Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:15]=3[N:14]=2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.C1C(=O)N([Br:31])C(=O)C1>CN(C=O)C>[Br:31][C:5]1[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=[C:2]([CH3:1])[C:3]=2[CH2:12][C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:15]=3[N:14]=2)[NH:7][CH:6]=1
Reactant: Cc1cc(C)c2[nH]ccc2c1Cc1nc2cc(C#N)ccc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1cc(C)c2[nH]cc(Br)c2c1Cc1nc2cc(C#N)ccc2[nH]1
Reaction time: 1 h

Procedure:
2-((5,7-Dimethyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile (Example 58-C) (61 mg, 0.203 mmol) was dissolved in DMF (2 mL) and NBS (40.1 mg, 0.225 mmol) was added at 0° C. and the reaction stirred for 1 hour. The reaction was then quenched with saturated aq. sodium thiosulfate and saturated aq. NaHCO3. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic phase was dried over MgSO4, concentrated and purified by flash column chromatography (0-40% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.33 (br. s., 1H) 11.39 (br. s., 1H) 7.97 (s, 1H) 7.83 (s, 1H) 7.41-7.64 (m, 2H) 6.86 (s, 1H) 4.82 (d, J=4.55 Hz, 2H) 2.43 (s, 3H) 2.21 (s, 3H). HRMS calcd. for C19H15BrN4 (M+H)+ 379.0553. found 379.0557.
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:9]([C@@H:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][N:18]4C3CCCCO3)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:35].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[OH-:66].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:35][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][NH:18]4)[CH3:12])[N:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:7]=2[C:2]=1[OH:66]
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(Br)c2n1-c1ccccc1
Reactant: [OH-]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(O)c2n1-c1ccccc1
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 6.9 %

Procedure:
A solution of [(S)-1-(7-bromo-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]-[9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (300 mg, 0.56 mmol), tris(dibenzylideneacetone)dipalladium (0) (10 mg, 11 μmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (19 mg, 45 μmol), potassium hydroxide (94 mg, 1.6 mmol) in dioxane (3 mL), and water (2 mL) in a sealed tube were degassed by bubbling argon through the solution then heated by microwave at 150° C. for 30 min. Further portions of tris(dibenzylideneacetone)dipalladium (0) (30 mg, 33 μmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (57 mg, 135 μmol) were added and the mixture heated by microwave at 180° C. for 1 hour. The reaction mixture was diluted with water and extracted with EtOAc (3×10 mL). The combined organic fractions were washed with brine, dried (MgSO4), concentrated in vacuo. The product was purified by prep HPLC (C18 phenomonix column, 10-90% MeCN in water 0.1% formic acid, 20 min gradient). The product was dissolved in HCl in methanol (1.25 M, 3 mL) and the reaction mixture stirred at RT for 10 min before being concentrated in vacuo. The product was purified by prep HPLC (C18 phenomonix column, 10-90% MeCN in water 0.1% formic acid, 20 min gradient) to give 327 as a white solid (15 mg, 7%). 1H NMR 400 MHz δ (d6-DMSO): 9.53-9.38 (1H, m), 8.10-7.99 (2H, m), 7.82-7.69 (1H, m), 7.62-7.27 (5H, m), 7.10-6.93 (2H, m), 5.37-5.17 (1H, m), 1.43 (3H, d, J=7.0 Hz), LCMS (Method K): RT=2.55 min, [M+H]+=390
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:23][CH:24]1[CH2:26][CH2:25]1)[CH2:6][CH2:7][C:8]1[NH:9][C:10]2[C:15]([C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:4]>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.[OH-].[Na+].O>[CH:24]1([CH2:23][N:5]2[CH2:6][CH2:7][C:8]3=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]3[CH2:2][C:3]2=[O:4])[CH2:26][CH2:25]1
Reactant: O=C(CCl)N(CCc1[nH]c2ccccc2c1-c1ccccc1)CC1CC1
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C1Cn2c(c(-c3ccccc3)c3ccccc32)CCN1CC1CC1
Reaction time: 0.17 h

