Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[K+].[Br-]>C(O)C.O.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2([NH:19][CH2:20][CH2:21][NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:12])[O:7]2)=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)NCCN)cc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)NCCNC2(c3ccc(Cl)cc3)OC(=O)c3ccccc32)cc1
Temperature: 25 °C

Procedure:
To a flask equipped with a Dean-Stark water separator is charged 500 ml. of toluene, 24.0 g. (0.10 mole) of 2-(p-chlorobenzoyl) benzoic acid and 21.4 g. (0.10 mole) of N-(2-aminoethyl)-4-methylbenzene sulfonamide. The mixture is stirred and refluxed until the water level in the separator is constant. The reaction is then allowed to cool to room temperature and the resultant solid is filtered off, washed with 100 ml. of toluene and dried to give the above named phalide; m.p. 177°-179° C.: infrared (KBr), peaks at 3.00, 3.09, 3.37, 3.42, 3.48, 5.76, 6.25, 6.71, 7.42, 7.72, 8.58, 9.12, 9.90, 11.45, 12.80, 13.70, 17.30 and 18.20μ; ultraviolet (95% ethanol) maximum at 226 mμ (E1cm1% 637), 257 mμ (shoulder); N.M.R. (pyridine- d6) δ 2.22 (CH3), 3.57(4H, NCH2CH2N unresolved multiplet).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[F:11].Cl.Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)=[CH:6][C:5]=1[F:11]
Reactant: COC(=O)c1ccc(O)cc1F
Reactant: Cc1cccc(CCl)n1
Agent: Cl
Product: COC(=O)c1ccc(OCc2cccc(C)n2)cc1F

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure E except KI (1.3 eq.) is also added from 2-Fluoro-4-hydroxy-benzoic acid methyl ester [197507-22-5] and 2-(chloromethyl)-6-methyl-pyridine hydrochloride [CAS 3099-29-4]. MS (ES+) 276.2
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:21]1[O:23][C@H:22]1[CH2:24]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O>CC(C)=O>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:24][C@H:22]2[CH2:21][O:23]2)[CH:8]=1)[CH3:2]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@H]2CO2)c1
Reactant: CCOC(=O)CCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCc1cccc(OC[C@H]2CO2)c1
Temperature: 25 °C
Yield: 93 %

Procedure:
To an acetone solution (0.15 M, 170 mL) of 3-(3-Hydroxy-phenyl)-propionic acid ethyl ester (5.0 g, 25.77 mmol) was added K2CO3 (10.69 g, 77.32 mmol), and the mixture was heated to reflux for 30 min. After cooling this mixture to RT, (2R)-(−)-glycidyl 3-nitrobenzenesulfonate (6.68 g, 25.77 mmol) was added, and the resulting mixture was heated to reflux overnight. After cooling to room temperature, the solids were removed by filtration and washed well with ethyl acetate. The filtrate was concentrated and partitioned between ethyl acetate and 1N HCl. The organic portion was washed successively with 5% NaHCO3 and brine, dried (MgSO4), filtered and concentrated to a solid. Purification by FCC (30% ethyl acetate/hexanes) gave the product as a white solid in 93% yield (6.0 g). LCMS (m/z) M+H: 187
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])=[C:4]([NH:14][C@H:15]([OH:18])[CH2:16][OH:17])[N:3]=1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].N1C=CN=C1>CN(C=O)C>[Si:19]([O:17][CH2:16][C@H:15]([NH:14][C:4]1[C:5]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])=[C:6]([Cl:8])[N:7]=[C:2]([Cl:1])[N:3]=1)[OH:18])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)C(=O)c1c(Cl)nc(Cl)nc1N[C@H](O)CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1c(Cl)nc(Cl)nc1N[C@H](O)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the subtitle product of step iv) (0.50 g) in DMF (10 ml) was added tert-butyldimethylsilyl chloride (0.51 g) at −10° C. in portions. To this mixture was then added imidazole in portions. The mixture was then stirred at 0° C. for 1 h and allowed to come to room temperature and stirred for 16 h. The mixture was quenched with water and extracted with EtOAc (2×250 ml). The combined organics were washed with water (3×20 ml) and brine (3×20 ml), the organic layer dried (MgSO4) and the solid filtered. The filtrate was evaporated to dryness and the residue chromatographed on silica gel eluting with EtOAc/isohexane (1:1) to yield the subtitle compound as an oil. Yield 1.0 g.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.N12CCCN=C1CCCC[CH2:16]2.IC.Cl>CN(C)C=O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10](=[O:14])[C:11]([O:13][CH3:16])=[O:12])=[CH:7][CH:8]=1
Reactant: CSc1ccc(CC(=O)C(=O)O)cc1
Reactant: C1CCC2=NCCCN2CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C(=O)Cc1ccc(SC)cc1

