Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][NH2:3].C(=O)([O-])[O-].[Na+].[Na+].[O:10]1[C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[O:13][CH2:12][C@@H:11]1[CH:20]=O>O.C1COCC1>[O:10]1[C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[O:13][CH2:12][C@@H:11]1[CH:20]=[N:3][OH:2]
Reactant: NO
Reactant: O=C[C@H]1COC2(CCCCC2)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: ON=C[C@H]1COC2(CCCCC2)O1
Reaction time: 0.08 h
Yield: 99.3 %

Procedure:
In 1000 mL of DI water was added hydroxyl amine hydrochloride (51.0 g, 734 mol) and the reaction was stirred for 5 minutes. Sodium carbonate (38.1 g, 360 mmol) was added in 3 large portions and the reaction was stirred for 15 minutes. THF (700 mL) was added to the reaction and (R)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (125 g, 734 mmol) was added in 1 portion in 800 mL of THF. The reaction was stirred for 4 hours and poured into a 4 L separatory funnel and the layers separated. The aqueous layer was extracted twice with MTBE (3000 mL total). The combined organic layers were washed with water (700 mL) and brine (300 mL), dried over MgSO4 and concentrated in vacuo to afford (S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135 g, 99%) as a clear viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17](O)=[O:18])[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:32][NH:33][CH:34]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([N:33]([CH3:32])[CH:34]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35]2)=[O:18])[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: CNC1CCN(C)C1
Reactant: COc1ccc(CN(c2cccc(C(=O)O)c2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(CN(c2cccc(C(=O)N(C)C3CCN(C)C3)c2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.2 %

Procedure:
A stirred solution of 253C (500 mg, 1.152 mmol) in DMF (1 mL) was treated with N,1-dimethylpyrrolidin-3-amine (0.217 mL, 1.73 mmol), BOP (663 mg, 1.5 mmol) and TEA (0.32 mL, 2.30 mmol), and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was triturated with water, and the solid was collected by filtration and dried in vacuo to obtain 254A (337 mg, 0.636 mmol, 55.2% yield) as a light grey solid. HPLC: Rt=1.56 min. (PHENOMENEX® Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min. with 1 min. hold time, flow rate=5 mL/min., detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; solvent B: 10% water/90% methanol/0.1% TFA). MS (ES): m/z=531.97 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:16]=1[C:17](Cl)=[O:18]>>[CH3:25][O:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:15]([O:14][CH3:13])[C:16]=1[C:17]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2)=[O:18]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: CN1CCc2c(N)cccc2C1
Product: COc1cccc(OC)c1C(=O)Nc1cccc2c1CCN(C)C2

Procedure:
5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline was reacted with 2,6-dimethoxybenzoyl chloride according to the procedure of Example 19 to yield 5-(2,6-dimethoxybenzamido)-2-methyl-1,2,3,4-tetrahydroisoquinoline; m.p. 191°-192° C. after recrystallization from benzene.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[C:16]([C:17]3[CH:18]=[N:19][NH:20][CH:21]=3)=[CH:15][CH:14]=[C:13]3[C:8]=2[CH2:9][CH2:10][C@H:11]([CH3:26])[N:12]3[C:22]([O:24][CH3:25])=[O:23])=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].CS(O[CH:41]1[CH2:44][N:43]([CH:45]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:42]1[CH3:58])(=O)=O>O>[CH:45]([N:43]1[CH2:44][CH:41]([N:20]2[CH:21]=[C:17]([C:16]3[C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=4)=[C:8]4[C:13](=[CH:14][CH:15]=3)[N:12]([C:22]([O:24][CH3:25])=[O:23])[C@@H:11]([CH3:26])[CH2:10][CH2:9]4)[CH:18]=[N:19]2)[CH:42]1[CH3:58])([C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: CC1C(OS(C)(=O)=O)CN1C(c1ccccc1)c1ccccc1
Reactant: COC(=O)N1c2ccc(-c3cn[nH]c3)c(Oc3ccc(F)cc3)c2CC[C@@H]1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)N1c2ccc(-c3cnn(C4CN(C(c5ccccc5)c5ccccc5)C4C)c3)c(Oc3ccc(F)cc3)c2CC[C@@H]1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.5 %

