Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-:4])C.[K+].[N+:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[C-:8].[OH:15][C@:16]12[CH2:33][CH2:32][C@@:30]3([CH3:31])[C@@H:26]([CH2:27][CH2:28][C:29]3=O)[C@@H:25]1[CH2:24][CH:23]=[C:22]1[C@:17]2([CH3:37])[CH2:18][CH2:19][C:20]([O:35][CH3:36])=[CH:21]1.[Cl-].[NH4+]>O1CCCC1>[CH:8]([NH:7]/[C:9](=[C:29]1/[CH2:28][CH2:27][C@@H:26]2[C@:30]/1([CH3:31])[CH2:32][CH2:33][C@@:16]1([OH:15])[C@H:25]2[CH2:24][CH:23]=[C:22]2[C@:17]1([CH3:37])[CH2:18][CH2:19][C:20]([O:35][CH3:36])=[CH:21]2)/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:4]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CC(C)(C)[O-]
Reactant: COC1=CC2=CC[C@H]3[C@@H]4CCC(=O)[C@@]4(C)CC[C@]3(O)[C@@]2(C)CC1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)/C(NC=O)=C1\CC[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@@]3(O)CC[C@]12C
Temperature: 0 °C
Reaction time: 5 h
Yield: 22.7 %

Procedure:
Potassium tert. butoxide (1.71 g) was added to dry tetrahydrofuran (60 ml) under nitrogen. The solution was cooled to 0° C. and a solution of ethyl isocyanoacetate (1.64 g) in tetrahydrofuran (10 ml) was added dropwise, while keeping the temperature below 0° C. Next, a solution of 9α-hydroxy-3-methoxyandrosta-3,5-dien-17-one (3.21 g) in tetrahydrofuran (60 ml) was added. After stirring for 5 hours at room temperature the mixture was poured into 400 ml of saturated aqueous ammonium chloride solution and extracted twice with ethyl acetate. The combined organic layers were washed three times with water, dried (MgSO4) and concentrated under reduced pressure. The crude product (3.20 g) was purified by chromatography (silica gel, toluene/acetone 4/1 containing 0.1% triethylamine) to provide 0.99 g of the title compound. NMR spectra showed the formation of the Z-isomer of the title compound as a mixture of the two rotamer forms of the 20-formamido group.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:17]([NH:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1)=[O:19])[CH2:13][CH:14]([CH3:16])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)O
Reactant: Nc1nncs1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)CC(NC(=O)OCc1ccccc1)C(=O)Nc1nncs1
Reaction time: 2 h
Yield: 71.4 %

Procedure:
9.6 g of N-benzyloxycarbonyl-DL-leucine and 3.7 g of triethylamine were dissolved in 150 ml of chloroform, to which was added dropwise 3.9 g of ethyl chlorocarbonate under sodium chloride-ice cooling conditions. The solution was stirred for 2 hours, to which was then added 3.7 g of 2-amino-1,3,4-thiadiazole, followed by stirring for further 24 hours. The reaction solution was washed with water, and after drying, the solvent was removed by distillation to obtain 9.0 g (yield: 71%) of 2-(N-benzyloxycarbonyl-DL-leucylamino)-1,3,4-thiadiazole as white crystals having a melting point of 118°-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8]C(=O)[C:6]2=[O:16].[OH:17]O.Cl>[OH-].[Na+]>[NH2:8][C:9]1[C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:6]([OH:16])=[O:17]
Reactant: COc1cc2c(c([N+](=O)[O-])c1)NC(=O)C2=O
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(C(=O)O)c(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a slurry of 5-methoxy-7-nitro-1H-indole-2,3-dione (3 g, 13.5 mmol) in aqueous 2N NaOH solution (30 mL), was added an aq. Solution of 33% hydrogen peroxide (3 mL) slowly at 0° C. After completion of the addition, the reaction mixture was stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was acidified with 2N HCl at 0° C. The resulting precipitate was filtered, washed with water (2-3 times) and dried under vacuum to obtain the title compound as yellow solid which was directly used for the next reaction.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.Cl.[NH2:19][OH:20]>O>[O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=[N:19][OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccccc1Oc1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: ON=Cc1ccccc1Oc1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
To 2-phenoxybenzaldehyde (4.96 g, 0.025 mole) were added anhydrous methanol (50 ml) and hydroxylamine hydrochloride (2.08 g, 0.03 mole), and the mixture was stirred at 60° C. for 3 hours. After completion of the reaction, water (200 ml) was added to the reaction mixture, which was extracted with methylene chloride and dried over magnesium sulfate. The crude product obtained by concentration under reduced pressure was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain 2-phenoxybenzaldoxime (3.95 g, yield: 74.1%) as a colorless oil.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C.O.CCOC(C)=O>[Br:1][C:14]1[S:13][C:12]([NH2:15])=[N:11][C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=1
Reactant: Nc1nc(-c2ccc(F)cc2)cs1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Nc1nc(-c2ccc(F)cc2)c(Br)s1
Temperature: 25 °C
Reaction time: 0.01 h

