Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[C:11]2[CH2:10][CH2:9][N:8]([C:12]([CH:14]3[C:16]([CH3:18])([CH3:17])[C:15]3([CH3:20])[CH3:19])=[O:13])[CH2:7][C:6]=2[NH:5][C:4]2[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([O:27]C)=O)[C:3]1=2.O.[NH2:30][NH2:31]>>[CH3:18][C:16]1([CH3:17])[C:15]([CH3:20])([CH3:19])[CH:14]1[C:12]([N:8]1[CH2:7][C:6]2[NH:5][C:4]3[CH:21]=[CH:22][CH:23]=[C:24]4[C:25](=[O:27])[NH:30][N:31]=[C:2]([C:3]=34)[C:11]=2[CH2:10][CH2:9]1)=[O:13]
Reactant: COC(=O)c1cccc2[nH]c3c(c(=O)c12)CCN(C(=O)C1C(C)(C)C1(C)C)C3
Reactant: NN
Solvent: O
Product: CC1(C)C(C(=O)N2CCC3=C(C2)Nc2cccc4c(=O)[nH]nc3c24)C1(C)C

Procedure:
The target product was prepared from methyl 5-oxo-2-(2,2,3,3-tetramethylcyclopropanecarbonyl)-1,2,3,4,5,10-hexahydrobenzo[b][1,7]naphthyridine-6-carboxylate and hydrazine hydrate according to the same procedure described as in Example 16 (Step 4). 1H NMR (DMSO-d6) δ 11.8 (s, 1H), 10.6-10.65 (m, 1H), 7.62-7.67 (m, 1H), 7.47-7.48 (m, 1H), 7.24-7.31 (m, 1H), 4.36-4.41 (m, 2H), 3.70-3.76 (m, 2H), 2.29-2.33 (m, 2H), 1.03-1.23 (m, 12H). MS (ESI) m/e [M+1]+ 369.
Reaction SMILES: [CH2:1]([NH:3][S:4]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])=[O:5])[CH3:2].CC(C)([O-])C.[K+].[C:20](OCC)(=[O:24])[C:21]([O-])=[O:22].Cl>C1COCC1>[CH2:1]([N:3]1[C:21](=[O:22])[C:20]([OH:24])=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:4]1(=[O:5])=[O:6])[CH3:2]
Reactant: CCNS(=O)(=O)Cc1ccccc1
Reactant: CCOC(=O)C(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCN1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Temperature: 145 °C
Yield: 2754.6 %

Procedure:
N-Ethyl-1-phenylmethanesulfonamide (20 g) was divided into batches of 0.5 g each and taken in an 8 mL vial. To each vial was added potassium tert-butoxide (0.426 g, 3.8 mmol), ethyl oxalate (0.408 mL, 3.01 mmol) and dry THF (4 mL). Each vial was heated in a microwave reactor at 145° C. under pressure for 20 mins. Reaction mixture from all the vials were combined and treated with 1.5 N HCl (75 mL) and extracted with EtOAc. The organic layer was washed with water (3×25 mL) and brine, dried over Na2SO4 and evaporated. A small amount of the DCM was added to the solid residue and stirred well. Filtration gave nearly pure title compound (21 g, 82.6%) as off-white solid; 1H NMR (300 MHz, CDCl3) 1.47 (t, 3H, J=7.2 Hz), 3.8 (q, 2H, J=7.2 Hz), 7.3-7.5 (m, 3), 7.9-8.0 (m, 2H).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[N:8]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:7][C:6]1=O)[CH2:2][CH2:3][CH3:4].C12CCCC(CCC1)B12[H]B2(C3CCCC2CCC3)[H]1.C(CN)O>O1CCCC1>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[N:8]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)CN(C(=O)OC(C)(C)C)c2ccc(C(=O)OC)cc21
Solvent: C1CCOC1
Solvent: NCCO
Product: CCCCN1CCN(C(=O)OC(C)(C)C)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Yield: 37.4 %

