Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.C(OC(C(N[C@H](C(N1CCC[C@H]1C(O)=O)=O)CCCCNC(=O)C(F)(F)F)CC(=O)C1C=CC=CC=1)=O)C.Cl.[CH2:42]([O:44][C:45]([CH:47]([NH:56][C@H:57]([C:59]([OH:61])=[O:60])[CH3:58])[CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:46])[CH3:43].C(OC(C(N[C@H](C(O)=O)C)CCC1CCCCC1)=O)C.C(C(N[C@H](C(O)=O)C)CCC1C=CC=CC=1)(O)=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>[H][H].C(O)C.O>[CH2:42]([O:44][C:45]([C@@H:47]([NH:56][C@H:57]([C:59]([OH:61])=[O:60])[CH3:58])[CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:46])[CH3:43]
Reactant: [H][H]
Reactant: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)O
Agent: CCOC(=O)C(CC(=O)c1ccccc1)N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)N1CCC[C@H]1C(=O)O
Agent: CCOC(=O)C(CCC1CCCCC1)N[C@@H](C)C(=O)O
Agent: C[C@H](NC(CCc1ccccc1)C(=O)O)C(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)O
Temperature: 20 °C
Yield: 73 %

Procedure:
N-(1-ethoxycarbonyl-3-oxo-3-phenylpropyl)-L-alanine [(1S/1R)=9.0] 5.0 g, (17 mmoles) was added to 100 ml of 10% (w/w) water-containing ethanol containing 0.5 N HCl. Thereto 50% (w/w) water-containing 5% Pd--C (5.0 g) was added and the catalytic reduction was carried out in hydrogen atmosphere (atmospheric pressure) under the conditions of an inner temperature of a range from about 15° to 25° C. and an agitation power of a range from 0.5 to 1 kW/m3 (amount of HCl based on substrate: 3 equivalents). Supply of hydrogen was stopped at the time when hydrogen is absorbed in 90% of the required amount. Then, the atmosphere was rapidly replaced with nitrogen to stop the reaction. The residual rate of the reaction intermediate was 10%, the formation rate of N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanine was 82%, the content of N-(1-ethoxycarbonyl-3-cyclohexylpropyl)-L-alanine was 0.2% (w/w) and the content of N-(1-carboxy-3-phenylpropyl)-L-alanine was 7% (w/w). Pd--C was rapidly removed by filtration and the Pd--C cake was conscientiously washed with 10 ml of 7% (w/w) water-containing ethanol and 5 ml of water. After 30 ml of water was added to the resulting filtrate, the filtrate was neutralized (pH 4.5) by slowly adding dropwise an aqueous 30% (w/w) sodium hydroxide solution. The filtrate was concentrated at the inner temperature of 50° C. under reduced pressure, and then concentrated under reduced pressure with appropriately adding water to give a slurry with replacing with water. The content of ethanol in the slurry was 2% (w/w), the content of sodium sulfate was 9% (w/w) and the pH was 5.0. After cooling to an inner temperature of 20° C., the crystal was filtered and washed with water in a 2-fold amount of the cake. The resulting crystal was vacuum-dried (30 mmHg to 1 mmHg) at a range from 40° to 60° C. to give N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine (3.1 g, 11 mmoles). The yield was 73%. HPLC purity: 99.1% (w/w), the content of N-(1(R)-ethoxycarbonyl-3-phenylpropyl)-L-alanine: 0.1% (w/w), the content of N-(1-ethoxycarbonyl-3-cyclohexylpropyl)-L-alanine: 0.2% (w/w), the content of N-(1-carboxy-3-phenylpropyl)-L-alanine: 0.1% (w/w).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([N+:28]([O-])=O)[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].CC(O)=O.O>CCOC(C)=O.[Fe]>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc([N+](=O)[O-])c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 112.7 %

