Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=C(C(C2N(C)N=C(C3C=CC=CC=3)N=2)O)C=CC=1)C.[CH3:23][N:24]1[CH:28]=[N:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:25]1.[F:35][C:36]1[CH:43]=[C:42]([F:44])[C:41]([O:45][CH3:46])=[CH:40][C:37]=1[CH:38]=[O:39]>>[F:35][C:36]1[CH:43]=[C:42]([F:44])[C:41]([O:45][CH3:46])=[CH:40][C:37]=1[CH:38]([C:28]1[N:24]([CH3:23])[N:25]=[C:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:27]=1)[OH:39]
Reactant: COc1cc(C=O)c(F)cc1F
Reactant: Cn1cnc(-c2ccccc2)n1
Agent: CCc1cccc(C(O)c2nc(-c3ccccc3)nn2C)c1
Product: COc1cc(C(O)c2nc(-c3ccccc3)nn2C)c(F)cc1F
Yield: 74.1 %

Procedure:
According to the procedure for Intermediate 370.2, 1-methyl-3-phenyl-1H-1,2,4-triazole (70 mg, 0.44 mmol) and Intermediate 391.1 (80 mg, 0.48 mmol) afforded 108 mg of Intermediate 391.2 as a white solid. LCMS 332.28 (M+H).
Reaction SMILES: [C:1]1([CH3:32])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:11]2[C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Br:33]N1C(=O)CCC1=O>O1CCCC1.O>[C:1]1([CH3:32])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[C:11]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:13]=[C:14]2[Br:33])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(S(=O)(=O)n2ccc(-c3ccc(F)cc3)c2-c2ccc(S(C)(=O)=O)cc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(Br)cc(-c3ccc(F)cc3)c2-c2ccc(S(C)(=O)=O)cc2)cc1
Reaction time: 5 h
Yield: 87 %

Procedure:
A solution of 1-(4-toluenesulfonyl)-2-(4-methylsulfonylphenyl)-3-(4-fluorophenyl)pyrrole (10.0 g, 0.021 mole) in 100 ml tetrahydrofuran was cooled in an ice bath and treated with N-bromosuccinimide (3.8 g, 0.021 mole) and stirred for five hours. The mixture was diluted with one liter of water and the resulting solid was collected by filtration, washed with water and dried. The crude product was recrystallized from ethyl acetate/hexane to yield 10.0 g (87% yield); m.p. 207°-207.5°.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]1([N:13]2[CH:17]=[C:16]([C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28](=[O:30])[CH3:29])[C@@H:23]([CH3:31])[CH2:22][NH:21]4)[CH:15]=[N:14]2)[CH2:12][CH2:11]1.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>ClCCCl>[CH:32]1([C:35]([N:21]2[C:20]3[C:25](=[CH:26][CH:27]=[C:18]([C:16]4[CH:15]=[N:14][N:13]([CH:10]5[CH2:12][CH2:11]5)[CH:17]=4)[CH:19]=3)[N:24]([C:28](=[O:30])[CH3:29])[C@@H:23]([CH3:31])[CH2:22]2)=[O:36])[CH2:34][CH2:33]1
Reactant: O=C(Cl)C1CC1
Reactant: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)cc2NC[C@@H]1C
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)cc2N(C(=O)C2CC2)C[C@@H]1C
Temperature: 50 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
N,N-Diisopropylethylamine (0.120 mL, 0.688 mmol) was added to a solution of (S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.068 g, 0.229 mmol) and cyclopropanecarbonyl chloride (0.031 mL, 0.344 mmol) in 1,2-dichloroethane (2.0 mL), and the mixture stirred at 50° C. for 16 h. The reaction mixture was concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 50-100% ethyl acetate-hexane) to afford (S)-1-(4-(cyclopropanecarbonyl)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.060 g, 72%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.68-0.77 (m, 1 H), 0.83-1.02 (m, 5 H), 1.02-1.08 (m, 5 H), 1.87-2.04 (m, 1 H), 2.12 (s, 3 H), 3.33 (m, 1 H), 3.74 (tt, J=7.33, 3.81 Hz, 1 H), 4.61 (m, 1 H), 4.69-4.86 (m, 1 H), 7.37-7.57 (m, 2 H), 7.65 (s, 1 H), 7.85 (s, 1 H), 8.25 (s, 1 H). MS (ESI, pos. ion) m/z 365. [M+1]+.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4](=[O:12])[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH:16][CH:17]1[O:33][C@H:32]([CH2:34][OH:35])[C@@H:22]([O:23][CH2:24][C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)[C@H:20]([OH:21])[C@@H:18]1[OH:19].CN(C=O)C.ON1C2C=CC=CC=2N=N1.[NH:51]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][C:53](O)=[O:54].C(N=C=NCCCN(C)C)C>>[NH:51]([C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:52][C:53]([NH:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4](=[O:12])[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:54].[OH:16][CH:17]1[O:33][C@H:32]([CH2:34][OH:35])[C@@H:22]([O:23][CH2:24][C:25]2[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=2)[C@H:20]([OH:21])[C@@H:18]1[OH:19]
Reactant: N[C@@H](CC(=O)OC1CCCCC1)C(=O)O
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(CO[C@H]2[C@H](O)[C@H](O)C(O)O[C@@H]2CO)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](CC(=O)OC1CCCCC1)C(=O)O
Temperature: 25 °C
Yield: 89.2 %

