25][CH:24]=3)=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)[CH3:14]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCC(CC)Cn1ccc2cc(Br)ccc21
Product: CCC(CC)Cn1ccc2cc(-c3ccc(OC(F)(F)F)cc3)ccc21

Procedure:
The title compound was prepared from 5-bromo-1-(2-ethylbutyl)-1H-indole and 4-(trifluoromethoxy)phenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (APCI, [M+H]+) m/z 362. 1HNMR (300 MHz, DMSO-d6): δ 7.82 (s, 1H), 7.77 (d, 2H, J=8.56 Hz), 7.51 (d, 1H, J=8.50 Hz), 7.44-7.39 (m, 4H), 6.49 (d, 1H, J=3.12 Hz), 4.07 (d, 2H, J=7.32 Hz), 1.80 (hep, 1 H), 1.24 (p, 4 H), and 0.85 ppm (t, 6 H). Elemental Analysis for C21H22F3NO: Calculated: C, 69.79; H, 6.14; N, 3.88. Found: C, 69.79; H, 5.85; N, 3.82.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([CH2:10][NH:11][C:12]2[S:16][N:15]=[C:14]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[CH:13]=2)[CH2:9][CH2:8]1>C1COCC1>[NH2:15][C:14]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][NH2:22])=[CH:23][CH:24]=1)=[CH:13][C:12](=[S:16])[NH:11][CH2:10][CH:7]1[CH2:9][CH2:8]1
Reactant: N#Cc1ccc(-c2cc(NCC3CC3)sn2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(C(N)=CC(=S)NCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 51.3 %

Procedure:
Add 1M lithium aluminum hydride in THF (3.0 mL, 3.0 mmol) to a solution of 4-[5-(cyclopropylmethyl-amino)-isothiazol-3-yl]-benzonitrile (210 mg, 0.82 mmol) in THF (8 mL) at room temperature under a nitrogen atmosphere. Stir the mixture at ambient temperature for 45 min, then quench the reaction sequentially with water (0.3 mL) and 5N aqueous NaOH (0.3 mL). Filter the slurry through Celite®, dry the filtrate over Na2SO4, filter and concentrate in vacuo. Purify the residue by chromatography on silica gel (8 g) eluting with DCM/2M ammonia in methanol (20:1) to obtain the desired intermediate (110 mg, 51%). MS (ES+) m/z: 245.1 (M-NH3+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:14]([O:16]CC)=O)=[O:5])[CH3:2].[O-:27][C:28]#[N:29].[K+].Cl>>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:14](=[O:16])[NH:29][C:28]1=[O:27])=[O:5])[CH3:2]
Reactant: N#C[O-]
Reactant: CCCCCCCCC(NCCCCCCC(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [K+]
Product: CCCCCCCCC1C(=O)NC(=O)N1CCCCCCC(=O)OCC

Procedure:
Ethyl 2-(6-ethoxycarbonylhexylamino)decanoate (7.4 g) was reacted with potassium cyanate and hydrochloric acid to give 1-(6-ethoxycarbonylhexyl)-5-octylhydantoin which formed colourless crystals, m.p. 68°-70° C., from light petroleum (b.p. 60°-80° C).
Reaction SMILES: [NH:1]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:2]([C:11]([N:13]([CH3:37])[C@H:14]([C:18]([NH:20][C@H:21]([C:34]([NH2:36])=[O:35])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=1)=[O:19])[CH:15]([CH3:17])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[CH3:45][N:46](C)C(=O)C.[OH-].[Na+].Cl.ON>O1CCOCC1.C(O)(=O)C.O.O>[C:30]([C:25]1[CH:24]=[C:23]([CH2:22][CH:21]([NH:20][C:18](=[O:19])[CH:14]([N:13]([C:11](=[O:12])[CH:2]([NH:1][C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])[CH2:3][C:4]2[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=2)[CH3:37])[CH:15]([CH3:17])[CH3:16])[C:34]2[O:35][N:46]=[CH:45][N:36]=2)[CH:28]=[CH:27][C:26]=1[OH:29])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)[C@@H](C(=O)N[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Reactant: CC(=O)N(C)C
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)c1ncno1)N(C)C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.9 %