Procedure:
A solution of 184.3 g 2-chloro-N-cyclopropylmethyl-N-[2-(3-phenyl-1H-indol-2-yl)ethyl]acetamide in 1843 ml methylene chloride is added dropwise under vigorous stirring to a suspension of 17.9 g N-benzyltributyl-ammoniumbromide in 1843 ml methylene chloride and 921 ml 30% sodium hydroxide. The mixture is stirred for further 10 minutes and diluted with 1 l water. The organic phase is separated, washed with water, dried and evaporated to dryness. The residue is dissolved in 500 ml boiling ethanol, cooled and treated with 500 ml ether. The resulting cristalline precipitate is filtered off, washed with ethanol/ather (1:1) and then ether to give 2,3-dihydro-3-cyclopropylmethyl-11-phenyl-1H-[1,4]diazepino[1,7-a]indol-4(5H)-one, m.p. 149°-150°.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:36]=[CH:35][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)=O.[O:37]1[CH2:40][CH:39]([NH2:41])[CH2:38]1>>[CH3:22][NH:21][C:19](=[O:20])[C@:18]([CH3:33])([N:17]([CH3:34])[C:15](=[O:16])[C:14]1[CH:35]=[CH:36][C:11]([C:10]#[C:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][NH:41][CH:39]3[CH2:40][O:37][CH2:38]3)=[CH:4][CH:5]=2)=[CH:12][CH:13]=1)[C:23]([NH:25][O:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)=[O:24]
Reactant: NC1COC1
Reactant: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Product: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(CNC3COC3)cc2)cc1

Procedure:
The same procedure as in Example 16-(2) was performed using (2S)-2-[{4-[(4-formylphenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (0.25 g) as obtained in Example 16-(1) and oxetan-3-amine (44 mg), whereby (2S)-N,2-dimethyl-2-{methyl[4-({4-[(oxetan-3-ylamino)methyl]phenyl}ethynyl)benzoyl]amino}-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (light yellow foam) was obtained (0.24 g, 85%).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([O:11][C:12](=[O:31])[C:13]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([CH3:30])[CH:24]=[CH:23]2)=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:10].O>CS(C)=O>[CH3:30][C:25]1[CH:24]=[CH:23][C:22]2[C:27](=[CH:28][CH:29]=[C:20]([C:13]3([C:12]([O:11][CH2:9][CH3:10])=[O:31])[CH2:4][CH:14]3[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:21]=2)[N:26]=1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)C=C(C(=O)OCC)c1ccc2nc(C)ccc2c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1CC1(C(=O)OCC)c1ccc2nc(C)ccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
Sodium hydride (0.52 g) was added in small portions to a stirred suspension of trimethylsulfoxonium iodide (2.81 g) in DMSO (28 mL) at room temperature. After 0.5 h, the clear reaction mixture was cooled to 0° C. and a solution of diethyl-2-(2-methyl-6-quinolinyl)-2-butenedioate (2.0 g) in DMSO (14 mL) was quickly added and the stirring continued for 0.5 h after which time water (30 mL) was added. The mixture was extracted twice with ether (30 mL), the organic phase was washed with saturated ammonium chloride, dried over sodium sulphate and evaporated under reduced pressure to give 2 g of the title product which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:3]=1[O:4][C:5]1[CH:10]=[C:9]([NH:11][CH3:12])[C:8]([N+:13]([O-])=O)=[CH:7][C:6]=1[C:16]1[C:17]2[CH:26]=[CH:25][N:24]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:18]=2[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1.CO.[Cl-].[NH4+]>C(OCC)(=O)C.ClCCl.[Zn]>[NH2:13][C:8]1[C:9]([NH:11][CH3:12])=[CH:10][C:5]([O:4][C:3]2[CH:37]=[CH:38][C:39]([F:41])=[CH:40][C:2]=2[F:1])=[C:6]([C:16]2[C:17]3[CH:26]=[CH:25][N:24]([S:27]([C:30]4[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=4)(=[O:29])=[O:28])[C:18]=3[C:19](=[O:23])[N:20]([CH3:22])[CH:21]=2)[CH:7]=1
Reactant: CNc1cc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3c2ccn3S(=O)(=O)c2ccc(C)cc2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CNc1cc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3c2ccn3S(=O)(=O)c2ccc(C)cc2)cc1N
Temperature: 0 °C
Yield: 99.3 %