Procedure:
To a cold solution of Asp(O-cHex)-Man(4-MBzl) (46.7 g, 86.4 mmol) in DMF (100 mL) diisopropylethylamine (15 mL, 86.1 mmol) was added. N-Hydroxybezotriazole (14.0 g, 104 mmol) was added followed by Boc-Gly (16.6 g, 94.8 mmol). The reaction mixture was stirred in the cold for a few minutes, and N-ethyl-N'-(dimethylaminopropyl)carbodiimide (18.2 g, 94.9 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was concentrated to a small volume and poured into 1.5 L of aqueous 10% K2CO3. The precipitated product was collected by filtration and was washed with water to a neutral pH to afford the titled compound (50.6 g).
Reaction SMILES: [C-:1]#[N:2].[K+].[Cl:4][C:5]1[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[CH:14][C:13]=2[F:20])=[C:9]([CH3:21])[N:8]=[C:7]([NH2:22])[N:6]=1>CS(C)=O.CN(C=O)C.CCOC(C)=O>[NH2:22][C:7]1[N:6]=[C:5]([Cl:4])[C:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:1]#[N:2])=[CH:14][C:13]=2[F:20])=[C:9]([CH3:21])[N:8]=1
Reactant: Cc1nc(N)nc(Cl)c1Cc1ccc(CCl)cc1F
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: Cc1nc(N)nc(Cl)c1Cc1ccc(CC#N)cc1F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Potassium cyanide (0.056 g) was added to a stirred solution of the product from step (ii) (0.13 g) in DMSO (imL) and DMF (1 mL). The mixture was stirred at rt for 15 h and then diluted with EtOAc (10 mL). The organic phase was washed with water and brine then dried, filtered and evaporated to give the subtitle compound, 0.12 g.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28][CH:29]=[CH2:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:33]1[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:31])[CH2:28]/[CH:29]=[CH:30]/[C:33]4[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1cccc(I)c1
Reactant: C=CCC(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C/C=C/c4cccc(C)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 39, Step 1, using 1-{4′-[4-(1-hydroxy-but-3-enyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-iodotoluene.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[C:4]([CH:8]=[O:9])[CH:5]=[N:6][CH:7]=1.[CH3:11][Mg]Br.CCOCC>C1COCC1>[Br:1][C:2]1[C:3]([Cl:10])=[C:4]([CH:8]([OH:9])[CH3:11])[CH:5]=[N:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: O=Cc1cncc(Br)c1Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1cncc(Br)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a round bottom flask is added 5-bromo-4-chloro-pyridine-3-carbaldehyde (490 mg, 2.22 mmol) in 10 ml of THF at 0° C., followed by the addition of methylmagnesium bromide, 3M in ether (0.89 ml, 2.67 mmol). The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is concentrated. The residue is diluted with EtOAc/saturated NH4Cl. The organic layer is separated, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 287 mg of 1-(5-bromo-4-chloro-pyridin-3-yl)-ethanol.
Reaction SMILES: [NH2:1][C@@H:2]1[C:32](=[O:33])[N:4]2[C:5]([C:16]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[C:6]([S:9][CH2:10][C:11]3[CH:12]=[N:13][NH:14][CH:15]=3)[CH2:7][S:8][C@H:3]12.C[Si](C)(C)NC(N[Si](C)(C)C)=O.[NH2:46][C:47]1[S:48][CH:49]=[C:50](/[C:52](=[N:56]/[O:57][C:58](=[O:60])[CH3:59])/[C:53](Cl)=[O:54])[N:51]=1.C(=O)(O)[O-].[Na+]>C1COCC1.C(#N)C.C(OCC)(=O)C>[NH2:46][C:47]1[S:48][CH:49]=[C:50](/[C:52](=[N:56]/[O:57][C:58](=[O:60])[CH3:59])/[C:53]([NH:1][C@@H:2]2[C:32](=[O:33])[N:4]3[C:5]([C:16]([O:18][CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:17])=[C:6]([S:9][CH2:10][C:11]4[CH:15]=[N:14][NH:13][CH:12]=4)[CH2:7][S:8][C@H:3]23)=[O:54])[N:51]=1
Reactant: CC(=O)O/N=C(\C(=O)Cl)c1csc(N)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3cn[nH]c3)CS[C@H]12
Agent: C[Si](C)(C)NC(=O)N[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3cn[nH]c3)CS[C@H]12)c1csc(N)n1
Temperature: 35 °C
Reaction time: 0.17 h

