Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](S)([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].[CH:9]1(Br)[CH2:12][CH2:11][CH2:10]1.O[O:15][S:16]([O-:18])=O.[K+]>CS(C)=O.CO.O>[CH:9]1([S:16]([C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:18])=[O:15])[CH2:12][CH2:11][CH2:10]1
Reactant: O=S([O-])OO
Reactant: CC(C)(C)S
Reactant: BrC1CCC1
Agent: C[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)S(=O)(=O)C1CCC1
Temperature: 90 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
To a solution of tert-butyl thiol XXIIa(i) (1.51 mL, 13.3 mmol) in DMSO (7.2 mL) was added NaOMe (800 mg, 14.7 mmol) and cyclobutylbromide (0.63 mL, 6.47 mmol) at rt. The resulting cloudy solution was heated to 90° C. and stirred for 5 hr at the same temperature. The reaction was quenched with water, extracted by ether, dried over MgSO4. The organic phase was concentrated to afford the crude sulfide. This sulfide was directly used for the next step. To a solution of the above crude sulfide in MeOH (30 mL) was added a solution of oxone (6.1 g, 9.82 mmol) in water (30 mL) at 0° C. The resulting cloudy solution was warmed to rt, then stirred for 5 hrs. The reaction mixture was concentrated using rotary evaporator, diluted with water, extracted with EtOAc. The organic layer was separated, dried over MgSO4, concentrated to afford the crude sulfone(XX(i)) which was recrystalized in hexanes to give 810 mg (71% for 2 steps) of tert-butyl cyclobutyl sulfone. 1H NMR (400 MHz, CDCl3) δ 3.92-4.01 (m, 1H), 2.62-2.73 (m, 2H), 2.20-2.28 (m, 2H), 1.94-2.14 (m, 2H), 1.36 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]3[CH2:13][N:14]([C:16](OC(C)(C)C)=O)[CH2:15][C@H:9]23)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C=O.[BH3-]C#N.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH2:11][C@@H:10]3[CH2:13][N:14]([CH3:16])[CH2:15][C@H:9]23)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CCN(c3ccc(Br)cc3)[C@H]2C1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C[C@H]2CCN(c3ccc(Br)cc3)[C@H]2C1
Reaction time: 2 h

Procedure:
To a solution of (3aR,6aR)-tert-butyl 1-(4-bromophenyl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (1.86 g, 5.1 mmol) in CH2Cl2 (50 mL) at 23° C. was added TFA (8 mL) and the mixture was allowed to stir for 2 hrs. The solvents were removed under vacuum and the residue was taken up in MeOH (50 mL) followed by the addition of formaldehyde (37%, 3 mL, 40 mmol) and NaBH3CN (950 mg, 15.1 mmol). The mixture was stirred at 23° C. for 10 hours, concentrated under reduced pressure and the residue was dissolved in CH2Cl2 (100 mL), washed sequentially with water (2×50 mL), brine (1×30 mL), and dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product mixture was purified via chromatography (SiO2, O-10% MeOH in CH2Cl2) to provide the title compound. 1H NMR (300 MHz, CDCl3): δ=7.28 ppm (m, 2H), 6.44 (m, 2H), 4.05 (m, 1H), 3.45 (m, 1H), 3.19 (m, 1H), 2.94 (m, 1H), 2.67 (m, 1H), 2.52 (m, 3H), 2.30 (s, 3H), 2.16 (m, 1H), 1.95 (m, 1H). MS (ESI, M+1): 280.8.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:8]([OH:10])=[O:9])[S:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:16]>ClCCl.CO>[CH3:1][S:2]([C:3]1[CH:4]=[C:5]([C:8]([OH:10])=[O:9])[S:6][CH:7]=1)=[O:16]
Reactant: CSc1csc(C(=O)O)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)c1csc(C(=O)O)c1
Reaction time: 1 h
Yield: 44.6 %