Procedure:
Bromine was added to a solution of 4-(4-fluoro-phenyl)-thiazol-2-ylamine (12 g, 62 mmol) in acetic acid at room temperature. The mixture was stirred at room temperature for 30 sec and solidified. The mixture was diluted with water and poured to ice-water. The light grey suspension was filtered. The solid obtained was taken up in EtOAc and carefully basified with aqueous K2CO3 (pH was adjusted to 8˜9). The EtOAc extract was dried over MgSO4 and concentrated to give crude 5-bromo-4-(4-fluoro-phenyl)-thiazol-2-ylamine (15.15 g). This was then mixed with 4-fluorophenol (6.9 g, 62 mmol) and Cs2CO3 (22 g, 68 mmol) in acetonitrile (120 mL) and heated at 70° C. for 2 h and concentrated. The residue was partitioned between EtOAc and water. The organic extract was dried over MgSO4, concentrated and chromatographed to give the title compound with some impurities. m/z 305.1 (MH+).
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][NH2:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:23](OC)(=[O:28])[CH2:24][C:25]([CH3:27])=O>>[CH2:1]([NH:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][N:19]1[C:23](=[O:28])[CH2:24][C:25]([CH3:27])=[N:22][CH2:21][CH2:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCNCCNCCNCCN
Reactant: COC(=O)CC(C)=O
Product: CCCCCCCCCCCCNCCNCCN1CCN=C(C)CC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 314.5 g (1 mole) of N-dodecyltriethylenetetramine and 116.1 g (1 mole) of methyl acetoacetate. At 140° to 150° C., 18 g of water and 32 g of methanol were distilled off to obtain 4-dodecylaminoethylaminoethyl-7-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[I:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][N:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])=[CH:9][CH:8]=1.[C:23](=[O:26])(O)[O-].[Na+].[CH3:28]N(C)C=O>>[I:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH:28]=[C:16]([CH:23]=[O:26])[C:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:14]2)=[CH:11][CH:12]=1
Reactant: O=C([O-])O
Reactant: CN(C)C=O
Reactant: CC(=NNc1ccc(I)cc1)c1ccccc1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cn(-c2ccc(I)cc2)nc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 1.08 ml (11.58 mmol) of phosphoryl chloride (POCl3) are slowly added dropwise to 10 ml of anhydrous N,N-dimethylformamide. After 30 minutes at 0° C., a solution of 1.95 g (5.792 mmol) of the product from Example 1A in 10 ml of N,N-dimethylformamide is added dropwise, and the reaction mixture is stirred at 0° C. for a further hour. The mixture is then allowed to warm to room temperature, stirred for a further hour and then warmed to 60° C. The reaction mixture is stirred at this temperature for 15 hours. The mixture is then allowed to cool to room temperature, 80 ml of saturated sodium bicarbonate solution are added and the mixture is extracted with ethyl acetate. The organic extract is washed successively with water and saturated sodium chloride solution. The mixture is dried over anhydrous sodium sulphate, and the solvent is then removed on a rotary evaporator. The residue obtained is triturated with diisopropyl ether. The solid is filtered off with suction, washed with diisopropyl ether and dried under high vacuum. This gives 1.34 g (62% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].Cl[CH2:12][CH2:13][N:14]([CH2:37][CH2:38]Cl)[C:15]1[CH:35]=[C:34]([Cl:36])[C:18]2[O:19][C:20]3[C:29]([CH3:30])=[CH:28][C:27]([C:31]([OH:33])=[O:32])=[CH:26][C:21]=3[S:22](=[O:25])(=[O:24])[CH2:23][C:17]=2[CH:16]=1.[CH3:40]O>>[CH3:40][O:33][C:31]([C:27]1[CH:28]=[C:29]([CH3:30])[C:20]2[O:19][C:18]3[C:34]([Cl:36])=[CH:35][C:15]([N:14]4[CH2:13][CH2:12][N:6]([CH2:5][C:4]5[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=5[O:2][CH3:1])[CH2:38][CH2:37]4)=[CH:16][C:17]=3[CH2:23][S:22](=[O:25])(=[O:24])[C:21]=2[CH:26]=1)=[O:32]
Reactant: COc1ccccc1CN
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N(CCCl)CCCl)cc1CS2(=O)=O
Reactant: CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(Cc4ccccc4OC)CC3)cc(Cl)c1O2