Procedure:
Under nitrogen atmosphere, to a suspension of diphenylmethyl 7β-amino-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (30.2 g) in THF (800 ml) was added herein 1,3-bis(trimethylsilyl)urea (25.8 g) was added at the room temperature. The reaction mixture was warmed at 35° C. and dissolved, and then it was cooled below 0° C. A suspension of 2-(2-aminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetylchloride monohydrochiloride salt (17.93 g) in acetonitrile (200 ml) was dropped into the above reaction mixture below 0° C. After stirring at the same temperature for 10 minutes, it was poured into a mixture of ethyl acetate (1.2 l) and ice-water (1.5 l). The aqueous layer was adjusted at pH 6.5 with saturated sodium bicarbonate solution. The organic layer was separated, washed with brine (1.0 l), and dried over magnesium sulfate, and then evaporated until the volume amounted to 500 ml. The solution was poured into IPE (1.5 l). The resulting precipitate was filtered, dried under reduced pressure to give diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetamido]-3-[(pyrazol-4-yl)methylthio]-3-cephem-4-carboxylate (41.3 g) as powder.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:11]I.O>CN(C=O)C>[Br:1][C:2]1[C:7]([O:8][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccnc1Br
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, to a solution of 2-bromo-3-hydroxypyridine (10.00 g) in DMF (100 ml) was added sodium hydride (60% oil, 2.5 g) at 0° C., and the mixture was stirred for 30 minutes. To the reaction mixture was added methyl iodide (4.0 ml), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated. Under reduced pressure, the residue was separated and purified with column chromatography (ethyl acetate/hexane=1:2) to give 2-bromo-3-methoxypyridine (9.24 g) as colorless crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]([CH3:10])=[N:3]1.[CH:11]([O:14][C:15]([N:17]1[C:26]2[C:21](=N[C:23]([C:27]([F:30])([F:29])[F:28])=[CH:24][CH:25]=2)[CH:20]([NH:31][CH2:32][C:33]2[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([C:43]([F:46])([F:45])[F:44])[CH:34]=2)[CH2:19][CH:18]1[CH2:47][CH3:48])=[O:16])([CH3:13])[CH3:12].N1C=CC=C[CH:50]=1>ClCCl>[CH:11]([O:14][C:15]([N:17]1[C:26]2[C:21](=[CH:50][C:23]([C:27]([F:29])([F:30])[F:28])=[CH:24][CH:25]=2)[C@H:20]([N:31]([CH2:32][C:33]2[CH:38]=[C:37]([C:39]([F:42])([F:40])[F:41])[CH:36]=[C:35]([C:43]([F:44])([F:46])[F:45])[CH:34]=2)[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH:5]=2)=[O:8])[CH2:19][C@@H:18]1[CH2:47][CH3:48])=[O:16])([CH3:13])[CH3:12]
Reactant: CCC1CC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Reactant: c1ccncc1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: ClCCl
Product: CC[C@H]1C[C@@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)c2cc(C)nn2C)c2cc(C(F)(F)F)ccc2N1C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.8 %