Procedure:
A stirred solution of 2.46 g (14.1 mmoles) of 4-methylthio-2-thiophenecarboxylic acid (prepared as described in Example 28 below) in 150 ml dichloromethane and 10 ml methanol was cooled to icebath temperature. A 120 ml dichloromethane solution of 2.82 g (13.9 mmoles) of m-chloroperoxybenzoic acid (technical grade, 80-85%) was slowly added to the cooled reaction solution. After 1 hour the reaction was essentially complete with a colorless precipitate forming. The precipitate was filtered and dried to give 1.18 g (6.20 mmoles) of desired compound as a colorless solid, m.p. 188°-190° C. The concentrated mother liquor was chromatographed (silica gel) to give an additional 0.83 g (4.36 mmoles) of desired 4-methylsulfinyl-2-thiophenecarboxylic acid, total yield 75% (10.56 mmoles).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][C:17]([N:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([Cl:27])[N:22]=3)[CH3:20])=[CH:18][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][S:29]([CH2:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)(=[O:31])=[O:30]>>[ClH:27].[CH2:1]([NH:8][C:9]1[N:13]([CH3:14])[C:12]2[CH:15]=[CH:16][C:17]([N:19]([CH3:20])[C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:37][C:36]4[CH:38]=[CH:39][C:33]([CH2:32][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:34][CH:35]=4)[N:22]=3)=[CH:18][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1ccc2c(c1)nc(NCc1ccccc1)n2C)c1ccnc(Cl)n1
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Product: CN(c1ccc2c(c1)nc(NCc1ccccc1)n2C)c1ccnc(Nc2ccc(CS(C)(=O)=O)cc2)n1
Product: Cl

Procedure:
The title compound was prepared following the procedure of Example 1 with N2-benzyl-N5-(2-chloropyrimidin-4-yl)-N5,1-dimethyl-1H-benzimidazole-2,5-diamine (95 mg, 0.25 mmol) and 4-[(methylsulfonyl)methyl]aniline (46 mg, 0.25 mmol) as a white solid (138 mg, 95%). 1H NMR (300 MHz, d6-DMSO) δ 9.20 (s, 1H), 7.76-7.80 (m, 3H), 7.38-7.41 (m, 3H), 7.29-7.34 (m, 2H), 7.22-7.24 (m, 4H), 7.08 (d, J=1.8 Hz, 1H), 6.84 (dd, J=8.1 and 1.8 Hz, 1H), 5.63 (d, J=6.0 Hz, 1H), 4.60 (d, J=6.0 Hz, 2H), 4.34 (s, 2H), 3.58 (s, 3H), 3.43 (s, 3H), 2.85 (s, 3H). MS (ESI) m/z=527 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Br:20][CH2:21][CH2:22][CH2:23][CH2:24]Br>CC(C)=O>[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: NC(=O)c1ccc(O)cc1[N+](=O)[O-]
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC(=O)c1ccc(OCCCCBr)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-hydroxy-2-nitrobenzamide 3 (0.7 g, 0.0038 mol) in 20 mL acetone was added potassium carbonate (2.0 g, 0.015 mol). The reaction mixture was stirred at room temperature for 10 min. Then 1,4-dibromobutane 4 (1.8 mL, 0.015 mol) was added. The resulting mixture was refluxed for 12 h. The progress of the reaction was monitored by thin layer chromatography (TLC). Potassium carbonate was filtered and washed with acetone. The combined filtrate and washings were evaporated. The residue was triturated with methyl tert-butyl ether; the solid separated was filtered and dried to give 4-(4-bromobutoxy)-2-nitrobenzamide 5. White solid (0.85 g, 70%). 1H NMR (400 MHz, CDCl3): δ 1.98-2.03 (m, 2H); 2.04-2.09 (m, 2H); 3.49 (t, J=6.0 Hz, 2H); 4.08 (t, J=5.2 Hz, 2H); 5.80 (br s, 2H); 7.13 (dd, J=2.4, 8.4 Hz, 1H); 7.47-7.52 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][OH:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21].O>CC(C)=O>[C:20]([O:12][CH2:11][CH2:10][N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: CCN(CCO)c1ccccc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCN(CCOC(C)=O)c1ccccc1
Yield: 99.9 %