Procedure:
A 100-mL round-bottom flask was charged with (S)-methyl 5-(4-fluorophenoxy)-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.300 g, 0.79 mmol) and N,N-dimethylformamide (10 mL), and the solution was cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 0.047 g, 1.17 mmol) was added, and the resulting mixture stirred for 30 min at room temperature. 1-Benzhydryl-2-methylazetidin-3-yl methanesulfonate (0.286 g, 0.86 mmol) was added, and the resulting mixture stirred overnight at 50° C. The reaction mixture was cooled to room temperature and poured into water (30 mL). The aqueous phase was separated and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 25% ethyl acetate-petroleum ether) to afford (2S)-methyl 6-(1-(1-benzhydryl-2-methylazetidin-3-yl)-1H-pyrazol-4-yl)-5-(4-fluorophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.100 g, 21%) as yellow oil. MS (ESI, pos. ion) m/z 617 [M+H]+.
Reaction SMILES: C([NH:3][C@@H:4]1[C:27](=[O:28])[N:6]2[C:7]([C:24]([O-:26])=[O:25])=[C:8]([CH2:11][N+:12]([CH3:23])([CH3:22])[CH2:13][C:14]3[NH:15][CH:16]=[C:17]([OH:21])[C:18](=[O:20])[CH:19]=3)[CH2:9][S:10][C@H:5]12)=O.[ClH:29].C(OCC)(=O)C>C(O)=O>[ClH:29].[ClH:29].[NH2:3][C@@H:4]1[C:27](=[O:28])[N:6]2[C:7]([C:24]([O-:26])=[O:25])=[C:8]([CH2:11][N+:12]([CH3:23])([CH3:22])[CH2:13][C:14]3[NH:15][CH:16]=[C:17]([OH:21])[C:18](=[O:20])[CH:19]=3)[CH2:9][S:10][C@H:5]12
Reactant: C[N+](C)(CC1=C(C(=O)[O-])N2C(=O)[C@@H](NC=O)[C@H]2SC1)Cc1cc(=O)c(O)c[nH]1
Agent: Cl
Solvent: O=CO
Solvent: CCOC(C)=O
Product: C[N+](C)(CC1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1)Cc1cc(=O)c(O)c[nH]1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a cooled solution of 7β-formamido-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl) methyl}ammonio]methyl-3-cephem-4-carboxylate (4.084 g) in formic acid (8.1 ml) was added dropwise conc. hydrochloric acid (2.5 ml). The mixture was warmed to room temperature and stirred for 2.5 hours. The mixture was added dropwise to ethyl acetate (400 ml) and the supernatant was decanted. The residual oil was dissolved in methanol (50 ml) and the solution was poured into ethyl acetate (600 ml). The resulting precipitates were collected by filtration, washed with ethyl acetate and diisopropyl ether and dried in vacuo. The powder was dissolved in cold water (28 ml) and chromatographed on Diaion HP-20 (28 ml) at 5° C., and the elution was carried out with water. To the eluate (30 ml) was added dropwise cold isopropyl alcohol (19 ml) under cooling and the mixture was stirred at 5° C. for an hour. The resultant crystal was collected by filtration washed with a cooled mixture of isopropyl alcohol and water (10:1) and cold isopropyl alcohol, and dried in vacuo to give 7β-amino-3-[N,N-dimethyl-N-{(5-hydroxy-4-oxo-1,4-dihydropyridin-2-yl)methyl}ammonio]methyl-3-cephem-4carboxylate dihydrochloride (728 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[C:10]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:11]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30]O)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[CH2:1]([O:8][C:9](=[O:18])[C:10]1[C:11]([OH:17])=[CH:12][CH:13]=[CH:14][C:15]=1[O:16][CH2:30][CH2:29][CH2:28][CH2:27][NH:26][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCCCO
Reactant: O=C(OCc1ccccc1)c1c(O)cccc1O
Product: CC(C)(C)OC(=O)NCCCCOc1cccc(O)c1C(=O)OCc1ccccc1