Procedure:
3-(4-(Methylsulfanyl)phenyl)-2-oxopropanoic acid (16.2 g), N,N-dimethylformamide (81 ml) and 1,8-diazabicyclo[5.4.0]undec-7-ene (11.5 ml) were combined at 0° C. under nitrogen atmosphere. The mixture was stirred at the same temperature for an hour, and then iodomethane (9.59 ml) was added to the solution at the same temperature. The reaction mixture was stirred at room temperature for 4 hours, poured into 1N-hydrochloric acid, and extracted with ethyl acetate (twice). The combined organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with chloroform/ethyl acetate (30:1) as an eluent, and triturated with isopropyl ether/n-hexane to give methyl 3-(4-(methylsulfanyl)phenyl)-2-oxopropanoate (8.6 g) as a dark yellow solid.
Reaction SMILES: C([O:8][N:9]1[CH2:15][CH:14]=[CH:13][CH2:12][C@@H:11]([N:16]([CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:10]1=[O:42])C1C=CC=CC=1.CS(O)(=O)=O>>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([O:26][C:23]2[CH:24]=[CH:25][C:20]([S:17]([N:16]([C@@H:11]3[CH2:12][CH:13]=[CH:14][CH2:15][N:9]([OH:8])[C:10]3=[O:42])[CH2:34][CH2:35][N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)(=[O:19])=[O:18])=[CH:21][CH:22]=2)=[CH:32][CH:31]=1
Reactant: O=C1[C@H](N(CCN2CCOCC2)S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC=CCN1OCc1ccccc1
Agent: CS(=O)(=O)O
Product: O=C1[C@H](N(CCN2CCOCC2)S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC=CCN1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 106.1 %

Procedure:
To a solution of 2.83 g of N-(1-Benzyloxy-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-(R)-yl)-4-(4-chloro-phenoxy)-N-(2-morpholin-4-yl-ethyl)-benzenesulfonamide from Step B was added 35 mL of methane sulfonic acid. The reaction was stirred at room temperature for 20 hours. The reaction was then poured over ice. The aqueous layer was extracted with 100 mL of ethyl ether twice, followed by extraction of the aqueous layer with dichloromethane (4 times). The dichloromethane layers were combined and dried over Na2SO4(s). The liquids were filtered off, and solvent removal gave a light yellow film. Dilution with ethyl ether, filtration of the resulting solids, and washing with ethyl ether and hexanes followed by drying gave 2.56 g of an orange solid. MS: 522 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH4+].[Cl-].[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C>[NH:12]1[C:6]([C:5]2[CH:8]=[CH:9][C:2]([NH2:1])=[CH:3][CH:4]=2)=[N:7][N:14]=[N:13]1
Reactant: N#Cc1ccc(N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2nnn[nH]2)cc1
Temperature: 120 °C
Yield: 44.4 %