Procedure:
2-Methoxybenzylamine (1 mL, 2.28 mmol) was added to a solution of Example 102j (0.6 g, 1.25 mmol) in methanol (10 mL), followed by the addition of n-tetrabutylammonium iodide (0.010 g, 0.02 mmol) in an atmosphere of nitrogen and sealed in a pressure reactor vessel at 110° C. for 6 h. It was processed as described in the synthesis of Example 129k to obtain the title compound as a white solid. Yield: 0.250 g, (35.81%); 1H NMR (DMSO-d6): δ 2.60-2.70 (m, 4H, 2CH2), 2.72 (s, 3H, CH3), 3.20-3.30 (m, 4H, 2CH2), 3.70 (s, 2H, CH2), 3.90 (s, 3H, OCH3), 3.95 (s, 3H, CH3), 4.70 (s, 2H, CH2), 6.80 (s, 1H, Ar), 6.90 (s, 1H, Ar), 6.95-7.00 (m, 2H, Ar), 7.30 (t, 1H, Ar), 7.40 (d, 1H, Ar), 8.10 (s, 1H, Ar), 8.50 (s, 1H, Ar); MS: m/e (CI+) 557 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH:13]=[O:14])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].Cl.O>O1CCCC1.C(O)(C)C>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][OH:14])[CH2:11][O:10][C:9]1([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@H](C=O)COC1(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1[C@H](CO)COC1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To an ice cold mixture of (S)-4-formyl-2,2-dimethyl-oxazolidine-3-carboxylic acid t-butyl ester (2.00 g, 8.72 mmol) in tetrahydrofuran (15 mL) and isopropanol (15 mL) was added sodium borohydride (0.99 g, 26.17 mmol). After addition was complete the mixture was stirred at 0° C. for 1 h. Upon completion of the reaction 1N aqueous hydrochloric acid (10 mL) was slowly added. The mixture was poured into water and extracted with ethyl acetate (3×30 mL). The combined organic fractions were washed with a saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained (R)-4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid t-butyl ester (1.88 g, 93%) as a colorless oil and was used without further purification: LR-ES-MS m/z calculated for C11H21NO4 [M]+ 231, observed 232 [M+H]+.
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.CCN(C(C)C)C(C)C.CS(O[C@H:29]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=2)[C:30]1=[O:42])(=O)=O>C(#N)C>[F:1][C@H:2]1[C@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C@@H:29]2[CH2:33][CH2:32][N:31]([CH2:34][C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)[C:30]2=[O:42])[CH2:3]1
Reactant: Oc1ccc([C@@H]2CCNC[C@H]2F)cc1
Reactant: Cc1ccc(CN2CC[C@H](OS(C)(=O)=O)C2=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(CN2CC[C@@H](N3CC[C@@H](c4ccc(O)cc4)[C@H](F)C3)C2=O)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 66.8 %