Procedure:
The title compound is prepared from 2,6-dihydroxybenzoic acid benzyl ester and 4-(Boc-amino)-1-butanol analogous to Example 1109 step A.
Reaction SMILES: ClCCl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16])[C:9](Cl)=[O:10].[NH2:19][C:20]1[N:25]2[N:26]=[CH:27][CH:28]=[C:24]2[N:23]=[C:22]([CH2:29][CH2:30][CH:31]([O:33][Si](C)(C)C)[CH3:32])[CH:21]=1.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[OH:33][CH:31]([CH3:32])[CH2:30][CH2:29][C:22]1[CH:21]=[C:20]([NH:19][C:9](=[O:10])[C:8]2[CH:7]=[C:6]([O:5][CH3:4])[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=2)[N:25]2[N:26]=[CH:27][CH:28]=[C:24]2[N:23]=1
Reactant: CC(CCc1cc(N)n2nccc2n1)O[Si](C)(C)C
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(C(=O)Nc2cc(CCC(C)O)nc3ccnn23)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
A dry dichloromethane solution (5 ml) containing 650 mg of 3,4,5-trimethoxybenzoyl chloride was slowly added dropwise to 5 ml of a pyridine solution containing 520 mg of the crystals obtained in step (7), and stirred at room temperature for 2 hours. After completion of the reaction, a saturated aqueous NaHCO3 solution was added and the reaction mixture was extracted with dichloromethane. The organic layer was collected and washed with a 1N aqueous hydrochloric acid until the pH of the water layer became about 1. The organic layer was allowed to stand for 2 hours, washed with water and a saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from dichloromethane-n-hexane to provide 480 mg of the object compound as colorless crystals. Table 2 shows the structure and melting point of the compound obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=O)[NH:10]2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:16])=O>ClCCl>[Cl:16][C:9]1[CH:8]=[N:7][C:6]2[C:11](=[CH:12][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: CSc1ccc2ncc(=O)[nH]c2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CSc1ccc2ncc(Cl)nc2c1
Temperature: 25 °C
Yield: 33.7 %

Procedure:
A solution of 7-methylsulfanyl-1H-quinoxalin-2-one (9.23 g, 48.0 mmol, 1.0 eq) in phosphorus oxychloride (36 mL, 384.0 mmol, 8.0 eq) is heated under reflux for 30 minutes. Then the reaction mixture is cooled down to room temperature and the solvent is evaporated. The residue is poured into ice water, the resulting mixture is basified with saturated sodium hydrogen carbonate to pH=8˜9 and extracted with ethyl acetate (3×50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:dichloromethane, 4:1 to 1:1, v/v) to afford 2-chloro-7-methylsulfanyl-quinoxaline as a green solid (3.41 g, 33% yield).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]2[NH:15][C:16](C3C=CC(B4OC(C)(C)C(C)(C)O4)=CC=3)=[CH:17][N:18]=2)[CH2:3]1.Br[C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][CH:44]=1)[CH:41]=[C:40]([C:45]1[NH:49][C:48]([C@@H:50]3[CH2:54][CH2:53][CH2:52][N:51]3[C:55](=[O:65])[C@@H:56]([NH:60][C:61](=[O:64])[O:62][CH3:63])[CH:57]([CH3:59])[CH3:58])=[N:47][CH:46]=1)[CH:39]=[CH:38]2.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[OH:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:11])[CH3:12])=[O:8])[C@H:4]([C:14]2[NH:15][C:16]([C:35]3[CH:36]=[CH:37][C:42]([C:35]4[CH:44]=[CH:43][C:42]5[C:37](=[CH:38][CH:39]=[C:40]([C:45]6[NH:49][C:48]([C@@H:50]7[CH2:54][CH2:53][CH2:52][N:51]7[C:55](=[O:65])[C@@H:56]([NH:60][C:61]([O:62][CH3:63])=[O:64])[CH:57]([CH3:59])[CH3:58])=[N:47][CH:46]=6)[CH:41]=5)[CH:36]=4)=[CH:43][CH:44]=3)=[CH:17][N:18]=2)[CH2:3]1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
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: COCCOC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6C[C@H](O)CN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 85 °C
Yield: 21.9 %

Procedure:
(2S,4S)-tert-butyl 4-hydroxy-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (200 mg, 0.44 mmol) and methyl (S)-1-((S)-2-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (219 mg, 0.44 mmol) were combined in DME (5 mL). Pd(PPh3)4 (51 mg, 0.0446 mmol) and K2CO3 (2M H2O, 0.73 mL, 1.45 mmol) were added, and the solution was degassed with N2 for 10 min. The solution was heated to 85° C. and stirred o/n. The following morning, the solution was cooled to rt. The solution was diluted with EtOAc, washed with sat. NaHCO3, brine, dried over MgSO4, and concentrated. The residue was purified by silica gel chromatography to yield product (36 mg).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([OH:6])=[O:5].[O:13]([CH2:20][CH2:21]O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[K+]>>[O:13]([CH2:20][CH2:21][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=1[C:1]([OH:12])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCOc1ccccc1
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1cccc(CCOc2ccccc2)c1C(=O)O
Temperature: 90 °C