Procedure:
Add a solution of 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (50 mg, 0.31 mmol) in dry dichloromethane (0.5 mL) to a solution of 4-(3,5-bis-trifluoromethyl-benzylamino)-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (159 mg, 0.28 mmol) in dry dichloromethane (2 mL) and pyridine (0.045 mL, 0.56 mmol) at 0° C. Stir the mixture at room temperature for 3 h. Add a solution of 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (57 mg, 0.36 mmol) in dry dichloromethane (0.5 mL) and stir the mixture overnight. Remove the solvents under reduced pressure and purify the residue by silica gel flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (106 mg, 56%). MS (ES+): 680 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].[CH:12](O)=[O:13]>>[C:12](=[N:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11])=[O:13]
Reactant: Nc1ccc(C(=O)O)cc1O
Reactant: O=CO
Product: O=C=Nc1ccc(C(=O)O)cc1O
Temperature: 25 °C

Procedure:
A solution of 4-amino-3-hydroxybenzoic acid (10.0 g) in 85% formic acid (60 mL) was heated at reflux for 3 h and then cooled to room temperature. The precipitated solid was filtered, washed with methanol, and dried under vacuum to produce 4-carbonylamino-3-hydroxybenzoic acid. A portion of this material (1.00 g) and zinc chloride (3.76 g) were suspended in m-xylene (135 L), and treated with 2 drops of concentrated sulfuric acid. The reaction mixture was azeotroped for 8 h, cooled to room temperature, and treated with water (20 mL). The resulting solid was collected by filtration, washed with water, and dried under high vacuum to afford benzoxazole-6-carboxylic acid. A portion of this material (0.80 g) was suspended in anhydrous dichloromethane (30 mL) under a nitrogen atmosphere and treated with oxalyl chloride (12.3 mL of a 2M solution in dichloromethane) and 1 drop of DMF. This suspension was stirred at room temperature for 16 h. The solvent was evaporated under reduced pressure. The residue was suspended in dichloromethane (20 mL) and poured into an ice-cold 2M solution of ammonia in methanol (122 mL). The mixture was stirred at 0° C. for 1 h, and concentrated under reduced pressure. The solid residue was washed with dichloromethane and water, and dried under high vacuum to afford benzoxazole-6-carboxamide. A portion of this material (80 mg) was dried by azeotropic distillation with toluene (5.3 mL) and treated with 3-chlorophenyl isocyanate (83.3 mg). The mixture was heated at reflux for 6 h, allowed to cool to room temperature, and treated with methanol (5 mL). The precipitated solid was collected by filtration, washed with methanol and dichloromethane, and dried under high vacuum to yield the title compound. 1H NMR (DMSO-d6) δ 7.18 (d, 1H, J=8.0 Hz), 7.39 (t, 1H, J=8.0 Hz), 7.49 (d, 1H, J=8.0 Hz), 7.86 (d, 1H, J=1.6 Hz), 7.97 (d, 1H, J=8.4 Hz), 8.09 (dd, 1H, J=8.4, 1.6 Hz), 8.50 (s, 1H), 8.98 (s, 1H), 10.90 (s, 1H), 11.24 (s, 1H). MS (ESI) m/z 314, 316.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:21]=[C:20]2[C:13]([NH:14][CH:15]=[C:16]2[CH2:17][CH2:18][NH2:19])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37])(OCC)=O>C(N(CC)CC)C>[CH2:2]([O:9][C:10]1[CH:21]=[C:20]2[C:13](=[CH:12][CH:11]=1)[NH:14][CH:15]=[C:16]2[CH2:17][CH2:18][N:19]1[C:31](=[O:32])[C:30]2[C:29](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:28]1=[O:37])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: NCCc1c[nH]c2ccc(OCc3ccccc3)cc12
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCc1c[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Yield: 99.3 %