Procedure:
51.8 g of 2-(N-ethylanilino)ethanol and 31.7 g of triethylamine were dissolved in 320 ml of acetone, and to this solution 24.9 g of acetyl chloride was slowly added dropwise while stirring under ice cooling. This mixture was stirred for 3 hours at room temperature, and the reaction solution was poured into 500 ml of water. An organic layer was extracted with ethyl acetate, washed with water, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 64.9 g of 2-(ethylphenylamino)ethyl acetate.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[CH:8](Br)[C:9]([C:11]([F:14])([F:13])[F:12])=O.[NH2:16][CH:17]([C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([Cl:29])=[CH:23][C:22]=1[Cl:30])[C:18]([NH2:20])=[O:19].Cl>O>[Cl:30][C:22]1[CH:23]=[C:24]([Cl:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=1[C:17]1[C:18](=[O:19])[NH:20][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][N:16]=1
Reactant: COc1cc(C(N)C(N)=O)c(Cl)cc1Cl
Reactant: O=C(C(Br)Br)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(-c2ncc(C(F)(F)F)[nH]c2=O)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixed solution of 16.7 g of sodium carbonate and 60 ml of water was added dropwise 10.6 g of 1,1-dibromo-3,3,3-trifluoroacetone at such a rate that the temperature of the reaction mixture became not higher than 55° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 30 minutes, followed by adding 80 ml of water and then 7.42 g of 2-amino-2-(2,4-dichloro-5-methoxyphenyl)acetamide, and the reaction was allowed to proceed at 60° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to 10° C. or lower, made acidic by adding 9.0 ml of concentrated hydrochloric acid at the same temperature, and extracted with ethyl acetate. The organic layer was washed with water and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=4:1), which afforded 2.2 g (yield, 22%) of the desired compound, 3-(2,4-dichloro-5-methoxyphenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (compound 1-1009).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[CH3:9]CN(C(C)C)C(C)C.BrC1[C:28]2[C:23](=[CH:24][CH:25]=[C:26](OC)[N:27]=2)[N:22]=[CH:21]C=1N>CN(C)C=O>[CH3:9][N:22]1[CH2:21][CH2:26][N:27]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=2)[CH2:28][C:23]21[CH2:24][CH2:25]2
Reactant: COc1ccc2ncc(N)c(Br)c2n1
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1ccnc(Cl)n1
Solvent: CN(C)C=O
Product: CN1CCN(c2nccc(N)n2)CC12CC2
Temperature: 120 °C
Yield: 33.4 %

Procedure:
A mixture of 2-chloro-4-pyrimidinamine (200 mg, 1.544 mmol), Hunig's base (1348 μl, 7.72 mmol) and 4-methyl-4,7-diazaspiro[2.5]octane (Ref.: WO2009061879 (A1)) (338 mg, 1.698 mmol) in N,N-dimethylformamide (DMF) (1.7 ml) was heated to 120° C. via a microwave reactor for 15 min. The reaction mixture was purified by RP-HPLC to yield 2-(4-methyl-4,7-diazaspiro[2.5]oct-7-yl)-4-pyrimidinamine (113 mg, 0.515 mmol, 33% yield). MS (ES+) m/z 220.1 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.CCN(CC)CC.[C:14](Cl)(=[O:16])[CH3:15]>C(#N)C>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:14](=[O:16])[CH3:15])[CH:6]=1
Reactant: Cc1c[nH]cn1
Reactant: CC(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)n1cnc(C)c1

Procedure:
To a solution of 4-methylimidazole (2.70 g, 33.0 mmol) in 10 mL of acetonitrile at 0° C. was added NEt3 (4.00 g, 39.6 mmol) and acetyl chloride (2.80 g, 36.3 mmol). The mixture was allowed to attain RT then filtered to remove the ppt and the filtrate was concentrated to give 1-(4-methyl-imidazol-1-yl)-ethanone, which was used without further purification in the next step. To a solution of 1-(4-methyl-imidazol-1-yl)-ethanone (4.10 g, 33.0 mmol) in 15 mL acetonitrile was added SEM-Cl (5.80 g, 35.0 mmol) and the solution was stirred at 25° C. for 10 h. The solvents were removed by evaporation and to the residue was added 100 mL of 2.5 M NaOH and the mixture was stirred at 25° C. for 1 h. The reaction mixture was then extracted with ether (3×100 mL), dried over Na2SO4 and concentrated. The title compound was purified by chromatography on Silica gel eluting with 75% EtOAc/hexanes to give 4.30 g (61%) of a colorless oil: Mass spectrum (ESI, m/z): Calcd. for C10H20N2O4Si, 213.1 (M+H). found 213.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[CH:6][N:5]=[C:4]2[N:10]([Si](C(C)C)(C(C)C)C(C)C)[CH:11]=[CH:12][C:3]=12.C([O-])([O-])=[O:24].[K+].[K+].[O:29]1[CH2:34][CH2:33]O[CH2:31][CH2:30]1>CCOC(C)=O>[Cl:1][C:2]1[C:7](/[CH:8]=[CH:31]/[C:30]([O:29][CH2:34][CH3:33])=[O:24])=[CH:6][N:5]=[C:4]2[NH:10][CH:11]=[CH:12][C:3]=12
Reactant: C1COCCO1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)c(C=O)cnc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cnc2[nH]ccc2c1Cl
Temperature: 80 °C
Yield: 50 %