Procedure:
A mixture of 4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (64 mg, 0.15 mmol), AcOH (0.90 mL), water (0.10 mL) and iron powder (149 mg, 2.66 mmol) was stirred at room temperature for 20 min. The mixture was diluted with EtOAc and filtered through a short silica gel plug. The filtrate was concentrated under reduced pressure, diluted with EtOAc and washed with aq. Na2CO3. The organic layer was dried, filtered and concentrated under reduced pressure to give the sub-title compound (66 mg) as a yellowish solid, which was used without further purification. LCMS calc. for C20H31N4O4 (M+H)+: m/z=391.2. Found: 391.1.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]([OH:16])=[O:15])=[N:10][N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=3)[C:8]2=[O:27])=[CH:4][CH:3]=1.[CH:30](O)([CH3:32])[CH3:31]>S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]([O:16][CH:30]([CH3:32])[CH3:31])=[O:15])=[N:10][N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:26])[CH3:25])[CH:18]=3)[C:8]2=[O:27])=[CH:4][CH:3]=1
Reactant: CC(C)O
Reactant: CC(=O)Nc1cccc(-n2nc(C(=O)O)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)Nc1cccc(-n2nc(C(=O)OC(C)C)c(=O)n(Cc3ccc(Cl)cc3)c2=O)c1
Temperature: 80 °C
Yield: 30 %

Procedure:
According to Scheme 7 Step 5: A mixture of 4-(4-chlorobenzyl)-2-(3-acetamidophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid 7.6 (100 mg, 0.24 mmol), isopropylalcohol (3 mL) and sulfuric acid (2 drops) was heated at 80° C. for 20 hours. The reaction mixture was diluted with a saturated solution of NaHCO3 (50 mL) and the aqueous layer was extracted twice with DCM (50 mL). The organic layers were combined and selectively dried over MgSO4, filtered and concentrated under reduced pressure to afford a brown solid. The crude solid was purified by flash chromatography with silica gel (Merck Flashmart prepacked column 7 g SiO2) using CH2Cl2/MeOH 98/2 as eluant to afford isopropyl 4-(4-chlorobenzyl)-2-(3-acetamidophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate (33 mg, 30%) as a beige solid.
Reaction SMILES: [C:1](=[C:3]1[CH:8]=[C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11]([CH3:23])=[C:12]([C:18]([O:20]CC)=[O:19])[NH:13]3)[CH:6]=[CH:5][CH2:4]1)=[O:2].C1COCC1.[Li+].[OH-].Cl>C(OCC)(=O)C.O>[C:1](=[C:3]1[CH:8]=[C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11]([CH3:23])=[C:12]([C:18]([OH:20])=[O:19])[NH:13]3)[CH:6]=[CH:5][CH2:4]1)=[O:2]
Reactant: CCOC(=O)c1[nH]c2cccc(C3=CC(=C=O)CC=C3)c2c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)[nH]c2cccc(C3=CC(=C=O)CC=C3)c12
Reaction time: 6 h

Procedure:
To a solution of ethyl 5-carbonylphenyl-3-methyl-indole-2-carboxylate (10 mg, 0.034 mmol) and THF (0.5 mL) was added a solution of LiOH (3.6 mg, 0.15 mmol) and water (0.2 mL). The solution was stirred for 6 h, poured into a mixture of 1 N HCl (1 mL) and ethyl acetate (2 mL). The organic layer was separated, the aqueous layer extracted with ethyl acetate and the combined organic layers was washed with water (1 mL). The solution was dried (MgSO4), filtered and concentrated to give the title compound as a white solid.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH2:28][CH2:29][CH2:30][CH3:31])=[C:25]([C:32](=[O:48])[C:33]3[CH:38]=[C:37]([I:39])[C:36]([CH2:40][CH3:41])=[C:35]([I:42])[C:34]=3[O:43][CH2:44][C:45]([OH:47])=[O:46])[C:24]=2[CH:49]=1>C(Cl)Cl>[CH2:28]([C:26]1[O:27][C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:8](=[O:17])[C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)=[CH:49][C:24]=2[C:25]=1[C:32](=[O:48])[C:33]1[CH:38]=[C:37]([I:39])[C:36]([CH2:40][CH3:41])=[C:35]([I:42])[C:34]=1[O:43][CH2:44][C:45]([OH:47])=[O:46])[CH2:29][CH2:30][CH3:31]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCCCc1oc2ccc(N)cc2c1C(=O)c1cc(I)c(CC)c(I)c1OCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1oc2ccc(NC(=O)c3ccc(OC)cc3)cc2c1C(=O)c1cc(I)c(CC)c(I)c1OCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Triethylamine (28 mg, 0.28 mmol) and anisoyl chloride (47 mg, 0.28 mmol) were added to a solution of 5-amino-2-n-butyl-3-(3,5-diiodo-4-ethyl carboxymethoxybenzoyl)-benzofuran (prepared as in Example 1(g) (150 mg, 0.23 mmol) in methylene chloride (5 ml) . The resulting mixture was stirred at room temperature overnight, then washed with brine, dried using MgSO4 and concentrated to produce 172 mg (95%) of 2-n-butyl-3-(3,5-diiodo-4-ethyl carboxymethoxybenzoyl)-5-(4-methoxybenzamido)benzofuran.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5](=O)[CH2:6]2.Cl.[NH2:12][OH:13]>C(O)C>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5](=[N:12][OH:13])[CH2:6]2
Reactant: CN1C2CCC1CC(=O)C2
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CN1C2CCC1CC(=NO)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.8 %