Procedure:
To a stirred solution of 4-amino-benzonitrile (300 mg, 2.53 mmol; CAS Reg. No. 873-74-5) in dry DMF (6 ml) was added NH4Cl (547 mg, 10.2 mmol) and NaN3 (660 mg, 10.2 mmol) at room temperature. The reaction mixture was then heated at 120° C. for 12 h. After cooling, TLC shows formation of new spot, filtered the solid material by sintered funnel and washed the solid residue by EtOAc (4×5 ml). Combined organic layers were reduced under pressure at 60° C. and diluted the residue with EtOAc (25 mL). Organic layer was washed with H2O (15 ml), brine (12 ml) and dried over Na2SO4; which was then concentrated under reduced pressure to give the crude material (300 mg). Crude product was then purified by column chromatography [SiO2 (230-400 mesh), MeOH:DCM 5:95] to give the title compound (180 mg, 44.4%) as light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([C:11]([F:31])([C:25]2[O:26][C:27]([CH3:30])=[N:28][N:29]=2)[CH:12]2[CH2:24][C:15]3[NH:16][C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][C:22]=4[C:14]=3[CH2:13]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:32][CH2:33]N(C(C)C)C(C)C.C([Si](C)(C)C)#C.[OH-].[Na+]>CN(C=O)C.[Cu]I.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>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]2[NH:16][C:15]3[CH2:24][CH:12]([C:11]([S:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([C:32]#[CH:33])[CH:3]=4)(=[O:10])=[O:9])([F:31])[C:25]4[O:26][C:27]([CH3:30])=[N:28][N:29]=4)[CH2:13][C:14]=3[C:22]=2[CH:21]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nnc(C(F)(C2Cc3[nH]c4ccc(Cl)cc4c3C2)S(=O)(=O)c2cccc(Br)c2)o1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#C[Si](C)(C)C
Solvent: CN(C)C=O
Product: C#Cc1cccc(S(=O)(=O)C(F)(c2nnc(C)o2)C2Cc3[nH]c4ccc(Cl)cc4c3C2)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 52.8 %

Procedure:
A solution of 76 mg (0.133 mmol) of (RS, SR)-2-[(3-bromo-benzenesulfonyl)-fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)-methyl]-7-chloro-1,2,3,4-tetrahydro-cyclopenta[b]indole (example 106) in 1.5 mL of DMF was treated with 1 mg (0.005 mmol) of CuI, 37 mg (0.29 mmol) of DIPEA, 17 mg (0.015 mmol) of tetrakis(triphenylphosphine)palladium and 71 mg (0.72 mmol) of ethynyltrimethylsilane and the resulting suspension stirred at 80° C. during 4 hrs. Diluted aqueous NaOH was added and the mixture extracted twice with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and evaporated. Chromatography on silica gel with heptane/EtOAc (1:1) gave 33 mg (48%) of (RS, SR)-7-chloro-2-[(3-ethynyl-benzenesulfonyl)-fluoro-(5-methyl-[1,3,4]oxadiazol-2-yl)-methyl]-1,2,3,4-tetrahydro-cyclopenta[b]indole as a yellow solid, MS: 471 (MH+).
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH3:6].[C:14](OC(=O)C)(=[O:16])[CH3:15].N1C=CC=CC=1.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:14]([O:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=1)[CH2:3][CH2:4][CH2:5][CH3:6])(=[O:16])[CH3:15]
Reactant: CCCCC(O)c1cccc(C)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC(OC(C)=O)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
65.4 g of 3-(1-hydroxypentyl)toluene are dissolved in 500 ml of absolute methylene chloride at 0° C., and 104 ml of acetic anhydride, 89 ml of pyridine and 1 g of dimethylaminopyridine are added in succession. The reaction solution is stirred at 0° C. for 1 hour and at 25° C. for 2 hours and then poured onto 1 l of ice-water. After the organic phase has been separated off, it is extracted 3 times with 200 ml of methylene chloride each time. The organic phases are washed 3 times with 200 ml of 2N HCl each time, 3 times with 200 ml of saturated NaHCO3 each time and twice with 200 ml of water each time, dried over magnesium sulphate and concentrated in vacuo. The residue is distilled at 95° C./0.1 mm (bulb tube).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][C:20]1[CH:24]=[CH:23][S:22][C:21]=1[C:25]([O:27][CH3:28])=[O:26].C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][CH2:19][C:20]1[CH:24]=[CH:23][S:22][C:21]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(O)c1
Reactant: COC(=O)c1sccc1CBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1sccc1COc1cccc(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
To a solution of 3-acetamidophenol (4.79 g, 31.7 mmol) in dimethylformamide (50 ml) was added cesium carbonate (5.67 g, 17.4 mmol), followed by stirring at room temperature for 30 minutes. To the resulting mixture was added methyl 3-bromomethyl-2-thiophenecarboxylate (8.94 g, 38.0 mmol), and the mixture was stirred overnight at room temperature. After the reaction was completed, the reaction mixture was poured into a 5% aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (hexane/ethyl acetate=5/1), followed by trituration with hexane to give methyl 3-(3-acetamidophenoxymethyl)-2-thiophenecarboxylate as a white solid (7.27 g, 75%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH2:21][C:22]#[N:23])=O>O>[O:20]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:12]=[C:21]1[C:22]#[N:23]
Reactant: N#CCOc1ccccc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc2ccccc2o1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 43 %