Procedure:
A solution of 1-tert-butyl 6-methyl 4-butyl-3-oxo-3,4-dihydroquinoxaline-1,6(2H)-dicarboxylate (440 mg) and 9-BBN dimer (600 mg) in tetrahydrofuran (10 mL) was heated at 65° C. for 10 h. The mixture was cooled to room temperature, ethanolamine (0.15 mL) was added and the resulting solution was concentrated under reduced pressure. The residue was washed with hexanes, filtered, and the filtrate was concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 ethyl acetate/hexanes) afforded 158 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.50, 7.34, 7.28, 3.88, 3.77, 3.38–3.30, 1.65–1.51, 1.42–1.34, 0.99–0.94.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([CH:22]([C:24]3[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=3[Cl:33])[OH:23])=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=2)[CH2:12][O:13][CH3:14])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:34]([F:37])([F:36])[F:35].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:23])[C:24]3[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=3[Cl:33])=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=2)[CH2:12][O:13][CH3:14])(=[O:9])=[O:10])=[CH:4][C:3]=1[C:34]([F:35])([F:37])[F:36]
Reactant: COCN(c1cc(C)cnc1C(O)c1cc([N+](=O)[O-])ccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: COCN(c1cc(C)cnc1C(=O)c1cc([N+](=O)[O-])ccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 52.3 %

Procedure:
To a solution of 4-chloro-N-{2-[(2-chloro-5-nitro-phenyl)-hydroxy-methyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (441 mg, 0.76 mmol) in CH2Cl2 (5 mL) was added Dess-Martin periodinane (645 mg, 1.52 mmol) and stirred for 6 h at room temperature. 10% Na2S2O3 (5 mL) and saturated aqueous NaHCO3 solution (5 mL) was added and stirred for 30 min. Aqueous layer was separated and extracted with EtOAc (2×25 mL). Combined organic layers were washed with saturated aqueous NaHCO3 solution (20 mL), brine (20 mL), dried (anhydrous Na2SO4), concentrated and purified (SiO2, 40% EtOAc-hexanes) to obtain 4-chloro-N-[2-(2-chloro-5-nitro-benzoyl)-5-methyl-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (230 mg) as yellow syrup in 52% yield. ESMS m/z (relative intensity): 545.9 (M-31)+ (100), 578 (M+H)+ (50), 599.9 (M+Na)+ (65).
Reaction SMILES: [C:1]1([CH:7]([C:13]#[N:14])[C:8](OCC)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>CCOCC>[OH:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:13][NH2:14]
Reactant: CCOC(=O)C(C#N)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: NCC(CO)c1ccccc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 20 %

Procedure:
To the suspension of ethyl phenylcyanoacetate (1.0 g, 5.3 mmol) in anhydrous ether (200 mL) was added lithium aluminum hydride at 0° C. The mixture was stirred at 0° C. for 18 h. After adding water (1 equiv.), 15% sodium hydroxide (1 equiv.) and water (3 equiv.) to the above solution, the precipitation was removed by filtration. The filtrate was concentrate to dry by lyophilization. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 0%-10% methanol in methylene chloride (0.1% NH4OH) in 30 min afforded 3-hydroxy-2-phenyl-propylamine (0.16 g, 20%).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:43])[CH2:38][CH2:39][CH2:40][CH2:41]Br)[CH3:35]>>[CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:41][CH2:40][CH2:39][CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:43])=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCCBr
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3ccc(O)cc3)cc2)cccc1[N+](=O)[O-]
Product: CCOC(=O)CCCCOc1ccc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)cc1