Procedure:
A 500-mL one-neck round-bottomed flask equipped with a magnetic stirrer was charged with 8-methyl-8-aza-bicyclo[3.2.1]octan-3-one (5.00 g, 35.9 mmol), hydroxylamine hydrochloride (7.08 g, 102 mmol) sodium acetate (39.0 g, 476 mmol) and ethanol (45 mL). After stirring at ambient temperature for 4 h, the reaction mixture was evaporated to a solid residue. This residue was triturated with ethyl acetate (200 mL) and filtered. Evaporation of the filtrate to dryness gave 5.08 g (93% yield) of 8-methyl-8-aza-bicyclo[3.2.1]octan-3-one oxime as a white solid: mp 140-142° C.; 1H NMR (300 MHz, CD3OD) δ 3.76 (m, 2H), 3.33-3.23 (m, 2H), 2.75 (m, 1H), 2.69 (s, 3H), 2.46-2.14 (m, 4H), 1.88-1.66 (m, 2H); MS (APCI) m/z 155 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([N:20]3[CH2:25][CH2:24][C:23]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)([OH:26])[CH2:22][CH2:21]3)[C:15](=O)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[OH2:36]>C(O)C.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]([OH:36])[CH:14]([N:20]3[CH2:25][CH2:24][C:23]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)([OH:26])[CH2:22][CH2:21]3)[CH2:15][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1oc2cc(OCc3ccccc3)ccc2cc1N1CCC(O)(c2ccc(F)cc2)CC1
Reactant: O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: OC1c2ccc(OCc3ccccc3)cc2OCC1N1CCC(O)(c2ccc(F)cc2)CC1
Reaction time: 8 h
Yield: 60 %

Procedure:
To a slurry of 7-benzyloxy-3-[4-(4-fluorophenyl)-4-hydroxy-piperidine-1-yl]-chromenone (8.24 g, 18.5 mmol) in ethanol (400 mL) and tetrahydrofuran (600 mL) was added sodium borohydride (7.0 g, 185 mmol). The mixture was stirred overnight. Additional sodium borohydride (7.0 g) was added and the reaction mixture was stirred for 3 days. Water was added and the solvent was removed at reduced pressure at 45° C. The solids which formed were collected and washed well with water and then ether. The solid was further dried in vacuo overnight to give 5.01 g, 60% of 3R*4S*7-benzyloxy-3-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]-chroman-4-ol which was suitable for use without further purification. A sample recrystallized from ethyl acetate/chloroform had mp. 194-195° C.; NMR δ7.56-7.30 (m, 8H), 7.06 (long range coupled t, J=8.7 Hz, 2H) 6.63 (dd, J=2.4, 8.5 Hz, 1H), 6.47 (d, J=2.4 Hz, 1H), 5.04 (s, 2H), 4.77 (d, J=4.5Hz, 1H), 4.37 (dd, J=3.5, 10.4Hz, 1H), 4.13 (t, J=10.4 Hz, 1H), 3.82 (brs, 1H), 3.11 (br d, J=11.2 Hz, 1H), 2.92-2.71 (m, 4H), 2.21-2.06 (m, 2H), 1.87-1.73 (m, 2H), 1.54 (s,1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH2:15][CH2:16][CH3:17])[CH:8]=[CH:7][CH:6]=1.CCCCCC.C([Li])CCC.CN(C)[CH:31]=[O:32]>CCOCC.O>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[CH2:15][CH2:16][CH3:17])[CH:8]=[CH:7][C:6]=1[CH:31]=[O:32]
Reactant: CN(C)C=O
Reactant: CCCc1cccc2cccc(OCOC)c12
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCc1cccc2ccc(C=O)c(OCOC)c12
Temperature: -35 °C