Procedure:
To a stirred suspension of 5-benzyloxytryptamine hydrochloride (1.0 g in 10 mL of dry tetrahydrofuran) was added triethylamine (0.50 mL) followed by N-carbethoxyphthalimide (750 mg) and the mixture heated to reflux on an oil bath. After 48 hours the reaction was cooled to room temperature, filtered and the filtrate concentrated in vacuo. The resulting solid was suspended in a mixture of hexane/methylene chloride (2.5:1, 50 mL) and filtered to give the title compound (1.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][NH:6][C:7]([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH2:14][C@@H:13]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[C@H:12]1[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[S:8].C(N(CC)CC)C.C(OC(Cl)=O)C.[CH2:55]([CH2:57][NH2:58])[OH:56]>C(Cl)Cl.CCOC(C)=O>[OH:56][CH2:55][CH2:57][NH:58][C:36]([CH2:35][CH2:34][CH2:33]/[CH:32]=[CH:31]\[CH2:30][C@H:12]1[C@@H:13]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH2:14][C@@H:15]([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C@@H:11]1[CH2:10][O:9][C:7](=[S:8])[NH:6][CH2:5][C:4]1[CH:39]=[CH:40][CH:41]=[C:2]([Cl:1])[CH:3]=1)=[O:37]
Reactant: NCCO
Reactant: O=C(O)CCC/C=C\C[C@H]1[C@H](COC(=S)NCc2cccc(Cl)c2)[C@@H](OC2CCCCO2)C[C@H]1OC1CCCCO1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CCC/C=C\C[C@@H]1[C@@H](COC(=S)NCc2cccc(Cl)c2)[C@H](OC2CCCCO2)C[C@@H]1OC1CCCCO1)NCCO
Temperature: 25 °C
Yield: 61.2 %

Procedure:
A solution of acid 7 (60 mg, 0.10 mmol) and triethylamine (30 mg, 0.30 mmol) in CH2Cl2 (2 mL) was cooled to 0° C. and ethylchloroformate (11 μL, 0.12 mmol) was added. After 0.5 h ethanolamine (7.2 μL, 0.12 mmol) was added and the reaction was allowed to warm to room temperature for 12 h. The reaction was diluted with EtOAc and washed with 1N HCl, saturated aqueous NaHCO3 and brine. The organic portion was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 100% EtOAc followed by 19:1 EtOAc/MeOH) provided 40 mg of the above titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[N:10]([O-:12])=[O:11].[Na+].[N+]([O-])(O)=O.O>C(O)(=O)CC>[N+:10]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[OH:9])([O-:12])=[O:11]
Reactant: COc1cccc(O)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])O
Solvent: CCC(=O)O
Product: COc1ccc([N+](=O)[O-])c(O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 38102.4 %