Procedure:
The product from Example 60E and ethyl-5-bromovalerate was processed as described in Example 116A to provide the titled compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:13])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:3]=[C:4]([NH2:13])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:17][CH:16]=1
Reactant: Nc1cnc(OCC2CC2)c(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Nc1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example E, using 5-bromo-6-cyclopropylmethoxy-pyridin-3-ylamine and 4-chlorophenylboronic acid (44%). MS (LC/MS): 275.2 (M+H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:39]=[C:38]3[C:33]([CH2:34][CH2:35][CH2:36][NH:37]3)=[CH:32][CH:31]=2)O1.C([O-])([O-])=O.[K+].[K+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1.CCOC(C)=O.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>[O:15]([CH2:14][CH2:13][O:12][C:5]1[C:6]([C:8]([O:10][CH3:11])=[O:9])=[N:7][C:2]([C:30]2[CH:39]=[C:38]3[C:33]([CH2:34][CH2:35][CH2:36][NH:37]3)=[CH:32][CH:31]=2)=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1nc(Br)ccc1OCCOc1ccccc1
Reactant: CC1(C)OB(c2ccc3c(c2)NCCC3)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2ccc3c(c2)NCCC3)ccc1OCCOc1ccccc1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
Methyl 6-bromo-3-(2-phenoxyethoxy)picolinate (27A) (327 mg, 0.93 mmol), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinoline (27B) (181 mg, 0.7 mmol), tetrabutylammonium bromide (30 mg, 0.09 mmol), dichlorobis(triphenylphosphine)palladium(II) (26 mg, 0.04 mmol) and K2CO3 (322 mg, 2.33 mmol) were stirred in 1,4-dioxane (2 mL) and water (1 mL) at 90° C. for 45 minutes. The reaction mixture was allowed to cool to rt and diluted with EtOAc (5 ml), washed with H2O, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of PE/EtOAc 9:1-7:3, to provide 205 mg (72%) of the desired product methyl 3-(2-phenoxyethoxy)-6-(1,2,3,4-tetrahydroquinolin-7-yl)picolinate (27C): 1H NMR (300 MHz, CDCl3) δ7.69 (1H, m), 7.44 (1H, m), 7.27 (2H, m), 7.13 (2H, s), 6.94 (4H, m), 4.40 (2H, m), 4.34 (2H, m), 3.90 (3H, s), 3.27 (2H, t), 2.76 (2H, t), 1.92 (2H, m).
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[OH-].[Ca+2].[OH-].C(O)(=O)/C=C/C(O)=O.N.C([O-])(=O)/C=C/C([O-])=O.[Ca+2].C([O-])(=O)/C=C/C([O-])=O.[NH4+].[NH4+].[Ca].[NH2:38][C@H:39]([C:44]([O-:46])=[O:45])[CH2:40][C:41]([O-:43])=[O:42].[NH4+].[NH4+]>>[NH2:38][C@H:39]([C:44]([OH:46])=[O:45])[CH2:40][C:41]([OH:43])=[O:42]
Reactant: N[C@@H](CC(=O)[O-])C(=O)[O-]
Agent: N
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
A process for the preparation of aspartic acid via a fermentation process for the preparation of ammonium fumarate, wherein the pH of the fermentation broth is controlled by the addition of a calcium base to produce a calcium fumarate precipitate, characterised in that ammonium fumarate is produced by separating said precipitated calcium fumarate from said fermentation broth, and reacting said precipitate with a reagent selected from ammonia, ammonium carbonate, ammonia in combination with CO2 and mixtures thereof, to form ammonium fumarate solution and a co-product selected from calcium carbonate and calcium hydroxide, wherein the energy of indirect neutralisation of fumaric acid by ammonia serves as the driving force for the conversion of calcium fumarate to the desired ammonium fumarate product with a conversion yield of at least 90% and for the regeneration of a calcium base reagent, and wherein said ammonium fumarate product is enzymatically converted to ammonium aspartate and acidulated to form aspartic acid.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:10]2[CH:9]=[C:8]([O:20][CH2:21][CH2:22][NH:23][S:24]([C:27]3[N:28]=[CH:29][N:30]([CH3:32])[CH:31]=3)(=[O:26])=[O:25])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[CH:33]12[CH2:38][CH:37]1[C:36](=[O:39])[O:35][C:34]2=[O:40]>CN(C)C=O>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][CH:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:20][CH2:21][CH2:22][NH:23][S:24]([C:27]3[N:28]=[CH:29][N:30]([CH3:32])[CH:31]=3)(=[O:26])=[O:25])[CH:9]=2)[CH2:4][CH2:3][CH:2]1[NH:1][C:36]([C@H:37]1[CH2:38][C@H:33]1[C:34]([OH:40])=[O:35])=[O:39]
Reactant: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)[C@H](Cc2ccccc2F)[C@H](N)CC3)c1
Reactant: O=C1OC(=O)C2CC12
Solvent: CN(C)C=O
Product: Cn1cnc(S(=O)(=O)NCCOc2ccc3c(c2)C(Cc2ccccc2F)C(NC(=O)[C@H]2C[C@H]2C(=O)O)CC3)c1
Temperature: 110 °C

