Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[OH:13])[CH3:2].[Br:14][CH2:15][CH2:16][CH2:17]O.C(P(CCCC)CCCC)CCC.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.C1(C)C=CC=CC=1>[Br:14][CH2:15][CH2:16][CH2:17][O:13][C:5]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:4]=1[NH:3][CH2:1][CH3:2]
Reactant: CCNc1ccc([N+](=O)[O-])cc1O
Reactant: OCCCBr
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCNc1ccc([N+](=O)[O-])cc1OCCCBr
Reaction time: 8 h

Procedure:
2-Ethylamino-5-nitro-phenol (2.50 g, 13.7 mmol) was azeotroped with toluene to ensure dryness, then dissolved in Tetrahydrofuran (300 mL). 3-Bromo-1-propanol (1.50 mL, 16.6 mmol), Tributylphosphine (5.5 mL, 22 mmol), and 40% w/w DEAD in Toluene (40:60, Diethyl Azodicarboxylate:Toluene, 9.6 g) were added, and the reaction was stirred under an atmosphere of Nitrogen overnight. Solvent was partially removed (300 mL removed) and the mixture was diluted with 300 mL EtOAc, then washed with satd. sodium bicarbonate (100 mL), water (2×100 mL) and brine (100 mL). The organics were dried over sodium sulfate and conc. onto 15 g SiO2 and chromatographed (ISCO, 120 g, 0-30% EtOAc:Hex) to afford [2-(3-Bromo-propoxy)-4-nitro-phenyl]-ethyl-amine as a yellow solid. [2-(3-Bromo-propoxy)-4-nitro-phenyl]-ethyl-amine was dissolved in Tetrahydrofuran (200 mL) and Sodium hydride, 60% disp. in mineral oil 0.55 g) was added. After 2 h, no reaction was observed, so N,N-Dimethylformamide (10 mL) was added. After overnight stirring, the reaction was near completion and was quenched with water, diluted with 500 mL ether then washed with water (50 mL), satd. sodium bicarbonate (2×50 mL) and brine (100 mL), dried over sodium sulfate and conc. in vacuo onto 8 g SiO2, then chromatographed (ISCO, 0-30% EtOAc:Hex, 120 g SiO2). The isolated product was ˜85% purity, with the alkyl bromide as the major impurity. The mixture was redissolved in DMF (20 mL). Potassium tert-Butoxide (0.23 g, 2.0 mmol) was added and the mixture stirred under nitrogen for 1 h, then water (100 mL) was added. The precipitate was cooled for 20 min, then collected by filtration, washing with water (2×50 mL) to give 9-Ethyl-3-nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (1.99 g, 48%). 1H-NMR (CDCl3): 7.83 (dd, 1H, J=2.5, 8.4 Hz), 7.72 (d, 1H, J=2.5 Hz), 6.61 (d, 1H, J=8.4 Hz), 4.25 (t, 2H, J=6.4 Hz), 3.60 (t, 2H, J=5.4 Hz), 3.38 (q, 2H, J=7.2 Hz), 2.11 (m, 2H), 1.25 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@H:11]([OH:12])[CH:10]=[CH:9][CH2:8][O:7]1)=[O:5])[CH3:2].[CH3:13][C:14](OC(C)=O)=[O:15]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCN(CC)CC>[CH2:1]([O:3][C:4]([C@H:6]1[C@H:11]([O:12][C:14](=[O:15])[CH3:13])[CH:10]=[CH:9][CH2:8][O:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1OCC=C[C@H]1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1OCC=C[C@H]1OC(C)=O
Temperature: 25 °C

Procedure:
To a solution of trans-3-hydroxy-3,6-dihydro-2H-pyran-2-carboxylic acid ethyl ester (70 mg, 0.41 mmol) and DMAP (24 mg, 0.2 mmol) in CH2Cl2-Et3N (9:1, 5 mL) was added Ac2O (54 mg, 0.53 mmol). The resulting solution was stirred at ambient temperature for 2 H. The solution was diluted with CH2C12 (40 mL), washed with H2O (20 mL×2), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography with 20% EtOAc-hexane.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][C:24]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[S:26][C:25]=1[C:35]([NH2:37])=[O:36]>C(O)(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2([NH:23][C:24]3[CH:28]=[C:27]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=4)[S:26][C:25]=3[C:35](=[O:36])[NH:37]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)N1CCC2(CC1)NC(=O)c1sc(-c3ccncc3)cc1N2
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 51.7 %