Procedure:
Potassium carbonate (65.2 g) was added to a DMF solution (500 ml) of (2-formylphenyl)oxyacetonitrile (38 g), which was stirred at 60° C. for 2.5 hours. Water was added to the reaction mixture, which was extracted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried and concentrated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=10/1) to obtain the entitled compound (14.5 g).
Reaction SMILES: S(Cl)(Cl)=O.Cl.[CH3:6][O:7][C:8](=[O:15])[CH2:9][CH2:10][C@H:11]([NH2:14])[CH2:12][F:13].C(Cl)(Cl)Cl.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO.C(N(CC)CC)C>[C:20]([NH:14][C@H:11]([CH2:12][F:13])[CH2:10][CH2:9][C:8]([O:7][CH3:6])=[O:15])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)CC[C@H](N)CF
Agent: Cl
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)CC[C@@H](CF)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.0 ml of thionyl chloride was added drop-by-drop to a stirred mixture of 650 mg of 4 in 2.5 ml of methanol at room temperature. The resulting mixture was stirred at room temperature for 10 minutes, at reflux for two hours, cooled and stripped of solvent. The residue was mixed with 25 ml of chloroform and the mixture was stirred while 0.47 ml of benzoyl chloride was added drop-by-drop, then 1.2 ml of triethylamine was added, drop-by-drop. The mixture was stirred at room temperature for 16 hours, and the solvent was evaporated. The residue was mixed with 25 ml of water and the mixture was extracted with chloroform. The extract was washed successively with 1N hydrochloric acid, water, 1M sodium bicarbonate solution, and water. It then was dried (MgSO4), the solvent was evaporated, and the residue was recrystallized from methylene chloride/hexane to give 24, as fine white needles, m.p.: 99.5°-100.5° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([O-:27])=O)=[CH:23][CH:22]=4)[CH:15]=3)[CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)(C)C(Cl)=O.[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C1COCC1.C(N(CC)CC)C>[N:1]1([CH2:7][CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([C:25]([NH:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=5)=[O:27])=[CH:28][CH:29]=4)[CH:15]=3)[CH2:10]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C([O-])c1ccc(COc2ccc3c(c2)CCC(CCN2CCCCC2)C3)cc1
Reactant: Nc1ccccn1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccn1)c1ccc(COc2ccc3c(c2)CCC(CCN2CCCCC2)C3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.4 %

Procedure:
Triethylamine (0.11 ml) was added to THF suspension (6 ml) of 4-[[2-(2-piperidinoethyl)-6-tetraliny]oxymethyl]benzoate (300 mg). Trimethylacetyl chloride (0.095 ml) was added dropwise to the obtained suspension under ice-cooling, which was stirred for 30 minutes. The temperature of the reaction mixture was raised to room temperature, which was stirred for 1 hour. THF solution (1.0 ml) of 2-aminopyridine (110 mg) was added dropwise to the reaction mixture under ice-cooling, which was stirred for 1 hour. Then the reaction mixture was stirred at room temperature for 6 hours, and at 60° C. for 12 hours, which was refluxed with heating for 6 hours. Saturated sodium bicarbonate solution was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using alumina column chromatography (development solvent: THF), and recrystallized (ethyl acetate-IPE) to give the titled compound (30 mg).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C1(C)C=CC(S(O[CH2:14][C:15]#[C:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)(=O)=O)=CC=1>ClCCl>[CH3:1][N:2]([CH3:3])[CH2:14][C:15]#[C:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CNC
Reactant: Cc1ccc(S(=O)(=O)OCC#Cc2ccc([N+](=O)[O-])cc2)cc1
Solvent: ClCCl
Product: CN(C)CC#Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
190 ml (4.2 mmol) of dimethylamine dissolved in 2.5 ml of dichloromethane are added dropwise at 0° C. to a solution of 0.7 g (2.1 mmol) of 4-[3-(p-tolylsulphonyloxy)-prop-1-ynyl]-nitrobenzene in 10 ml of dichloromethane. The cooling is stopped and the mixture is stirred for 18 hours at ambient temperature. Then the reaction solution is washed with water and freed from solvent. The residue is chromatographed on silica gel (dichloromethane/methanol=10:1). The product is obtained as an oil.
Reaction SMILES: [NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[OH:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1.[O:30]1[CH:35]=[CH:34][CH2:33][CH2:32][CH2:31]1>C(Cl)Cl>[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:18][CH:19]1[CH2:20][CH2:21][CH:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:24]1
Reactant: C1=COCCC1
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)C1CCC(OC2CCCCO2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.7 %