Procedure:
To a solution of compound 4.0 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (1.7 g, 5 mmol, 1 equiv.) in dioxane (20 mL) at room temperature was added triethyl phosphonoacetate (3 mL, 15 mmol, 3 equiv.) and K2CO3 (3.45 g, 25 mmol, 5 equiv.). The resulting mixture was heated overnight at 80° C. under argon. Upon cooling to room temperature, the mixture was diluted with EtOAc (50 mL) and washed with water (50 mL) and brine (50 mL). The organic phase was dried over Na2SO4, after removal of solvent under vacuum. The resulting residue was purified with flash chromatography (Hexanes: EtOAc=6:1) to afford the desired product 4.1 (E)-ethyl 3-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)acrylate (0.63g; 50%). LC-MS:(M+H) 251.29
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[O:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.ClCCl.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1C=CC=CC=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:15][CH:14]=3)[O:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(-c2nc(-c3cccc(Cl)c3)co2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2nc(-c3cccc(Cl)c3)co2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 63.7 %

Procedure:
under an N2 atmosphere, 4-(4-(3-chlorophenyl)oxazol-2-yl)benzenamine (0.127 g, 0.469 mmol) was dissolved in dichloromethane (4.00 ml, 62.2 mmol). Benzoyl chloride (0.0572 ml, 0.493 mmol) was added followed by pyridine (0.200 ml, 2.47 mmol), and the reaction was allowed to stir at room temperature for 2.5 hours. The reaction was diluted with ethyl acetate and washed with 0.1N N HCl, and 5% NaHCO3. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude solid was triturated with ethyl acetate/hexanes and the resulting solid was collected by filtration to afford N-(4-(4-(3-chlorophenyl)oxazol-2-yl)phenyl)benzamide (0.112 g, 63.7% yield). ESI m/z=375.1 (M+H+).
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)=[O:5].[C:19]1([Mg]Br)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH4+].[Cl-]>C1COCC1>[C:4]([CH:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH2:7]1)(=[O:5])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)C1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
A stirred solution of tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate (2.27 g, 8.8 mmol) in dry THF (40 mL) was cooled in an ice bath and 1 M PhMgBr in THF (20 mL, 20.0 mmol) was added dropwise over 2 min. The mixture was stirred and the ice bath was allowed to melt. After 3 h, the mixture was poured into satd aq NH4Cl and extracted with ether (2×200 mL). The combined ether extracts were dried over MgSO4 and concentrated to leave an oil. Flash chromatography on a 40-g silica cartridge eluted with a 0 to 50% EtOAc in hexanes gradient afforded tert-butyl 3-benzoylpyrrolidine-1-carboxylate (2.04 g, 84%) as a clear colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][N:7]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:5])[CH3:2].[C:22](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.CCOCC>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][N:10]([CH3:22])[CH2:9][CH2:8][N:7]1[S:12]([C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)(=[O:13])=[O:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CNCCN1S(=O)(=O)c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C1CN(C)CCN1S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of 0.469 g (1.484 mmol) of the product of Example 52 dissolved in 10 mL of DMF was added 0.614 g (4.452 mmol) of potassium carbonate followed by 0.092 mL (1.484 mmol) of iodomethane and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was then diluted with ether and washed with water. The organics were dried over Na2SO4, filtered and concentrated in vacuo to provide 0.446 g (91%) of the N-methyl amine as a colorless oil. Electrospray Mass Spec: 330.9 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4](=[O:13])[CH:3]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl:22][C:23]1[CH:31]=[C:30]2[C:26]([C:27]([CH2:32][C:33]([NH2:36])([CH3:35])[CH3:34])=[CH:28][NH:29]2)=[CH:25][CH:24]=1>>[NH2:36][C:33]([CH3:34])([CH3:35])[CH2:32][C:27]1[C:26]2[C:30](=[CH:31][C:23]([Cl:22])=[CH:24][CH:25]=2)[NH:29][C:28]=1[CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[C:4](=[O:13])[CH2:5][CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]=1[OH:1]
Reactant: O=Cc1ccccc1
Reactant: O=C1C=C(O)C(c2ccccc2)C1
Reactant: CC(C)(N)Cc1c[nH]c2cc(Cl)ccc12
Product: CC(C)(N)Cc1c(C(C2=C(O)C(c3ccccc3)CC2=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
Using general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) was reacted with benzaldehyde and 2-(6-chloro-1H-indol-3-yl)-1,1-dimethyl-ethylamine (prepared in analogy to Lit. 9) to give the title compound as a pale yellow solid. MS: 485.4 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][O-:10].[Na+].O>CO>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:10][CH3:9])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(Br)cn1
Temperature: 70 °C
Yield: 84.1 %