Procedure:
To a stirred solution of 1-acetyl-4-piperidone (0.130 g, 0.920 mmol) and p-toluenesulfonic acid monohydrate (0.004 g, 0.02 mmol) in acetic acid (4 mL) was added 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.050 g, 0.23 mmol). The mixture was heated at 80° C. for 5 h. Then, the reaction was allowed to cool to room temperature and concentrated. The obtained residue was dissolved in methanol (25 mL) and the solution was stirred with solid NaHCO3 (1.5 g) for 20 min. Then, the solution was filtered, and the filtrate was concentrated. The obtained residue was triturated with H2O. The obtained yellow solid was triturated with hot ethyl acetate to give the title compound (0.0407 g, 52%) as a yellow solid:
Reaction SMILES: [In].[CH3:2][O:3][CH:4]([O:7][CH3:8])[CH:5]=[O:6].[CH2:9](Br)[CH:10]=[CH2:11]>C(O)C>[OH:6][CH:5]([CH2:11][CH:10]=[CH2:9])[CH:4]([O:7][CH3:8])[O:3][CH3:2]
Reactant: COC(C=O)OC
Reactant: C=CCBr
Agent: [In]
Solvent: CCO
Product: C=CCC(O)C(OC)OC
Temperature: 40 °C
Reaction time: 3 h

Procedure:
Indium powder (0.17 mol, 0.75 eq., 20 g, 100 mesh) was added to an ethanol (200 mL) solution containing 2,2-dimethoxyacetaldehyde (0.23 mol, 1.0 eq., 35 mL, 60 wt % solution in water) and allyl bromide (0.28 mol, 1.2 eq., 24 mL). The suspension was stirred at 40° C. for 3 h. The slurry was then centrifuged and the supernatant was decanted. The residual pellet was suspended in and washed 3 times with ethanol (3×150 mL). The combined supernatants were filtered and evaporated at reduced pressure to provide a thick oil (45° C., clear yellow oil, 56 g). The crude product resulting (25 g) was extracted with brine and ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered and evaporated at reduced pressure. Yield was 11 g (89%) of semi-purified oil. The product was purified by silica chromatography with a hexanes/ethyl acetate gradient on a Biotage SP-4 (FLASH 40+M) purification system. Purified yield 5.2 g (42%) clear colorless oil.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[C:10](=[O:21])[NH:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH:14]=2)=[O:7])=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CN1C(=O)CCC1>[O:21]=[C:10]1[C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:3][CH:4]=2)=[CH:14][C:13]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:12][NH:11]1
Reactant: O=C(Nc1cc(-c2ccncc2)c[nH]c1=O)c1ccc(Br)cc1
Reactant: C1CCNCC1
Solvent: CN1CCCC1=O
Product: O=C(Nc1cc(-c2ccncc2)c[nH]c1=O)c1ccc(N2CCCCC2)cc1
Temperature: 160 °C
Yield: 43 %

Procedure:
4-Bromo-N-(1,2-dihydro-2-oxo-5-(pyridin-4-yl)pyridin-3-yl)benzamide (30 mg, 0.081 mmol) I-20 was placed in a microwave tube equipped with a stirrer bar. NMP (0.75 mL) was added, followed by piperidine (1.5 mL). The reaction vessel was heated at 160° C. for 2 hours in a microwave. After cooling, the solvent and excess piperidine were removed in vacuo. The crude compound was recrystallized from methanol to give the title compound as a white solid (13 mg, 43% yield). MS (ES+) m/e=375. 1H NMR (DMSO-d6) δH 1.54-1.65 (6H, m), 3.30-3.38 (4H, m), 7.02 (2H, d), 7.61 (2H, d), 7.72-7.80 (1H, m), 7.78 (2H, d), 8.59 (2H, d), 8.77 (1H, d), 9.13 (1H, s), 12.58 (1H, bs).
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3].[CH3:10][C:11]([C:13]1[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=1)=[O:12].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:9][O:8][C:1]1[CH:7]=[CH:6][CH:5]=[CH:4][C:2]=1[O:3][C:16]1[CH:17]=[CH:18][C:13]([C:11](=[O:12])[CH3:10])=[CH:14][CH:15]=1
Reactant: COc1ccccc1O
Reactant: CC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1Oc1ccc(C(C)=O)cc1