Procedure:
A solution of 4-[2-(2,4-difluorophenoxy)-4-(methylamino)-5-nitrophenyl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (0.150 g, 0.258 mmol) in ethyl acetate (1.0 mL) was treated with methanol (1.0 mL) and saturated aqueous ammonium chloride solution (0.225 mL, 3.36 mmol) and cooled to 0° C. The reaction mixture was treated with zinc (0.135 g, 2.07 mmol) in two portions over 5 minutes. The reaction mixture was heated at 55° C. for 10 min, diluted with dichloromethane, filtered over Celite, and washed with dichloromethane. The filtrate was concentrated to residue. The residue was dissolved in dichloromethane (30 mL), washed with saturated sodium bicarbonate solution (20 mL), dried with sodium sulfate, filtered, and concentrated to give the desired product (0.141 g, 99%), which was used without further purification. LCMS calculated for C28H25F2N4O4S (M+H)+: m/z=551.2. found: 550.9.
Reaction SMILES: [CH2:1]([OH:10])[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([O:10][CH2:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCC#CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCC#CCOS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
To a cooled (0° C.) solution of 14.6 g (0.104 mole) of 2-nonyn-1-ol in 150 ml of dry methylene chloride and 23.14 ml (0.166 mole) of triethylamine there were added dropwise 10.7 ml (0.156 mole) of methanesulfonyl chloride. The reaction mixture was stirred for 30 minutes at the same temperature, diluted with methylene chloride (150 ml), washed with brine (100 ml), dried and evaporated under vacuum to provide 2-nonyn-1-ol methanesulfonate.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]([OH:13])=O.[CH3:14][O:15][C:16](=[O:23])[C@@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:18]>>[CH3:21][CH:20]([CH3:22])[CH2:19][C@@H:17]([NH:18][C:11]([C:3]1[O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]=1[CH3:1])=[O:13])[C:16]([O:15][CH3:14])=[O:23]
Reactant: Cc1c(C(=O)O)oc2ccccc12
Reactant: COC(=O)[C@H](N)CC(C)C
Product: COC(=O)[C@@H](CC(C)C)NC(=O)c1oc2ccccc2c1C

Procedure:
Prepared in a similar manner to example 4 using 3-methylbenzofuran-2-carboxylic acid and D-leucine methyl ester. MS (M+H, 304).
Reaction SMILES: [Br-].[C:2]([CH2:5][NH+:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH2:7]1)(O)=O.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=C.C(N(CC)CC)C>C1(C)C=CC=CC=1.O=[Mn]=O>[C:13]1([C:12]([O:16][CH3:17])=[O:15])[CH:2]=[CH:5][N:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2
Reactant: C=CC(=O)OC
Reactant: O=C(O)C[NH+]1C=CC=CC1
Agent: O=[Mn]=O
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccn2ccccc12
Temperature: 90 °C

Procedure:
To a suspension of 6.55 g of the pyridinium salt obtained in Step A (30 mmol) in 240 mL of toluene there are successively added 16.7 mL of methyl acrylate (150 mmol), 4.2 mL of triethylamine (30 mmol) and then, in portions, 20.9 g of MnO2 (240 mmol). The batch is then heated at 90° C. for 3 hours. After cooling, the reaction mixture is filtered over a cake of Celite and concentrated to dryness. The title product is then isolated by purification over silica gel (heptane/AcOEt gradient: 0-10%) in the form of an oil which crystallises in the cold state.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH-].[Na+].C[O:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[CH2:17][S:16](=[O:26])(=[O:25])[C:15]=2[CH:27]=1)=[O:10].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1>[CH2:1]([N:20]1[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[CH2:17][S:16](=[O:25])(=[O:26])[C:15]2[CH:27]=[C:11]([C:9]([OH:10])=[O:8])[CH:12]=[CH:13][C:14]1=2)[CH:2]=[CH2:3]
Reactant: COC(=O)c1ccc2c(c1)S(=O)(=O)Cc1ccccc1N2
Reactant: C=CCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: C=CCN1c2ccccc2CS(=O)(=O)c2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 13.41 %