Procedure:
148.1 g of anhydrous phthalic acid and roughly the molar equivalent 139.3 g of 2-phenoxyethanol were added to a 500 ml glass round-bottomed flask equipped with stirring blades, thermometer and Dimroth condenser, heated while slowly stirring, and after the generated heat at about 90° C. wore off, raised to a temperature of 130° C., which was maintained for 1 hour. The mixture was subsequently cooled to 60° C. The acid value (number of mg of KOH necessary to neutralize 1 g of a sample) of the reaction solution was 212.6. Since the acid value for the case where the reaction is 100% complete is 202.2, the reaction rate was computed to be 95%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[N+:12]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:1][C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Product: O=C(O)c1cc(NCc2ccc([N+](=O)[O-])cc2)ccc1O
Yield: 77.4 %

Procedure:
By following the similar procedure in Synthesis Example 1 by using 5-aminosalicylic acid (2.00 g, 13.0 mmole) and 4-nitrobenzyl bromide (3.38 g, 15.6 mmole), 2.90 g (79% yield) of 5-(4-nitrobenzyl)aminosalicylic acid was obtained as a pale yellow solid.: mp 211-212° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:15]O)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14].[ClH:17]>O1CCOCC1>[Cl:17][CH2:15][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: Cl
Reactant: CCC#CCOc1ccc(CO)cc1OC
Solvent: C1COCCO1
Product: CCC#CCOc1ccc(CCl)cc1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of (3-methoxy-4-pent-2-ynyloxy-phenyl)-methanol (27 g, 0.12 mol) in 450 ml of dioxan is added dropwise to 240 ml of concentrated hydrochloric acid. The reaction mixture is stirred for 1.5 hours at room temperature. Subsequently it is poured on water and extracted with ethyl acetate. The combined organic layer is washed with brine, dried over magnesium sulfate and evaporated in vacuo to obtain 4-chloromethyl-2-methoxy-1-pent-2-ynyloxy-benzene as yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.C(N(CC)CC)C.[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17]>O1CCOCC1>[N+:16]([C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:1][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=2)=[O:24])=[CH:26][CH:27]=1)([O-:18])=[O:17]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=c1cc(O)cc[nH]1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(Oc1cc[nH]c(=O)c1)c1ccc([N+](=O)[O-])cc1
Yield: 73.4 %

Procedure:
To a suspension of 1.00 g of 4-hydroxy-2-pyridone in 50 ml of dried dioxane were added 3.78 ml of triethylamine and a solution of 2.17 g of 4-nitrobenzoyl chloride in 30 ml of dried dioxane, and the mixture was refluxed for 6 hours. After the dioxane was distilled off, the residue was washed with water and then with a 1:1 mixture of methanol-acetone to obtain the title compound in an amount of 1.72 g (yield: 73.4%)
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]([O:21][CH3:22])[C:3]=1[OH:23].[C:24](Br)(=[O:26])[CH3:25]>FC(F)(F)C(O)=O>[C:24]([O:23][C:3]1[C:4]([O:21][CH3:22])=[C:5]([S:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:6]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][C:7]=2[C:2]=1[Cl:1])(=[O:26])[CH3:25]
Reactant: CC(=O)Br
Reactant: COc1c(O)c(Cl)c2c(c1Sc1ccccc1)CCN(C)CC2
Solvent: O=C(O)C(F)(F)F
Product: COc1c(OC(C)=O)c(Cl)c2c(c1Sc1ccccc1)CCN(C)CC2

Procedure:
A mixture of 0.45 g. (0.0013 mole) of 9-chloro-8-hydroxy-7-methoxy-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine and 0.2 ml. (0.0026 mole) of acetyl bromide in trifluoroacetic acid is heated to reflux on a steam bath for 2 hours. The reaction mixture is concentrated and the residue is taken up in 100 ml. of methylene chloride. This solution is dried and evaporated to give 8-acetoxy-9-chloro-7-methoxy-3-methyl-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:38][C@@H:39]([CH2:47][C:48]1[CH:53]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=1)[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>CN(C=O)C.CC(=O)OCC>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:38][C@H:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:47][C:48]2[CH:53]=[CH:52][C:51]([OH:54])=[CH:50][CH:49]=2)=[O:11])=[CH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 5 h
Yield: 77.1 %