Procedure:
0.15 ml of guaiacol 67, 167 mg of 4-fluoroacetophenone 68 and 335 mg of potassium carbonate are heated in 5 ml of dimethyl sulfoxide at 170° C. in a microwave for 10 min. The reaction solution is poured into water, and the emulsion is extracted three times with an ethyl tert-butyl ether. The combined organic phase is extracted twice with 1 N NaOH and once with saturated NaCl solution, dried and concentrated in vacuo. 240 mg of the desired product are obtained. C15H14O3 (242.28) MS (ESI): 215.10 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[CH2:26][OH:27]>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:21]3[CH2:25][CH2:24][CH2:23][C@H:22]3[CH2:26][OH:27])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: OC[C@@H]1CCCN1
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CCC[C@H]1CO

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and (S)-1-pyrrolidin-2-yl-methanol (CAN 23356-96-9) as starting materials, MS (EI): m/e=368.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.C(Cl)Cl.[Br:20]N1C(=O)CCC1=O>>[Br:20][CH:10]([C:9](=[O:16])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)CC(=O)Cc1ccc(Cl)cc1
Solvent: ClCCl
Product: CCOC(=O)C(Br)C(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.4 %

Procedure:
In a 250 mL round bottomed flask, to a solution of ethyl 4-(4-chlorophenyl)-3-oxobutanoate (4.04 g, 16.8 mmol) in methylene chloride (100 mL, 2000 mmol) was added N-bromosuccinimide (3.13 g, 17.6 mmol) and the mixture was stirred for 3 h at room temperature. Reaction was quenched via addition of a 10% aqueous solution of NaHSO3 (50 mL), and the resulting biphasic mixture was vigorously stirred for 15 minutes. The reaction mixture was transferred to a separatory funnel, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (30 mL). The combined organic layers were washed with a saturated aqueous solution of NaHCO3 (50 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford ethyl 2-bromo-4-(4-chlorophenyl)-3-oxobutanoate (5.23 g, yield 97.5%) as a yellow oil that was used without further purification. LC/MS (FA) ES− 317, 319, 321.
Reaction SMILES: CC1[C@@H]2[CH2:8][C@H:9]([O:34]C(/C=C/C3N=CN(C)C=3)=O)[C@@:10]3(C)[O:14][C@@:13]([O:31]C)(C(CO[C@@H]4OC[C@@H](O)[C@@H](O)[C@@H]4OC(C)=O)=C[C@@H]2[C@@H](C(C)C)CC=1)[CH:12]=[CH:11]3.CCN(CC)CC.CC(OC(C)=O)=[O:57]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:8][C:9]([CH2:10][C:11]([CH2:12][C:13]([OH:31])=[O:14])=[O:57])=[O:34]
Reactant: CC(=O)OC(C)=O
Reactant: CO[C@]12C=C[C@](C)(O1)[C@@H](OC(=O)/C=C/c1cn(C)cn1)C[C@H]1C(C)=CC[C@H](C(C)C)[C@H]1C=C2CO[C@@H]1OC[C@@H](O)[C@@H](O)[C@@H]1OC(C)=O
Agent: CN(C)c1ccncc1
Agent: CO[C@]12C=C[C@](C)(O1)[C@@H](OC(=O)/C=C/c1cn(C)cn1)C[C@H]1C(C)=CC[C@H](C(C)C)[C@H]1/C=C\2CO[C@@H]1OC[C@@H](O)[C@@H](O)[C@@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)CC(=O)CC(=O)O
Reaction time: 1 h
Yield: 83.3 %