Procedure:
To a solution of 3-methoxyphenol (11.1 g, 0.09 mmol) in propionic acid (90 mL) at 0° C., was added NaNO2 (6.3 g, 0.09 mmol, in 5 mL water) dropwise. The mixture was stirred at 0° C. for 1 hour. Concentrated nitric acid (12 mL) was then added dropwise and the mixture was stirred for 1 hour at 0° C. and 2 hour at r.t. Water (30 mL) was subsequently added and the resulting precipitate was collected and washed with 50% propionic acid, giving 2-nitro-5-methoxyphenol as yellow solid (5.8 g, 40% yield).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18]([O-:20])=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:22][CH:23]=1
Reactant: O=C([O-])C1=Cc2cc(OCc3ccc(F)cc3)ccc2CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1=Cc2cc(OCc3ccc(F)cc3)ccc2CCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 103.3 %

Procedure:
To 2-(4-fluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (462 mg, 1.42 mmol) dissolved in a mixed solvent of methanol (5 ml) and THF (5 ml) was added a 1N aqueous solution of sodium hydroxide (4.3 ml), and the resulting mixture was stirred at 50° C. for 2 hours. The reaction mixture was mixed with 1 N hydrochloric acid (4.3 ml) at 0° C., was concentrated under reduced pressure and was mixed with water, and an insoluble material was collected by filtration. The insoluble material was washed with water and was dried under reduced pressure to obtain 2-(4-fluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (458 mg).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:8][CH:7]=1)[CH:2]=[C:3]([CH3:5])[CH3:4].S(Cl)(Cl)=O.[CH2:21](O)[CH:22]([CH3:24])[CH3:23]>N1C=CC=CC=1.C1C=CC=CC=1>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([CH3:16])[C:13]([O:15][CH2:21][CH:22]([CH3:24])[CH3:23])=[O:14])=[CH:10][CH:11]=1)[CH:2]=[C:3]([CH3:5])[CH3:4]
Reactant: CC(C)=CCc1ccc(C(C)C(=O)O)cc1
Reactant: CC(C)CO
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(C)=CCc1ccc(C(C)C(=O)OCC(C)C)cc1
Temperature: 4 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of 21.8 g of 2-(p-prenylphenyl)propionic acid in 17.6 ml of pyridine and 200 ml of benzene was added dropwise a solution of 7.9 ml of thionyl chloride in 15 ml of benzene with stirring at 4° C. After one hour, 14.8 g of isobutyl alcohol was added. The mixture was stirred at room temperature for one hour and then at 60° C. for 2 hours. After cooling, the solution was washed with water, 2 N hydrochloric acid, water, 5% aqueous sodium hydroxide and water successively, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 20.1 g of isobutyl 2-(p-prenylphenyl)propionate. b.p. 126°-127° C./0.10 mmHg, IR νmaxneat ; 1730 cm-1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>CN(C)C=O.CCOCC>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:18][C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(COc1ccc([N+](=O)[O-])cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
27.6 g (0.2 mol) of 4-nitrophenol are dissolved in 300 ml of dimethylformamide and, after addition of 27.6 g (0.2 mol) of dried potassium carbonate, the mixture is stirred at room temperature for 45 minutes. Thereafter, 50.4 g (0.22 mol=34.9 ml) of benzyl bromoacetate are added dropwise, while stirring, and the suspension is then heated at 80° C. (oil bath temperature) for 5 hours. The oil bath is then switched off and the suspension is stirred for a further 15 hours, during which the reaction mixture slowly comes to room temperature. The undissolved inorganic salts are filtered off with suction and the mother liquor is concentrated to dryness in vacuo. The residue is dissolved in methylene chloride and, after washing twice with water, the solution is dried over sodium sulphate, filtered and concentrated. The product obtained is suspended in ether and filtered off with suction. Yield: 55.4 g (96.4% of theory).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16](O)=[O:17]>>[ClH:10].[NH2:11][CH2:12][C:13](=[O:19])[CH2:14][CH2:15][C:16]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1])=[O:17]
Reactant: OCc1ccccc1F
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: NCC(=O)CCC(=O)OCc1ccccc1F
Reaction time: 27 h

Procedure:
From 2-fluorobenzyl alcohol (5.7 g; 45 mmol) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol). The reaction was complete after 27 h at 100° C. The yield was 0.64 g (44%). Mp 91-94° C. (dec.)