Procedure:
350 g of 1-methoxymethoxy-8-propylnaphthalene was dissolved in 3 liters of absolute ether and cooled down to -35° C. 1.43 liters of a hexane solution of 1.6M n-butyl lithium was added to the solution at a temperature not higher than -30° C., followed by gradually raising the temperature and reaction at room temperature for further 1 hour. The reaction solution was again cooled down to -40° C., to which 222 ml of N,N-dimethylformamide was added in 15 minutes. The mixture was slowly raised to 10° C., to which water was added portion by portion, followed by extraction with ethyl acetate. The resultant organic phase was washed with a saturated saline solution and dried with anhydrous magnesium sulfate, after which it was concentrated under reduced pressure to obtain 460 g of a black reside. This residue was purified by silica gel column chromatography (5% ethyl acetate/hexane) to obtain 326 g of the captioned compound as a brown oily substance.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:32][CH2:31][N:30]3[C:23](=[CH:24][C:25]4[CH2:26][C:27]([CH3:34])([CH3:33])[CH2:28][C:29]=43)[C:22]2=[O:35])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16](Br)[C:15](=[O:19])[N:14]([CH3:20])[CH:13]=1)(=[O:3])[CH3:2].[O:36]1[CH:40]=[CH:39][C:38]([NH2:41])=[N:37]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:32][CH2:31][N:30]3[C:23](=[CH:24][C:25]4[CH2:26][C:27]([CH3:34])([CH3:33])[CH2:28][C:29]=43)[C:22]2=[O:35])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:41][C:38]2[CH:39]=[CH:40][O:36][N:37]=2)[C:15](=[O:19])[N:14]([CH3:20])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccon1
Reactant: CC(=O)OCc1c(-c2cc(Br)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cc(Nc3ccon3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 25 °C
Yield: 59 %

Procedure:
A 25-mL round-bottomed flask equipped with a reflux condenser was charged with [4-(5-bromo-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-{4,4-dimethyl-9-oxo-1,10-diazatricy-clo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-3-yl]methyl acetate 273a (161 g, 0.30 mmol), isoxazol-3-amine (25 mg, 0.30 mmol), cesium carbonate (196 mg, 0.60 mmol), and 1,4-dioxane (10 mL). After bubbling nitrogen through the suspension for 10 minutes, tris(dibenzylideneacetone)dipalladium(0) (14.0 mg, 0.015 mmol) and xantphos (17 mg, 0.030 mmol) were added. The system was subjected to three cycles of vacuum/argon flush and heated at reflux for 5 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (2×10 mL). The combined organic filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80/1 to 30/1) to afford 286a (96 mg, 59%) as yellow solid. MS-ESI: [M+H]+ 542.8.
Reaction SMILES: [OH:1][CH:2]([CH2:35][OH:36])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:8](O)=[O:9].[C:37]([O:40][C:41]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)=[O:42])(=O)[CH3:38]>>[OH:1][CH:2]([CH2:35][OH:36])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([NH:23][S:24]([C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)(=[O:25])=[O:26])[C:13]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[C:8]([N:46]1[CH2:45][CH2:44][N:43]([C:41]([O:40][CH2:37][CH3:38])=[O:42])[CH2:48][CH2:47]1)=[O:9]
Reactant: CC(=O)OC(=O)N1CCNCC1
Reactant: COc1cccc(Oc2c(NS(=O)(=O)c3ccc(SC)cc3)cc(C(=O)O)cc2OCC(O)CO)c1
Product: CCOC(=O)N1CCN(C(=O)c2cc(NS(=O)(=O)c3ccc(SC)cc3)c(Oc3cccc(OC)c3)c(OCC(O)CO)c2)CC1

Procedure:
In analogy to Example 121, by coupling 3-(2,3-dihydroxy-propoxy)-4-(3-methoxy-phenoxy)-5-(4-methylsulphanyl-benzenesulphonylamino)-benzoic acid with 1-acetoxycarbonylpiperazine there was obtained ethyl 4-[3-(2,3-dihydroxy-propoxy)-4-(3-methoxy-phenoxy)-5-(4-methylsulphanylbenzenesulphonylamino)-benzoyl]-piperazine-1-carboxylate as a white foam.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[S:8][S:7][C:6](=[S:9])[N:5]=1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][CH:14]=1)([O-:12])=[O:11]>O.C(O)C.C(Cl)Cl>[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][S:8][C:4]2[N:5]=[C:6]([SH:9])[S:7][N:3]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: Nc1nc(=S)ss1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(CSc2nsc(S)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.3 %