Procedure:
Bis-Acetoxy Eleutherobin (2800) and Methyl-Ketal Precursors of Eleuthosides A and B (2900+3000) as illustrated in FIG. 27. To a solution of natural eleutherobin (4) (10.0 mg, 0.015 mmol, 1.0 equivalent), Et3N (6.0 mL, 0.043 mmol, 3.0 equivalents), and 4-DMAP (0.40 mg, 0.0033 mmol, 0.2 equivalents) in CH2Cl2 (0.60 mL) at 0° C. was added Ac2O (1.0 M in CH2Cl2, 0.017 mL, 0.017 mmol, 1.1 equivalents) and the reaction was stirred at the same temperature for 1 hour. The reaction mixture was then quenched by addition of saturated NaHCO3 solution (0.50 mL) and extracted with CH2Cl2 (5×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated to provide a crude residue which was was purified by flash chromatography (silica gel, 2% MeOH in CH2Cl2) to afford triacetate 2800 (1.8 mg, 16%) along with an inseperable mixture of eleuthosides 2900 and 3000 (7.8 mg, 73%) as well as recovered 1 (0.5 mg, 5%). 2800. Rf=0.44 (silica gel, MeOH-- CH'2Cl2,1:20); [α]D -67.3 (c 1.2, CHCl3); FT-IR (neat) nmax 2962, 1746, 1740, 1644, 1634, 1372, 1226, 1156, 1068, 759, 668, 617 cm-1.
Reaction SMILES: S(O[CH2:12][C:13]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:16][CH2:15][CH2:14]1)(C1C=CC(C)=CC=1)(=O)=O.[C-:22]#[N:23].[Na+]>CS(C)=O.O>[C:22]([CH2:12][C:13]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][CH2:15][CH2:16]1)#[N:23]
Reactant: [C-]#N
Reactant: CCOC(=O)C1(COS(=O)(=O)c2ccc(C)cc2)CCC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1(CC#N)CCC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 41.1 %

Procedure:
To a stirred solution of Intermediate 220A (0.5 g, 1.601 mmol) in DMSO (2.5 mL) was added NaCN (0.196 g, 4.00 mmol) and the reaction mixture was stirred at 80° C. for 16 h. The reaction mixture was diluted with water and extracted with diethyl ether (3×30 mL) The combined organic layer was washed with water, dried over Na2SO4, filtered and the filtrate concentrated to afford Intermediate 220B as a brown oil (0.110 g, 41% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.19-4.01 (m, 2H), 3.01-2.97 (m, 2H), 2.45-2.32 (m, 2H), 2.08-1.83 (m, 4H), 1.25-1.18 (m, 3H).
Reaction SMILES: C(O[C:6]([C:8]1[N:13]=[C:12](O)[C:11]2[CH:15]=[C:16]([S:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:17][C:10]=2[C:9]=1[OH:25])=[O:7])CCC.C([O:30][C:31]([C:33]1C(O)=C2C=C(SC3C=CC=CC=3)SC2=C(O)[N:38]=1)=[O:32])CCC>>[OH:25][C:9]1[C:10]2[S:17][C:16]([S:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][C:11]=2[CH:12]=[N:13][C:8]=1[C:6]([NH:38][CH2:33][C:31]([OH:32])=[O:30])=[O:7]
Reactant: CCCCOC(=O)c1nc(O)c2cc(Sc3ccccc3)sc2c1O
Reactant: CCCCOC(=O)c1nc(O)c2sc(Sc3ccccc3)cc2c1O
Product: O=C(O)CNC(=O)c1ncc2cc(Sc3ccccc3)sc2c1O

Procedure:
The title compound was prepared from a mixture of 4,7-dihydroxy-2-phenylsulfanyl-thieno[3,2-c]pyridine-6-carboxylic acid n-butyl ester and 4,7 dihydroxy-2-phenylsulfanyl-thieno[2,3-c]pyridine-5-carboxylic acid n-butyl ester, example 17.a, under conditions analogous to experimental conditions 5.a. The products were obtained as a mixture of the two isomers; MS: (+) m/z 437.91, 439.91 (M+1, 79Br/81Br).
Reaction SMILES: [Cl-].[C:2]([C:5]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][NH+:14]([CH3:16])[CH3:15])[CH:8]=[CH:7][C:6]=1[Cl:17])([OH:4])=O.[NH2:18][C:19]1[CH:41]=[CH:40][C:22]2[CH2:23][CH2:24][C:25]3[C:26]([C:37]([NH2:39])=[O:38])=[N:27][N:28]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[C:29]=3[C:21]=2[CH:20]=1>>[Cl:17][C:6]1[C:5]([C:2]([NH:18][C:19]2[CH:41]=[CH:40][C:22]3[CH2:23][CH2:24][C:25]4[C:26]([C:37]([NH2:39])=[O:38])=[N:27][N:28]([C:30]5[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=5)[C:29]=4[C:21]=3[CH:20]=2)=[O:4])=[N:10][C:9]([S:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])=[CH:8][CH:7]=1
Reactant: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(N)cc1-2
Reactant: C[NH+](C)CCSc1ccc(Cl)c(C(=O)O)n1
Agent: [Cl-]
Product: CN(C)CCSc1ccc(Cl)c(C(=O)Nc2ccc3c(c2)-c2c(c(C(N)=O)nn2-c2ccc(F)cc2)CC3)n1