Procedure:
Prepared using General Procedure 7. Into a solution of 4-(tert-butyl)benzoic acid (8.3 g, 46.4 mmol) in DMF (100 mL) were added HATU (19.2 g, 50.6 mmol), TEA (17.6 mL, 126.4 mmol) and (S)-tert-butyl 2-amino-3-(4-hydroxyphenyl)propanoate (10.0 g, 42.1 mmol). After 5 h, the reaction mixture was diluted with EA, washed with saturated aqueous NaHCO3 and brine, then dried (Na2SO4), concentrated, and purified by chromatography (EA/hexanes) to provide 12.9 g (69%) of tert-butyl (4-(tert-butyl)benzoyl)-L-tyrosinate. LCMS-ESI (m/z) calculated for C24H31NO4: 397.5; no m/z observed, tR=3.59 min (Method 1). 1H NMR (400 MHz, CDCl3) δ7.71-7.65 (m, 2H), 7.47-7.39 (m, 2H), 7.04 (t, J=5.7 Hz, 2H), 6.78-6.70 (m, 2H), 6.59 (d, J=7.5 Hz, 1H), 4.91 (dt, J=7.5, 5.6 Hz, 1H), 3.15 (qd, J=14.0, 5.6 Hz, 2H), 1.45 (s, 9H), 1.33 (s, 9H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([OH:15])=O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1>>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:18][CH2:17][CH2:16][C@H:12]2[C:13]([NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[O:15])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)CC1

Procedure:
Working analogously to Example 1, starting from N-[(phenyl-methoxy)carbonyl]-L-proline and 4-(aminomethyl)-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester, the expected product is obtained in the form of a creamy white solid (Yield=99%).
Reaction SMILES: C([O:8][CH2:9][C:10]([O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:41])[C:18]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:40])[CH2:31][O:32]CC4C=CC=CC=4)=[CH:25][CH:24]=3)=[CH:19][O:20]2)=[CH:15][CH:14]=1)=[O:11])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:8][CH2:9][C:10]([O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17](=[O:41])[C:18]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:40])[CH2:31][OH:32])=[CH:25][CH:24]=3)=[CH:19][O:20]2)=[CH:15][CH:14]=1)=[O:11]
Reactant: O=C(COCc1ccccc1)Oc1ccc(-c2coc3cc(OC(=O)COCc4ccccc4)ccc3c2=O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(CO)Oc1ccc(-c2coc3cc(OC(=O)CO)ccc3c2=O)cc1
Reaction time: 22 h

Procedure:
Benzyloxy-acetic acid 4-[7-(2-benzyloxy-acetoxy)-4-oxo-4H-chromen-3-yl]-phenyl ester 42 (1 gram, 1.82 mmol) is dissolved in ethyl acetate (50 ml) in a pressure vessel, Palladium on carbon (5%, 0.5 gram) added and the mixture stirred under an atmosphere of hydrogen (4 Kg) for 22 hours. The catalyst is removed by filtration, ethyl acetate distilled under vacuum. The crude 43 can be purified by column chromatography on silica gel using benzene:ethyl acetate (8:2) as eluant to get the desired product.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.[S:29]1[CH2:33][CH:32]([CH2:34][OH:35])[NH:31][CH2:30]1.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([N:31]1[CH:32]([CH2:34][OH:35])[CH2:33][S:29][CH2:30]1)=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Reactant: OCC1CSCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccccc1C(=O)N1CSCC1CO
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40 %

Procedure:
1.9 g (8.4 mmol) of o-benzoylbenzoic acid and 1.13 g (8.4 mmol) of 1-hydroxybenzotriazole hydrate were combined in 50 ml of methylene chloride and stirred for 20 minutes at room temperature. 1.0 g (8.4 mmol) of 4-thiazolidinemethanol was added, followed by 1.6 g (8.4 mmol) of ethyl-3-(3-dimethylaminopropyl)carbodiimide. The reaction mixture was stirred for 18 hours at room temperature and washed with water, first at pH 2.5 and then at pH 9.5. The organic phase was dried and evaporated to give a foam which was chromatographed on silica gel using 1:1/chloroform:ethyl acetate as the eluant to yield 1.1 g (40%) of the title compound. 1H NMR (CDCl3) δ: 7.4-7.85(m,9H); 4.65(m,1H) ; 4.20-4.40(m,2H); 3.96(m,1H); 3.60-3.70(m,2H); 3.0-3.30(m,2H). High Resolution Mass Spectrum: m/e=328.1015±0.8 ppm (calculated for C18H18NO3S).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][CH:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30])[C:16]([N:18]1[CH2:22][CH2:21][S:20][CH2:19]1)=[O:17]>>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][CH:15]([NH:14][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13])[C:16](=[O:17])[N:18]1[CH2:22][CH2:21][S:20][CH2:19]1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: NC(Cc1ccccc1F)C(=O)N1CCSC1
Product: O=C(NC(Cc1ccccc1F)C(=O)N1CCSC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
From 5-chloro-1H-indole-2-carboxylic acid and (±)-2-amino-3-(2-fluoro-phenyl)-1-thiazolidin-3-yl-propan-1-one. mp 216-217° C.