Procedure:
Allyl bromide (0.042 mL, 0.49 mmol), tetrabutylammonium hydrogen sulphate (0.033 g, 0.099 mmol) and 25% aqueous sodium hydroxide (0.5 mL) were added to a solution of Example 166e (0.1 g, 0.33 mmol) in benzene (2 mL). The reaction mixture was stirred for 7 h at room temperature, treated with water and extracted with ethyl acetate. The organic extract was washed with water, 10% aqueous HCl, dried, concentrated and subjected to hydrolysis as described in Example 1i to obtain the title compound. Yield: 13.41%; 1H NMR (DMSO-d6): δ 4.50 (d, 2H, CH2), 5.00 (s, 2H, CH2), 5.30 (d, 2H, CH2), 5.80 (m, 1H, CH), 7.30-7.60 (m, 5H, Ar), 8.10 (d, 1H, Ar), 8.20 (s, 1H, Ar); MS: m/e (ES+) 330 (M+).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[N+:21]([C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1)([O-:23])=[O:22]>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:31]([NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=2)=[O:32])[C:3]1=[O:20]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)Nc2cccc([N+](=O)[O-])c2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 3-nitrophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 288°-289° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[C:18]([OH:20])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][C@H:23]([C:28]([NH2:30])=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C.O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[C:18](=[O:20])[NH:22][CH:23]([C:28](=[O:29])[NH2:30])[CH2:24][CH:25]([CH3:27])[CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](N)C(N)=O
Reactant: O=C(NC1CCCCC1C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CC(NC(=O)C1CCCCC1NC(=O)OCc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.8 %

Procedure:
To a solution of the carboxylic acid of step 2 (10.2 g, 36.9 mmol), L-Leucineamide hydrochloride (6.18 g, 40.5 mmol), EDCI hydrochloride (5.48 g, 40.6 mmol), and HOBT (5.48 g, 40.6 mmol) in 100 mL of anhydrous DMF, was added N-methylmorpholine (12.0 mL, 109 mmol). The reaction mixture was stirred at ambient temperature for 24 h, then added 300 mL of water and 400 mL of ethyl acetate. The organic layer was separated and washed with two 300 mL portions of a 0.5 M HCl solution, 300 mL of water, then dried over sodium sulfate, filtered and recrystallized from ethyl acetate/hexanes to give 13.2 g of [2-(1-Carbamoyl-3-methyl-butylcarbamoyl)-cyclohexyl]-carbamic acid benzyl ester as a white solid. Yield: 92%, MS: 412 (M+Na+), mp=188.0-189.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:17][CH2:16][N+:11]3([CH2:15][CH2:14][CH2:13][CH2:12]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Cl:18][C:19]1[N:20]=[C:21]([CH3:25])[NH:22][C:23]=1[Cl:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:18][C:19]1[N:20]=[C:21]([CH3:25])[N:22]([CH2:12][CH2:13][CH2:14][CH2:15][N:11]2[CH2:10][CH2:9][N:8]([C:5]3[N:6]=[CH:7][C:2]([F:1])=[CH:3][N:4]=3)[CH2:17][CH2:16]2)[C:23]=1[Cl:24]
Reactant: Cc1nc(Cl)c(Cl)[nH]1
Reactant: Fc1cnc(N2CC[N+]3(CCCC3)CC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c(Cl)n1CCCCN1CCN(c2ncc(F)cn2)CC1
Yield: 85.2 %