Procedure:
cis-N-(2-{[7-Amino-8-(2-fluorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}ethyl)-1-methyl-1H-imidazole-4-sulfonamide (50 mg, 0.109 mmol) was dissolved in dimethylformamide (2 mL), 3-oxabicyclo[3.1.0]hexane-2,4-dione (13.4 mg 0.12 mmol) was added and the reaction mixture was heated to 110° C. for 2 h. The solvent was removed in vacuo and the crude product was taken up in dichloromethane and washed successively with water (2×) and saturated sodium chloride solution (1×) and dried (magnesium sulfate). The solvent was evaporated in vacuo and the crude product was used for the next step without further purification. Yield: 63 mg (colorless foam).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([O:9][C:10]3[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:31]1[CH2:36][CH2:35][O:34][C:32]1=[O:33]>CC(C)=O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([O:9][C:10]3[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16]([O:18][CH:31]4[CH2:36][CH2:35][O:34][C:32]4=[O:33])=[O:17])=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1
Reactant: O=C1OCCC1Br
Reactant: CC(Oc1ccc(Oc2nc3ccc(Cl)cc3s2)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(Oc1ccc(Oc2nc3ccc(Cl)cc3s2)cc1)C(=O)OC1CCOC1=O
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
21 g (0.06 mole) of 2-[4-(6-chloro-2-benzthiazolyloxy)-phenoxy]-propionic acid were initially taken together with 10.4 g (0.075 mole) of potassium carbonate in 100 ml of acetone and the mixture was stirred for approx. 1/2 hour at 45° C., a thick paste being formed. 11.6 g (0.07 mole) of 2-bromobutyrolactone in 50 ml of acetone were then added dropwise in the course of 1/2 hour. When the addition was complete, the reaction mixture became highly fluid; the conversion was followed by means of thin-layer chromatography and was approx. 70% after 5 hours. Altogether, the mixture was stirred for 16 hours at approx. 50° C. After cooling, the salt was filtered off, the acetone was removed by distillation and the residue was taken up in approx. 200 ml of toluene and washed with water and saturated sodium bicarbonate solution. After drying, the toluene was removed by distillation and the residue remaining was dried in vacuo (0.05 mbar) for one hour at approx. 70° C. The product remaining after drying was 22 g (91.3% of theory) of a very viscous oil, which was identified by 1H nuclear magnetic resonance spectroscopy as 2-oxotetrahydrofuran-3-yl 2-[4-(6-benzthiazolyloxy)-phenoxy]-propanoate. ##STR12##
Reaction SMILES: Cl[C:2]1[N:11]2[CH:12]=[N:13][N:14]=[C:10]2[C:9]2[CH:8]=[C:7]([O:15][CH3:16])[C:6]([O:17][CH3:18])=[CH:5][C:4]=2[N:3]=1.C(N(CC)CC)C.[CH3:26][OH:27]>>[CH3:26][O:27][C:2]1[N:11]2[CH:12]=[N:13][N:14]=[C:10]2[C:9]2[CH:8]=[C:7]([O:15][CH3:16])[C:6]([O:17][CH3:18])=[CH:5][C:4]=2[N:3]=1
Reactant: CO
Reactant: COc1cc2nc(Cl)n3cnnc3c2cc1OC
Solvent: CCN(CC)CC
Product: COc1cc2nc(OC)n3cnnc3c2cc1OC

Procedure:
A mixture of 500 mg 5-chloro-8,9-dimethoxy-1,2,4-triazolo[4,3-c]quinazoline and 25 ml triethylamine in 25 ml. methanol is stirred at 40° C. for 24 hrs. The solution is then evaporated in vacuo to dryness, treated with water, and the aqueous layer extracted several times with chloroform. The combined chloroform extracts, after washing with H2O, is dried over sodium sulfate and evaporated in vacuo to dryness. The residue is dissolved in minimum chloroform and chromotrographed on silica gel, elution being carried out with chloroform and then with chloroform containing increasing concentrations of methanol. The desired fractions are collected, evaporated to dryness in vacuo and the residue crystallized from methylene chloride/diethyl ether to obtain 5,8,9-Trimethoxy-1,2,4-triazolo-[4,3-c]quinazoline, m.p. 245°-250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([CH:22]2[CH2:27][CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][CH2:23]2)[N:17]=1.[OH-].[K+].O>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([C:16]2[NH:20][C:19](=[O:21])[N:18]([CH:22]3[CH2:23][CH2:24][C:25]([CH3:28])([CH3:29])[CH2:26][CH2:27]3)[N:17]=2)[CH:4]=1
Reactant: CC1(C)CCC(n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCC(n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)CC1
Yield: 85.8 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-3-(4,5-dihydro-1-(4,4-dimethylcyclohexyl)-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (Example-117, 0.150 g, 0.348 mmol), KOH (0.039 g, 0.696 mol), water (2 mL) and THF (5.0 mL) to afford 0.100 g of the desired product.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=O)[CH2:9]1)=O)(C)(C)C.[NH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.CC#N.O.CC#N>O>[CH:31]([N:14]([CH2:13][C@H:11]1[C@H:10]([CH2:34][N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:9][NH:8][CH2:12]1)[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=1)([CH3:33])[CH3:32]
Reactant: C1CCNCC1
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC
Solvent: O
Solvent: CC#N
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2CN2CCCCC2)C(C)C)ccc1OC