Procedure:
A solution of Boc-Phe(4-F)-N-Me-Val-Tyr(3-tBu)-NH2 (600 mg, 0.976 mmol) and N,N-dimethylacetamide (0.2 ml, 1.5 mmol) in dioxane (3 ml) was stirred at room temperature for 1 hour and mixed with a solution of sodium hydroxide (108 mg) and hydroxyamine hydrochloride (190 mg) in acetic acid/water (7 ml/3 ml). The mixture was stirred at room temperature for 10 min., mixed with water and filtered; a solution of the thus obtained precipitate in acetic acid/dioxane (10 ml/10 ml) was stirred at 60° C. overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:1), giving the titled compound (474 mg, 76%).
Reaction SMILES: [O-][N+:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[S:19](=[O:22])(=[O:21])[CH2:20][C:11]=3[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:9]2)[CH:3]=1>C(O)(=O)C.O.[Fe]>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=4[S:19](=[O:22])(=[O:21])[CH2:20][C:11]=3[C:10]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:9]2)[CH:3]=1
Reactant: CCOC(=O)c1nn(-c2ccc[n+]([O-])c2)c2c1CS(=O)(=O)c1ccccc1-2
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1nn(-c2cccnc2)c2c1CS(=O)(=O)c1ccccc1-2
Temperature: 85 °C

Procedure:
To a solution of ethyl 1-(1-oxidopyridin-3-yl)-1,4-dihydrothiochromeno[4,3-c]pyrazole-3-carboxylate 5,5-dioxide (300 mg, 0.78 mmol) in glacial acetic acid (15 mL) is added iron powder (175 mg, 3.12 mmol). The reaction mass is heated to 85° C. for 1 h under nitrogen. The reaction progress is monitored by TLC. The solvent is removed completely under reduced pressure. The crude material obtained is diluted with water and is extracted with ethylacetate. The organic layer is separated and is dried using sodium sulphate and concentrated under reduced pressure to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ=8.85-8.84 (d, J=4.7 Hz, 1H), 8.79-8.78 (m, 1H), 8.07-8.03 (m, 2H), 7.70-7.59 (m, 3H), 6.87-6.85 (d, J=7.84 Hz, 1H), 5.00 (s, 2H), 4.40-4.35 (q, 2H), 1.35-1.32 (t, J=7.12 Hz, 3H). MS (ESI+): 370.2. HPLC (max plot): 97.29%; Rt 3.24 min.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].CC1(C)C(C)(C)OB([C:31]2[CH:32]=[CH:33][C:34]([NH2:37])=[N:35][CH:36]=2)O1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:31]3[CH:36]=[N:35][C:34]([NH2:37])=[CH:33][CH:32]=3)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3ccc(N)nc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 90 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
1-Methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (1 g, 2.71 mmol) (for a preparation see Example 4) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinamine (0.487 g, 2.213 mmol) were combined in ethanol (4.7 ml) and toluene (4.70 ml) to give a light yellow solution. K2CO3 (0.449 g, 3.25 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (0.156 g, 0.135 mmol) were added and the resulted mixture was stirred at 90° C. under nitrogen for 16 h then was cooled to room temperature and concentrated in vacuo. The residue was partitioned between water (40 mL) and EtOAc (50 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (50 mL) and the combined organic phases were washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 12 to 63% AcOEt in Hexanes followed by 10% (2M NH3 in MeOH) in DCM) gave a residue which was further purified by flash chromatography on silica gel (gradient: 1 to 5% (2M NH3 in MeOH) in DCM) to give 1-methylethyl[(2S,4R)-1-acetyl-6-(6-amino-3-pyridinyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (0.74 g, 1.885 mmol, 69.6% yield) as a yellow foam.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([F:28])[CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:29][C@H:30]([C:32]([OH:34])=[O:33])[CH3:31]>>[F:28][C:22]1[CH:21]=[C:20]([CH:25]=[C:24]([O:26][CH3:27])[CH:23]=1)[O:19][C:13]1[CH:12]=[C:11]2[C:16]([C:17]([OH:18])=[C:8]([C:6]([NH:29][C@@H:30]([CH3:31])[C:32]([OH:34])=[O:33])=[O:7])[N:9]=[CH:10]2)=[CH:15][CH:14]=1
Reactant: C[C@H](N)C(=O)O
Reactant: CCCCOC(=O)c1ncc2cc(Oc3cc(F)cc(OC)c3)ccc2c1O
Product: COc1cc(F)cc(Oc2ccc3c(O)c(C(=O)N[C@@H](C)C(=O)O)ncc3c2)c1