Procedure:
A mixture of 3.17 g (0.01 mol) of 8-(5-fluoro-2-pyrimidinyl)-8-aza-5-azoniaspiro[4.5]decane, 2.26 g (0.015 mol) of 4,5-dichloro-2-methyl-1H-imidazole and 76 g (0.02 mol) of potassium carbonate in 80 ml of dimethylformamide is maintained at reflux for 12 hours. The mixture is subsequently evaporated to dryness and the resulting crude product is redissolved in chloroform and washed repeatedly with water. The organic phase is dried and evaporated, and then the resulting crude product is purified by chromatography on a column of silica gel. 3.3 g (85% yield) of 2-{4-[4-(4,5-dichloro-2-methylimidazol-1-yl)butyl]piperazin-1-yl)-5-fluoropyrimidine are obtained in the form of an oil.
Reaction SMILES: [CH3:1][CH2:2][C@:3]1([C@@H:31]2[O:35][C@@H:34]([C@H:36]3[O:41][C@@:40]([OH:44])([CH2:42][OH:43])[C@H:39]([CH3:45])[CH2:38][C@@H:37]3[CH3:46])[CH2:33][C@@H:32]2[CH3:47])[O:7][C@@H:6]([C@@:8]2([CH3:30])[O:12][C@:11]3([O:17][C@H:16]([C@H:18]([C@@H:20]([O:26][CH3:27])[C@@H:21]([C:23]([O-:25])=[O:24])[CH3:22])[CH3:19])[C@H:15]([CH3:28])[C@@H:14]([OH:29])[CH2:13]3)[CH2:10][CH2:9]2)[CH2:5][CH2:4]1.[Na+].N12CCC(CC1)CN2.[CH2:57](Br)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>C(#N)C>[CH3:1][CH2:2][C@:3]1([C@@H:31]2[O:35][C@@H:34]([C@H:36]3[O:41][C@@:40]([OH:44])([CH2:42][OH:43])[C@H:39]([CH3:45])[CH2:38][C@@H:37]3[CH3:46])[CH2:33][C@@H:32]2[CH3:47])[O:7][C@@H:6]([C@@:8]2([CH3:30])[O:12][C@:11]3([O:17][C@H:16]([C@H:18]([C@@H:20]([O:26][CH3:27])[C@@H:21]([C:23]([O:25][CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)=[O:24])[CH3:22])[CH3:19])[C@H:15]([CH3:28])[C@@H:14]([OH:29])[CH2:13]3)[CH2:10][CH2:9]2)[CH2:5][CH2:4]1
Reactant: BrCc1ccccc1
Reactant: CC[C@@]1([C@@H]2O[C@@H]([C@H]3O[C@@](O)(CO)[C@H](C)C[C@@H]3C)C[C@@H]2C)CC[C@H]([C@]2(C)CC[C@]3(C[C@H](O)[C@@H](C)[C@@H]([C@@H](C)[C@@H](OC)[C@H](C)C(=O)[O-])O3)O2)O1
Agent: C1CN2CCC1CN2
Agent: [Na+]
Solvent: CC#N
Product: CC[C@@]1([C@@H]2O[C@@H]([C@H]3O[C@@](O)(CO)[C@H](C)C[C@@H]3C)C[C@@H]2C)CC[C@H]([C@]2(C)CC[C@]3(C[C@H](O)[C@@H](C)[C@@H]([C@@H](C)[C@@H](OC)[C@H](C)C(=O)OCc4ccccc4)O3)O2)O1
Temperature: 25 °C
Reaction time: 336 h

Procedure:
Monensin sodium salt (1.0 g, 1.4 mmol) in acetonitrile (20 ml) was treated with diazabicyclo [2.2.2] octane (0.3 g, 2.7 mmol) followed by benzyl bromide (2 g, 11.7 mmol) and cryptand [2.2.2]. The reaction mixture was stirred at room temperature with exclusion of light for 14 days. After 10 days an additional quantity of benzyl bromide (2 g, 11.7 mmol) was added. The solvent was evaporated and the crude product redissolved in dichloromethane, washed with deionized water and dried over magnesium sulfate. The crude product was chromatographed on silica gel eluting with hexane-ethyl acetate gradient. Excess benzyl bromide eluted from the column first followed by benzylmonensin which was isolated as a colorless oil after removal of the solvent (280 mg, 26%), (MS, positive ion ESI showed 783 peak; calc. for sodiated product 783). This compound has been reported previously (Tsukube J. Org. Chem. 56, 875, 1991).
Reaction SMILES: Cl([O-])(=O)(=O)=O.[OH:6][C:7]1[CH:28]=[CH:27][C:10]([CH:11]=[CH:12][CH2+:13]2[C:18]3[CH:19]=[C:20]4[O:25][CH2:24][O:23][C:21]4=[CH:22][C:17]=3[CH:16]=[C:15]([CH3:26])O2)=[CH:9][CH:8]=1.O.[NH2:30][NH2:31]>C(O)C>[OH:6][C:7]1[CH:28]=[CH:27][C:10]([CH:11]=[CH:12][C:13]2[C:18]3[CH:19]=[C:20]4[O:25][CH2:24][O:23][C:21]4=[CH:22][C:17]=3[CH2:16][C:15]([CH3:26])=[N:31][N:30]=2)=[CH:9][CH:8]=1
Reactant: CC1=Cc2cc3c(cc2[CH2+](C=Cc2ccc(O)cc2)O1)OCO3
Reactant: NN
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCO
Solvent: O
Product: CC1=NN=C(C=Cc2ccc(O)cc2)c2cc3c(cc2C1)OCO3
Reaction time: 0.5 h