Procedure:
The title compound is prepared analogously as described in Example 5 from (3S*,4R*)-3-formyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester and piperidine. MS (LC-MS): 462.1 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 3.74 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:25]=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28].C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:16]=1)[CH2:25][N:29]([CH2:30][CH3:31])[CH2:27][CH3:28])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CCNCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN(CC)C[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Reaction time: 48 h
Yield: 7.2 %

Procedure:
A solution consisting of 2.86 g (8 mmol) N-tert-butoxycarbonyl-O-benzyl-L-tyrosinal (Example 3, Step B) and 0.832 mL (8 mmol) diethyl amine in 36 mL methanol containing 1% acetic acid was stirred at 25° C. for 20 minutes, at which time a solution of 1.06 g (16 mmol) sodium cyanotrihydridoborate (Aldrich, Milwaukee, Wis.) in 12 mL methanol was added and the resulting mixture stirred for 48 hours. The reaction was quenched by the addition of 3 M HCl in 3 mL increments until the vigorous bubbling subsided. The mixture was neutralized with saturated NaHCO3 solution then extracted with three 100 mL portions of ethyl acetate. The combined extracts were washed with 100 mL brine, dried over anhydrous sodium sulphate and evaporated at reduced pressure to give an amber oil which was chromatographed on a silica gel column using 50:50:1 ethyl acetate:hexane:methanol as eluant to give 236 mg (7%) of (S)-[1-(4-benzyloxy-benzyl)-2-diethylamino-ethyl]-carbamic acid tert-butyl ester as a clear, colorless oil.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[C:21]2[C:22](=[O:30])[C:23]3[S:29][CH:28]=[CH:27][C:24]=3[CH2:25][O:26][C:20]=2[CH:19]=[CH:18][CH:17]=1>CC(N(C)C)=O.C(OCC)(=O)C>[F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4]([NH:15][C:16]1[C:21]2[C:22](=[O:30])[C:23]3[S:29][CH:28]=[CH:27][C:24]=3[CH2:25][O:26][C:20]=2[CH:19]=[CH:18][CH:17]=1)=[O:5]
Reactant: Nc1cccc2c1C(=O)c1sccc1CO2
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1cccc2c1C(=O)c1sccc1CO2)C(F)(F)F
Reaction time: 1 h
Yield: 89 %

Procedure:
In dimethylacetamide (3 ml) was dissolved 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (0.32 g, 2.03 mmol), and thionyl chloride (148 μl, 2.03 mmol) was added thereto at -15° C., followed by stirring at -15° to -5° C. for one hour. To this reaction mixture was added 9-amino-4,10-dihydrothieno[3,2-c][1]benzoxepin-10-one obtained in Reference Example 11 (0.23 g, 1.02 mmol), and the mixture was stirred overnight at room temperature. After concentration of the reaction mixture under reduced pressure, the obtained oily residue was dissolved in ethyl acetate (20 ml). The organic layer was washed successively with a 5% aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained oily residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1), followed by trituration with hexane to give Compound 7 (0.34 g, 89%).
Reaction SMILES: C.C([O-])=O.[NH4+].Cl[C:7]1[C:8]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:9]=2[S:10][C:11]=1[C:12]([OH:14])=[O:13].[OH-].[Na+]>CO.O.[Pd]>[CH3:19][C:16]1[CH:17]=[CH:18][C:8]2[CH:7]=[C:11]([C:12]([OH:14])=[O:13])[S:10][C:9]=2[CH:15]=1
Reactant: Cc1ccc2c(Cl)c(C(=O)O)sc2c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Cc1ccc2cc(C(=O)O)sc2c1
Reaction time: 0.33 h
Yield: 95 %

Procedure:
A suspension of palladium on 5% wet charcoal (50% water) (1.065 g) and ammonium formate (2.52 g) in methanol (30 ml) is stirred for 20 minutes in an inert atmosphere; a solution of 2.52 g of ammonium formate in 5 ml of water and a solution consisting of 2.26 g of 3-chloro-6-methyl-benzo[b]thiophene-2-carboxylic acid (18), 70 ml of methanol and 10 ml of 1N NaOH is then added. The mixture is kept under reflux stirring in an inert atmosphere for 15 hours. 0.425 g of Pd/C (5% wet) is then added, and the reaction mixture is again maintained under reflux for 24 hours. The mixture is then cooled, diluted with methanol, filtered through a Celite bed, and the catalyst is washed with further methanol. The filtrate is then evaporated until dry at low pressure and the residue treated with 70 ml of 1N HCl and 250 ml of ethyl acetate. The organic phase is washed with brine (3×) and evaporated until dry, to obtain 1.82 g of compound (1) in the form of a white solid; HPLC purity=98.2%, yield=94.7%.