Procedure:
A solution of 4-((3S,4S)-3-fluoropiperidin-4-yl)phenol (7.10 g, 36.4 mmol, intermediate F) and DIEA (16 mL, 92 mmol) in 100 mL of acetonitrile was heated to 80° C. This solution was treated dropwise with a solution of (S)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl methanesulfonate (10.5 g, 37.0 mmol, intermediate J) in acetonitrile (80 mL) over a period of 4 hours. After the addition was completed, the reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was then allowed to cool to rt, and the volume was reduced by rotary evaporation to 80 mL. A satd. NH4Cl solution (100 mL) was then added, and the layers were separated. The aqueous layer was extracted with DCM (2×100 mL) and the organic layers were combined, dried over Na2SO4 and concentrated in vacuo to give a crude product. The crude product was purified by silica gel chromatography (750 g of silica gel) eluting with a gradient of 0% to 20% of solvent B in solvent A, where Solvent B=20% methanol/DCM and solvent A=DCM. Fractions containing the product were combined. Evaporation of the solvents gave 9.3 grams of the desired product with 97% purity by LC/MS analysis (conditions B). The product thus obtained (8.5 g) was slurried in acetone:hexane (1:5, 200 mL) and the solid product was isolated by filtration and air dried. Careful SFC analysis showed the presence of a 2.1% impurity in the product. Using a Cell4 0.46×25 cm 5 μm column and eluting with 45% methanol in CO2 at 3 mL/min, the desired product eluted at 3.800 minutes and the undesired impurity eluted at 4.848 minutes. The product was then further purified by SFC Chromatography using a Cell4 3×25 cm 5 μm column at 150 mL/min injecting 1.5 mL of a 80 mg/mL solution. Concentration of the active fractions provided 7.82 grams (20.4 mmol, 56%) of >99.7% pure example 1 as a white powder. LC/MS (Conditions B), RT=2.512 min, (M+H)+=383.3. 19F NMR δ −182.83. 1H NMR (400 MHz, chloroform-d) δ 7.20-7.08 (m, 6H), 6.98-6.78 (m, 2H), 5.68 (s, 1H), 4.77-4.54 (m, 1H), 4.53-4.34 (m, 2H), 3.68 (t, J=8.8 Hz, 1H), 3.41-3.29 (m, 1H), 3.28-3.09 (m, 2H), 2.82 (d, J=10.8 Hz, 1H), 2.74-2.54 (m, 2H), 2.47 (td, J=9.9, 3.6 Hz, 1H), 2.34 (s, 3H), 2.19-1.94 (m, 2H), 1.92-1.80 (m, 2H). 13C NMR (101 MHz, chloroform-d) δ 172.4, 154.9, 137.5, 133.3, 133.0, 129.5, 128.7, 128.3, 115.5, 92.6, 90.8, 65.0, 54.4, 54.2, 48.7, 48.0, 47.8, 46.8, 43.7, 31.7, 31.6, 21.1, 19.6.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH3:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][N:6]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:22](=[O:25])(O)[O-].[Na+]>C(Cl)Cl>[C:13]([C:9]1[C:8]([OH:11])=[CH:7][N:6]=[C:5]([CH2:4][CH:3]([NH2:2])[CH3:12])[C:10]=1[C:22](=[O:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(N)Cc1ccc(O)cn1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC(N)Cc1ncc(O)c(C(=O)c2ccccc2)c1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The starting material is prepared as follows: The mixture of 0.5 g of 2-(2-aminopropyl)-5-pyridinol hydrochloride, 0.85 g of benzoyl chloride, 10 ml of methylene chloride and 10 ml of saturated aqueous sodium bicarbonate is stirred at room temperature for 1 hour. The organic phase is separated, dried evaporated and the residue recrystallized from diethyl ether to give the dibenzoyl-2-(2-aminopropyl)-5-pyridinol melting at 110°-112°.
Reaction SMILES: C(OC[CH:10]1[CH2:15][O:14][CH:13]([N:16]2[CH:23]=[CH:22][C:20]([NH2:21])=[N:19][C:17]2=[O:18])[CH2:12][S:11]1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.C(Cl)Cl.[C:33](=O)(O)[O-:34].[Na+]>C(Cl)Cl>[OH:34][CH2:33][SH:11]1[CH2:10][CH2:15][O:14][CH:13]([N:16]2[CH:23]=[CH:22][C:20]([NH2:21])=[N:19][C:17]2=[O:18])[CH2:12]1
Reactant: O=C([O-])O
Reactant: Nc1ccn(C2CSC(COCc3ccccc3)CO2)c(=O)n1
Agent: ClB(Cl)Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Nc1ccn(C2C[SH](CO)CCO2)c(=O)n1
Temperature: -78 °C

Procedure:
1-(5-benzyloxymethyl-1,4-oxathian-2-yl)cytosine (0.12 g) was dissolved in methylene chloride (10 ml), and the solution was cooled to -78° C. To the solution, 1M boron trichloride solution (3.7 ml) was added dropwise, and the resultant mixture was stirred at the same temperature for 4 hours. Mixed solvent of methanol-methylene chloride (1/1, 8 ml) was added thereto, and sodium bicarbonate was added to neutralize the reaction mixture. Upon raising the temperature of the reaction mixture to room temperature, the solvent was distilled off under reduced pressure to obtain white solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:31])([CH3:30])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[CH2:12][CH:13]([CH2:16][C:17]1[N:18]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:19]=[CH:20][N:21]=1)[CH2:14][NH2:15].[CH:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1)=[O:33].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=C1>O.CN(C)C=O>[CH:32]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([NH:15][CH2:14][CH:13]([CH2:16][C:17]2[N:18]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[CH:19]=[CH:20][N:21]=2)[CH2:12][C:8]2[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:30])[CH3:31])[CH:11]=[CH:10][N:9]=2)=[O:39])=[CH:36][CH:35]=1)=[O:33]
Reactant: C[Si](C)(C)CCOCn1ccnc1CC(CN)Cc1nccn1COCC[Si](C)(C)C
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1cnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1ccnc1CC(CNC(=O)c1ccc(C=O)cc1)Cc1nccn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 132.4 %