Procedure:
Prepared in analogy to Example A-50 by reacting 7-(3-fluoro-5-methoxy-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (compound of example A-73 a) with L-alanine in a pressure tube for 3 days at 90 C. MS-(−)-ion M−1=399.1.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:13]([C@:15]12[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:22][CH2:21][C@@H:20]1[NH:19][CH2:18][CH2:17][CH2:16]2)[CH3:14]>C(Cl)Cl.CO>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:19]3[C@@H:20]4[C@:15]([CH2:13][CH3:14])([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[CH2:22][CH2:21]4)[CH2:16][CH2:17][CH2:18]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: CC[C@@]12CCCN[C@H]1CCc1ccccc12
Solvent: ClCCl
Solvent: CO
Product: CC[C@@]12CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CCc1ccccc12
Yield: 44 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans-10b-ethyl-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 44% of theory; TLC: rf=0.42 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=360 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:17])[F:16])[CH:9]=[O:10])[CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:26])[C:24]=1[CH3:25].CC(C)([O-])C.[K+].[NH4+].[Cl-]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:9]([OH:10])[CH2:25][C:24]3[C:23]([Cl:26])=[CH:22][N:21]=[CH:20][C:19]=3[Cl:18])[CH:11]=[CH:12][C:13]=2[O:14][CH:15]([F:16])[F:17])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: Cc1c(Cl)cncc1Cl
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: OC(Cc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A solution of 3-cyclopropylmethoxy-4-difluoromethoxy-benzaldehyde (5.00 g) and 3,5-dichloro-4-methylpyridine (2.57 g) in 50 ml dry THF was cooled to −30° C. Solid potassium t-butoxide (tBuOK, 1.96 g) was added portionwise maintaining the temperature between −30° C. and −20° C., thus obtaining a dark red solution. After completion of the addition, the mixture was stirred at −30° C. for 1 hour. A saturated aqueous solution of NH4Cl (50 ml) was then added to the reaction mixture, maintaining the temperature between −5° C. and −10° C. The color of the reaction mixture turned to yellow.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[NH:10][CH:11]=[CH:12][N:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:14][O:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH3:14][O:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:13]1[CH:12]=[CH:11][N:10]=[C:9]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: COC(=O)CCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCn1ccnc1-c1ccccc1
Temperature: 75 °C
Reaction time: 21 h
Yield: 46.6 %

Procedure:
Add sodium hydride (1.3 g, 42 mmol) to a mixture of 2-phenyl-1H-imidazole (5.0 g, 35 mmol), 8-bromooctanoic acid methyl ester (8.22 g, 35 mmol), potassium carbonate (5.75 g, 42 mmol), and tetra-n-butylammonium iodide (0.77 g, 2 mmol) in DMF (250 mL) at 0° C. under nitrogen. Heat the mixture to 75° C. and stir for 21 hours. Remove the solvent under reduced pressure, dissolve the residue in chloroform (200 mL), wash with water (100 mL) and brine (100 mL), and dry over sodium sulfate. Remove the solvent under reduced pressure and purify the residue by flash column chromatography on silica gel, eluting with methanol/methylene chloride (1:9), to afford 8-(2-phenylimidazol-1-yl)octanoic acid methyl ester (4.90 g, 47%).
Reaction SMILES: [Na].C(OC([NH:7][N:8]=[C:9]([C:15]1[O:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[CH:16]=1)[CH2:10][O:11][C:12](=[O:14])C)=O)C.C(O)(=O)C>C(O)C.O>[O:19]1[C:15]([C:9]2[CH2:10][O:11][C:12](=[O:14])[NH:7][N:8]=2)=[CH:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]1=2
Reactant: CCOC(=O)NN=C(COC(C)=O)c1cc2ccccc2o1
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: O=C1NN=C(c2cc3ccccc3o2)CO1
Reaction time: 48 h

Procedure:
A solution of sodium (0.45 g.) in ethanol (30 ml.) was added to a stirred solution of acetoxymethyl 2-benzo[b]furyl ketone ethoxycarbonylhydrazone (5.48 g.) in ethanol (30 ml.) and the mixture was stirred at laboratory temperature for 2 days. Further sodium (0.45g.) in ethanol (30 ml.) was added and the mixture was stirred at laboratory temperature for a further 30 hours, diluted with water (300 ml.), adjusted to pH 5 with acetic acid and extracted with 100 ml. and then 50 ml. of ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried and evaporated to dryness and the residue was purified by chromatography on a silica gel column (Merck 7734; 400 g.) using initially a 3:2 v/v mixture of petroleum ether (b.p. 60°-80° C.) and ethyl acetate as eluant. 7500 ml. of this eluant were used, the eluate being discarded, and elution was continued with ethyl acetate (1000 ml.). The eluate was evaporated to dryness under reduced pressure and the residue was stirred with a mixture of methanol and diethyl ether. The mixture was filtered and the solid residue was purified by chromatography on a silica gel column (Merck 9385; column size 25 cm. long and 20 mm. diameter) using a 1:1 v/v mixture of petroleum ether (b.p. 60°-80° C.) and ethyl acetate as eluant. The first 40 ml. of eluate were discarded and the next 90 ml. of eluate were evaporated to dryness under reduced pressure. The residue was stirred with a mixture of diethyl ether and petroleum ether (b.p. 60°-80° C.) and the mixture was filtered. There was thus obtained as solid product 5-(2-benzo[b]furyl)-3H,6H-1,3,4-oxadiazin-2-one, m.p. 209°-211° C.