Procedure:
A mixture of 5 g (12.3 mM) of 1-(4-hydroxystyryl)-3-methyl-6,7-methylenedioxy-2-benzopyrylium perchlorate (m.p. 306° to 308° C. d.), 100 ml of 99.5% ethanol and 1.85 ml (36.9 mM) of 100% hydrazine hydrate are refluxed for one hour. The end-product is beginning to precipitate already in the first minutes of the reaction. The mixture is evaporated at reduced pressure, the partially crystalline residue is suspended in 100 ml of water, the crystals are filtered, washed with 3×10 ml of water, the crude product is resuspended in 300 ml of hot water, stirred for 30 minutes, filtered hot, washed with 2×20 ml of hot water and dried at 80° to 100° C. Yield 2.18 g, m.p. 243 to 248° C. d. For further purification this product is refluxed in 10 ml of 99.5% of ethanol, filtered after cooling, washed with 3×2 ml of ethanol and dried. Yield 2.08 g (52.8%), m.p. 246° to 248° C. (decomp.).
Reaction SMILES: C(O)C.C([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=2[O:28]C)=[O:19])=[CH:14][CH:13]=1)C1C=CC=CC=1.Br>[Pd].C(O)(=O)C.O.CCOCC>[OH:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[C:18]([C:15]1[CH:14]=[CH:13][C:12]([OH:11])=[CH:17][CH:16]=1)=[O:19]
Reactant: COc1ccc(OC)c(C(=O)c2ccc(OCc3ccccc3)cc2)c1
Agent: [Pd]
Agent: Br
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1ccc(O)c(C(=O)c2ccc(O)cc2)c1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
Palladium on carbon catalyst (10%, 1.0 g, 0.94 mmol) was added to a stirred ethanol (500 ml) solution of (4-benzyloxyphenyl)-(2,5-dimethoxyphenyl)-methanone (10.86 g, 31.2 mmol) and the suspension hydrogenated for 18 h. The catalyst was removed by filtration, and the solvent evaporated to give an orange coloured gum. This was dissolved in glacial acetic acid (16 ml), hydrogen bromide (33% w/w in acetic acid, 8.20 ml, 46.76 mmol) added, and the resulting mixture heated to 70° C. for 18 h. The mixture was diluted with water (25 ml) and the product extracted into ethyl acetate (3×25 ml). The combined extracts were washed with brine, dried over magnesium sulfate and evaporated to a yellow gum, which was purified by column chromatography on silica gel 60, with 7:3 petrol/ethyl acetate as eluent. This gave a yellow gum, which was dissolved in a minimum of ether and precipitated by adding petrol, to give the title product as a yellow powder.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([C:10]1[N:15]=[C:14]([CH2:16][N:17]2[CH2:21][CH2:20][N:19]([C@@H:22]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:18]2=[O:34])[CH:13]=[CH:12][CH:11]=1)(=O)[CH3:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:7]([C:10]1[N:15]=[C:14]([CH2:16][N:17]2[CH2:21][CH2:20][N:19]([C@@H:22]([C:30]([CH3:33])([CH3:31])[CH3:32])[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[C:18]2=[O:34])[CH:13]=[CH:12][CH:11]=1)([CH3:1])=[CH2:8]
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)c1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)c1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
A solution of methyltriphenylphosphonium bromide (0.33 g, 0.923 mmol) in THF (2.5 mL) was treated with a solution of potassium tert-butoxide in THF (0.89 mL, 1 M) dropwise, stirred for 1 hour at 25° C., treated with a solution of the product from Example 117A (0.116 g, 0.298 mmol) in THF (2 mL), stirred at 25° C. for 16 hours, quenched with saturated ammonium chloride solution and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 15%-25% ethyl acetate in hexane to give the title compound (0.040 g, 35% yield).