Procedure:
A solution of 2.2 grams (0.055 mole) of sodium hydroxide in 7 ml of water and 20 ml of ethanol was stirred and 4.0 grams (0.027 mole) of 5-amino-1,2,4-dithiazol-3-thione was added portionwise. After all of the 5-amino intermediate was in solution, 4.7 grams (0.027 mole) of 4-nitrophenylmethyl chloride was added dropwise. Upon completion of addition the reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in 20 ml of water then extracted with two 25 ml portions of diethyl ether. The aqueous layer was acidified with concentrated hydrochloric acid to yield a gummy solid. The solid was extracted from the aqueous layer with two 25 ml portions of ethyl acetate. The combined extracts were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield a gummy solid. The solid was dissolved in methylene chloride and filtered to remove a small amount of insoluble material. The filtrate was concentrated under reduced pressure to yield 2.8 grams of 3-(4-nitrophenylmethylthio)-5-mercapto-1,2,4-thiadiazole as a solid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].B(OB=O)=O.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH:22]=O)[CH:20]=2)[CH:15]=[CH:14]1.C(OC)(OC)OC.C(N)CCC.Cl>C(OCC)(=O)C>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH:22]=[CH:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5])[CH:20]=2)[CH:15]=[CH:14]1
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccc2cc[nH]c2c1
Agent: Cl
Agent: O=BOB=O
Solvent: CCOC(C)=O
Solvent: CCCCN
Solvent: COC(OC)OC
Product: CC(=O)CC(=O)C=Cc1ccc2cc[nH]c2c1
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
Ethyl acetate (7 mL), 2,4-pentanedione (9.35 mL, 90.9 mmol) and boron trioxide (5.76 g, 82.7 mmol) was placed in a 200 mL reaction vessel with a reflux condenser. To the stirring mixture at 85° C. was added dropwise a solution of 1H-indole-6-carboxaldehyde (2.00 g, 13.8 mmol) and trimethyl orthoformate (1.6 mL, 14 mmol) in 14 mL of ethyl acetate. After the reaction mixture was stirred for 30 min at 95° C., n-butylamine (6.8 mL, 69 mmol) was added dropwise with additional stirring for 2 h. The reaction mixture was cooled to 50° C. before addition of 3N HCl (32 mL). After being stirred at 50° C. for 30 min, the mixture was filtered to remove solids. The filtrate was diluted with ethyl acetate, washed with brine twice, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 75/25) followed by recrystallization (hexane/ethyl acetate) to obtain the title compound as a pale yellow crystal (0.92 g, 29%).
Reaction SMILES: [CH2:1]([N:5]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](OCC1C2C=CC=CC=2C2C1=CC=CC=2)=[O:13])[CH:2]([CH3:4])[CH3:3].[C:42]([NH:48][C@H:49](C(O)=O)[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44]>>[CH3:41][C:38]1[CH:37]=[CH:36][C:35]([S:32]([N:5]([C@H:6]([C:29]([OH:31])=[O:30])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@@H:49]([NH:48][C:42]([C:43]([CH3:46])([CH3:45])[CH3:44])=[O:47])[CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:13])[CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:34])=[O:33])=[CH:40][CH:39]=1
Reactant: CC(C)(C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NC(=O)C(C)(C)C)C(=O)O)cc1

Procedure:
The title compound was prepared from solid phase bound Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine as described in general procedure Bb using Nα-pivaloyl-L-phenylalanine (300 mg, 1.2 mmol). The final product was purified by preparative HPLC to yield 49 mg (66%) of the desired material.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrC[CH2:45][O:46]C>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH2:15][O:46][CH3:45])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: COCCBr
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: COCCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-bromo-2-methoxyethane and isolated as light-yellow gum (2.5 mg, 18%). MS(m/e): 341.3 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:10]=[O:11].[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.Cl>C(#N)C>[OH:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[CH:10]=[O:11]
Reactant: Cc1cc(C)cc(O)c1
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C)c(C=O)c(O)c1
Yield: 84.5 %

Procedure:
A mixed solution of 3,5-dimethylphenol (20.0 g, 164 mmol), paraformaldehyde (14.8 g, 492 mmol), magnesium chloride (23.4 g, 246 mmol) and triethylamine (80 mL, 573 mmol) in acetonitrile (500 mL) was heated under reflux for 4 hours. The reaction solution was acidified with hydrochloric acid, which was extracted with diethyl ether. The organic layer was washed with a saturated sodium hydrogen carbonate solution and a saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9) to obtain 20.8 g (yield 84%) of the title compound. Melting point: 48-49° C. (hexane).