Procedure:
The title compound was synthesized from 0.355 g of the title compound of Step 1 and the title compound of Example 244 (0.32 g) by the same procedure used in Example 255. The title compound is a white solid (0.49 g, 87%). Its structure was confirmed by 1H NMR and LC/MS: 1H NMR (CD3CN): δ 2.18 (s, 6H), 2.57 (m, 2H), 2.85 (m, 4H), 3.00 (m, 4H), 3.26 (m, 2H), 5.88 (s, 1H), 6.94 (d, 1H), 7.27-7.38 (m, 5H), 7.47-7.62 (m, 3H), 7.69 (d, 1H, J=9 Hz), 9.40 (s, 1H). ESI mass spectrum for C28H27ClFN6O2S+: 565 (M+1).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].C(N(CC)CC)C.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOC(C)=O.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[C:1]([O:9][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: BrCc1ccccc1
Reactant: C=CCCCCC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CCCCCC(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
To a solution of 6-heptenoic acid (4.71 g, 36.75 mmol) in AcOEt (80 mL) at 0° C. were successively added triethylamine (15.3 mL, 110.24 mmol), benzyl bromide (13.1 mL, 110.24 mmol) and Bu4NI (6.79 g, 18.37 mmol). The reaction mixture was stirred at 0° C. for 2 H and concentrated in vacuo. The residue is taken up in AcOEt, the organic phase was washed with a saturated aqueous NaHCO3 and H2O. The organic phase was dried over MgSO4 and the solvent removed in vacuo. Flash chromatography of the residue on silica gel (n-heptane/EtOAc, 9:1) provided compound C-9 (6.00 g; 75%) as a colorless oil. 13C-NMR (62.89 MHz, CDCl3): 24.42, 28.34, 33.37, 34.13, 66.08, 114.73, 128.19, 128.55, 136.16, 138.37, 173.43.
Reaction SMILES: [I:1][CH:2]1[CH:6]2[O:7][C:8](=[O:14])[CH:9]3[CH:10]([C:11]([OH:13])=O)[CH:3]1[CH2:4][CH:5]23.Cl.[NH2:16][CH2:17][C:18]#[N:19].F[P-](F)(F)(F)(F)F.N1([PH+](N2CCCC2)N2CCCC2)CCCC1.C(N(CC)CC)C>CN(C)C=O>[C:17]([CH2:18][NH:19][C:11]([CH:10]1[CH:3]2[CH2:4][CH:5]3[CH:6]([CH:2]2[I:1])[O:7][C:8](=[O:14])[CH:9]13)=[O:13])#[N:16]
Reactant: O=C(O)C1C2CC3C(OC(=O)C31)C2I
Reactant: N#CCN
Agent: C1CCN([PH+](N2CCCC2)N2CCCC2)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCNC(=O)C1C2CC3C(OC(=O)C31)C2I
Temperature: 0 °C
Reaction time: 4.5 h

Procedure:
To (3R/S,3aR/S,5S/R,6S/R,6aS/R,7S/R)-6-iodo-2-oxohexahydro-2H-3,5-methano-cyclopenta[b]furan-7-carboxylic acid (1.51 g, 4.90 mmol) was added aminoacetonitrile hydrochloride (502 mg, 5.43 mmol) and) benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (2.56 g, 4.91 mmol. After adding dimethylformamide (10 mL), the reaction mixture was cooled to 0° C. and triethylamine (1.7 mL, 12 mmol) was added. After stirring the reaction mixture at ambient temperature for 4.5 h, the product was extracted into ethyl acetate. The combined organic phases were washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. Chromatography of the residue on silica gel with 1:1 ethyl acetate:hexanes eluent gave (3R/S,3aR/S,5S/R,6S/R,6aS/R,7S/R)-N-(cyanomethyl)-6-iodo-2-oxohexahydro-2H-3,5-methanocyclopenta[b]furan-7-carboxamide as a colorless syrup.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C@@H:8]([CH2:28]Cl)[CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[SH:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:30])[NH:7][C@H:8]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:28][S:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[NH2:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccccc1S
Reactant: CC(C)(C)OC(=O)N[C@@H](CCl)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CSc1ccccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.2 %