Procedure:
To a dimethylformamide (2 mL) solution of the compound (300 mg) produced in Example 29 and 4-formylbenzoic acid (116 mg), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (hereafter abbreviated to EDC) (274 mg) and 1-hydroxybenzimidazole (104 mg) were added in this order. The reaction solution was stirred at room temperature for 17 hour. To the reaction solution, water (10 mL) was added. The aqueous layer was extracted twice with dichloromethane (20 mL). The combined organic layer was washed with saturated sodium chloride solution (20 mL) and then dried over anhydrous magnesium sulfate. After removing the anhydrous magnesium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (ethyl acetate:methanol: 28% aqueous ammonia=1:0:0→100:10:1) to obtain the title compound (510 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:10]=2)[C:5]([OH:16])=[C:4]([C:17]([OH:19])=O)[N:3]=1.Cl.C([O:25][C:26](=[O:35])[C@@H:27]([NH2:34])[CH2:28][O:29]C(C)(C)C)(C)(C)C>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([CH3:14])[CH3:15])[CH:10]=2)[C:5]([OH:16])=[C:4]([C:17]([NH:34][C@@H:27]([CH2:28][OH:29])[C:26]([OH:35])=[O:25])=[O:19])[N:3]=1
Reactant: CC(C)Oc1ccc2c(O)c(C(=O)O)nc(Cl)c2c1
Reactant: CC(C)(C)OC[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Product: CC(C)Oc1ccc2c(O)c(C(=O)N[C@@H](CO)C(=O)O)nc(Cl)c2c1

Procedure:
Prepared in analogy to Example A-2 e) and f) from 1-chloro-4-hydroxy-7-isopropoxy-isoquinoline-3-carboxylic acid (can be obtained according to U.S. Pat. No. 6,093,730, October 1998, Weidmann et al.) and (S)-2-amino-3-tert-butoxy-propionic acid tert-butyl ester hydrochloride; MS-(+)-ion: M+1=369.0 amu.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Reactant: CCCCN
Product: CCCCNc1c(C(=O)OCC)cnc2c(N)cccc12
Yield: 78 %

Procedure:
The compound prepared in Example 3 was reacted with butylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 78%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:20][CH2:19][C:18]3[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]4[CH:23]=[N:22][N:21]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)[C:16]=4[CH:17]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl.[F:44][C@@H:45]1[CH2:49][CH2:48][NH:47][CH2:46]1>C(#N)C.C(OCC)(=O)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([N:21]2[C:16]3[CH:17]=[C:18]4[C@:13]([CH2:31][O:32][CH3:33])([CH2:14][C:15]=3[CH:23]=[N:22]2)[CH2:12][N:11]([S:8]([C:5]2[CH:6]=[N:7][C:2]([N:47]3[CH2:48][CH2:49][C@@H:45]([F:44])[CH2:46]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:20][CH2:19]4)=[CH:25][CH:26]=1
Reactant: F[C@@H]1CCNC1
Reactant: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CC[C@@H](F)C3)nc1)C2

Procedure:
A solution of (R)-6-(6-chloropyridine-3-sulfonyl)-4a-methoxymethyl-1-(4-fluorophenyl)-4,4a,5,6,7,8-hexahydro-1H-1,2,6-triazacyclopenta[b]naphthalene (0.098 g), diisopropylethylamine (0.194 g) and (R)-3-fluoropyrrolidine hydrochloride in acetonitrile was heated at 130° C. in a microwave reactor for 45 minutes. The solution was diluted with ethyl acetate, washed with water followed by brine, dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate in cyclohexane (0 to 3:2 by volume), to afford the title compound as a white solid (0.089 g). LCMS (Method F): 542 (M+H)+, Retention time 5.0 minutes
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH2:33][C:34]3[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:41])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:42].[Li+]>C(COC)OC>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:42])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH2:33][C:34]2[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:41])(=[O:31])=[O:32])=[CH:26][CH:25]=1)[C:20]([OH:21])=[O:22])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2ccc(S(=O)(=O)Cc3c(Cl)cccc3Cl)cc2)C(=O)O1
Agent: [Li+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1ccc(S(=O)(=O)Cc2c(Cl)cccc2Cl)cc1)C(=O)O

Procedure:
In analogy with Example 5e), 6.7 g (10.83 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-{[p-(2,6-dichlorobenzylsulfonyl)phenyl]methyl}dihydrofuran-2-(3H)-one in 170 ml of dimethoxyethane are hydrolysed with 43.3 ml of a 1M lithium hydroxide solution (RT, 17 h). Partitioning between 3× methylene chloride, NH4Cl/citric acid solution and saline, and stirring the crude product in ether, affords the title compound: tRet (II)=15.5 min.