Procedure:
Pyridinium-4-toluenesulfonate (2.57 g, 10.2 mmol) was added to a solution of ethyl 4-hydroxycyclohexanecarboxylate (8.8 g, 51.10 mmol) and 3,4-dihydro-2H-pyran (8.60 g, 102 mmol) in DCM (200 mL) and the reaction was stirred at rt for 16 h. The reaction was quenched with saturated aq NaHCO3. The layers were separated and the organic layer was washed with water. The organic layer was dried (Na2SO4), filtered, and concentrated. Purification via flash chromatography on a 200 g silica column using an eluent of EtOAc in hexanes (5-10%) afforded the title compound as a clear oil (11.1 g, 85%).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:35])[C:11]([NH:13][C@H:14]1[C@H:20]([CH3:21])[N:19]([C:22]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[C:18]2[CH:30]=[CH:31][CH:32]=[CH:33][C:17]=2[NH:16][C:15]1=[O:34])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].CS(O[CH2:41][C:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[N:45]=[CH:44][C:43]=1[CH:52]1[CH2:54][CH2:53]1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C=O)C.CCOC(C)=O>[CH:52]1([C:43]2[CH:44]=[N:45][C:46]3[C:51]([C:42]=2[CH2:41][N:16]2[C:15](=[O:34])[C@@H:14]([NH:13][C:11](=[O:12])[C@@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH3:35])[C@H:20]([CH3:21])[N:19]([C:22]([CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:23])[C:18]4[CH:30]=[CH:31][CH:32]=[CH:33][C:17]2=4)=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:54][CH2:53]1
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2N(C(=O)C2CCOCC2)[C@H]1C)N(C)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)OCc1c(C2CC2)cnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2c(C3CC3)cnc3ccccc23)c2ccccc2N(C(=O)C2CCOCC2)[C@H]1C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 60 h
Yield: 51.8 %

Procedure:
To a rt solution of tert-butyl methyl((S)-1-((2S,3S)-2-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (110 mg, 225 μmol) in DMF (563 μl) was added (3-cyclopropylquinolin-4-yl)methyl methanesulfonate (74.9 mg, 270 μmol), cesium carbonate (95.4 mg, 293 μmol), and sodium iodide (43.9 mg, 293 μmol). The reaction was stirred at rt for 2.5 days, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-1-((3-cyclopropylquinolin-4-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (78 mg, 52%) as an off-white solid. MS m/z 670 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=1.[NH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:25]1([NH:24][C:21]([C:18]2[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:16][CH:17]=2)=[O:23])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)nn1
Reactant: NN1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NN2CCOCC2)nn1
Yield: 37 %

Procedure:
To a stirred solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid (215 mg, 0.69 mmol) in DMF (5 mL) at room temperature under argon was added N-aminomorpholine (78 mg, 0.76 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (244 mg, 0.76 mmol) and N,N-diisopropylethylamine (446 mg, 3.4 mmol). After 15 h the reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica, dichloromethane:methanol 1:0 to 97.5:2.5) afforded the title compound (101 mg, 37%) as a white gum. MS: m/e=396.1 [M+H]+.