Procedure:
A solution of tert-butyl[(2R)-1-{[tert-butyl(diphenyl)silyl]oxy}-3-chloropropan-2-yl]carbamate (58, 390 mg, 0.87 mmol) in dry DMF (2.5 ml) was treated with neat 2-aminobenzenethiol (351 mg, 2.8 mmol) followed by cesium carbonate (560 mg, 1.72 mmol). The mixture was stirred at room temperature for 3 h, diluted with DCM and washed with 1M NaOH followed by saturated NaHCO3, dried over MgSO4, filtered and concentrated to afford the title compound (482 mg) as an oil, which was submitted without further purification to the next synthetic step. MS: m/z=537.2 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([NH:12][CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[OH:15])[CH2:9]2)=[CH:4][CH:3]=1.OC1C=C2C(CCC(NCC(C3C=CC=C(Cl)C=3)O)C2)=CC=1.Br[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47]>>[C:46]([CH2:45][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([NH:12][CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[OH:15])[CH2:9]2)=[CH:4][CH:3]=1)([O:48][CH2:49][CH3:50])=[O:47]
Reactant: Oc1ccc2c(c1)CC(NCC(O)c1ccccc1)CC2
Reactant: CCOC(=O)CBr
Agent: Oc1ccc2c(c1)CC(NCC(O)c1cccc(Cl)c1)CC2
Product: CCOC(=O)COc1ccc2c(c1)CC(NCC(O)c1ccccc1)CC2

Procedure:
Among the preparative methods of the products of formula (A) hereinabove, an 0-alkylation is described that, starting from 2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-phenylethanol or from 2-[(7-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)amino]-1-(3-chlorophenyl)ethanol, by reaction with ethyl bromoacetate gives the 2-[(7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl)-amino]-1-phenylethanol or the 2-[(7-carbethoxymethoxy-1,2,3,4-tetrahydronaphth-2-yl)-amino]-1-(3-chlorophenyl)ethanol. This reaction does not actually give good results because the yield in end product is very low.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:24]C2CCCCO2)[CH:18]([F:23])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:31]C2CCCCO2)[CH2:12][C@@H:11]1O.[N+](=C)=[N-].C1(C)C=CC(S([Cl:52])(=O)=O)=CC=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([OH:24])[CH:18]([F:23])[CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([OH:31])[CH2:12][C@H:11]1[Cl:52]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCC(F)[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Agent: C=[N+]=[N-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC(F)[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@H](Cl)C[C@H]1O
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A mixture of 1.2 g of (5Z,13E)-(9S,11R,15R,16RS)-9-hydroxy-16-fluoro-11,15-bis(tetrahydropyran-2-yloxy)-5,13-prostadienoic acid methyl ester (prepared from the corresponding acid in methylene chloride with 0.5-molar diazomethane solution at 0° C.), 800 mg of p-toluenesulfonic acid chloride, and 4 ml of pyridine is agitated for 16 hours at 0° C., then for 48 hours at 25° C. The mixture is worked up according to Example 1. Yield: 1.45 g of the 9-tosylate as an oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]([NH2:25])[CH3:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:26])=[N:5]1)([CH3:3])[CH3:2].[O-:27][C:28]#[N:29].[K+]>C(O)(=O)C.O>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]([NH:25][C:28]([NH2:29])=[O:27])[CH3:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:26])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(C(C)N)ccc2-3)n(C(C)C)n1
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(C(C)NC(N)=O)ccc2-3)n(C(C)C)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 4.1 %

Procedure:
To a solution of 1-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-ethylamine (0.120 g, 0.325 mmol) in acetic acid (0.0923 mL) and water (3.45 mL) was added a solution of potassium cyanate (0.132 g, 0.00162 mol) in Water (1.0 mL, 0.056 mol) dropwise. The reaction was stirred at 50° C. overnight, cooled down, filtered, and rinsed with cold water. The crude was precipitated in methanol/water and repurified by reverse-phase HPLC to give 542 as a beige solid (5.5 mg). MS(ESI+) 413.1. 1H NMR (400 MHz, DMSO) δ 8.27 (d, J=8.2 Hz, 1H), 7.12 (dd, J=8.3, 1.5 Hz, 1H), 6.98 (d, J=1.4 Hz, 1H), 6.47 (d, J=8.2 Hz, 1H), 5.83-5.68 (m, 1H), 5.47 (s, 2H), 4.70 (p, J=7.1 Hz, 1H), 4.44-4.25 (m, 2H), 3.42 (t, J=4.9 Hz, 2H), 2.32 (s, 3H), 1.52 (dd, J=6.5, 1.6 Hz, 6H), 1.32 (d, J=7.0 Hz, 3H)