Procedure:
A mixture of 2,5-dibromopyridine (10 g, 42.37 mmol) and NaOMe (6.86 g, 127.1 mmol) in MeOH (100 mL) was heated at 70° C. and refluxed for 10 h. The mixture was allowed to cool to room temperature, was treated with water (100 mL) and extracted with EtOAc (2×150 mL). The combined organic extracts were dried over sodium sulphate and concentrated under reduced pressure to give a pale yellow, volatile oil of 5-bromo-2-methoxypyridine (6.7 g, 84% yield), which was used without purification in the next step. 1H NMR (400 MHz, CDCl3): δ 8.19 (s, 1H), 7.62 (dd, 1H), 6.65 (d, 1H), 3.90 (s, 3H); LC-MS m/z calcd for [M+H]+ 189.96. found 190.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]([CH3:14])([CH3:13])[CH2:9][C:10](=O)[CH3:11])([CH3:4])([CH3:3])[CH3:2].[C:16]([O:19][CH2:20][CH3:21])(=[O:18])[CH3:17].Cl>O1CCCC1>[CH2:20]([O:19][C:16](=[O:18])/[CH:17]=[C:10](\[CH3:11])/[CH2:9][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])([CH3:13])[CH3:14])[CH3:21]
Reactant: CC(=O)CC(C)(C)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)CC(C)(C)NC(=O)OC(C)(C)C

Procedure:
(1,1-dimethyl-3-oxobutyl)carbamic acid tert-butylester (2.5 g; 11.6 mmol) was dissolved in tetrahydrofuran (15 mL) and added dropwise to the reaction mixture which was heated to reflux for 12 h. Ethyl acetate (100 mL) and hydrochloric acid (1 N; 100 mL) were added and the phases were separated. The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with an aqueous solution of sodium hydrogen carbonate (saturated; 100 mL), dried (magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica (3×40 cm) using ethyl acetate/heptane (1:2) as eluent to afford 2.0 g of (E)-5-tert-Butoxycarbonylamino-3,5-dimethylhex-2-enoic acid ethyl ester.
Reaction SMILES: [C:1]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:6]=[C:5]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][CH2:15][NH:16]C(=O)OC(C)(C)C)[CH:4]=[C:3]([CH2:24][NH:25][CH2:26][CH2:27][CH2:28][NH:29][CH2:30][CH2:31][CH2:32][NH:33]C(=O)OC(C)(C)C)[CH:2]=1.[ClH:47]>>[Cl-:47].[C:1]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:6]=[C:5]([CH2:7][NH2+:8][CH2:9][CH2:10][CH2:11][NH2+:12][CH2:13][CH2:14][CH2:15][NH3+:16])[CH:4]=[C:3]([CH2:24][NH2+:25][CH2:26][CH2:27][CH2:28][NH2+:29][CH2:30][CH2:31][CH2:32][NH3+:33])[CH:2]=1.[Cl-:47].[Cl-:47].[Cl-:47].[Cl-:47].[Cl-:47]
Reactant: Cl
Reactant: CC(C)(C)OC(=O)NCCCNCCCNCc1cc(CNCCCNCCCNC(=O)OC(C)(C)C)cc(-c2ccccc2)c1
Product: [Cl-]
Product: [NH3+]CCC[NH2+]CCC[NH2+]Cc1cc(C[NH2+]CCC[NH2+]CCC[NH3+])cc(-c2ccccc2)c1
Reaction time: 2 h
Yield: 60 %

Procedure:
To the crude N1,N1′-([1,1′-biphenyl]-3,5-diylbis(methylene))bis(N3-(3-ammoniopropyl)propane-1,3-diaminium) chloride from Step 2 was added methanolic HCl (150 mL, 1.0 M). The reaction mixture was stirred for 2 h and concentrated under reduced pressure. The solid was collected by vacuum filtration and washed with Et2O (30 mL) and hot MeOH (30 mL) to afford the desired product (6.8 g, 60%) as a white solid. 1H NMR (D2O, 500 MHz) δ ppm 7.85 (s, 2H), 7.74 (d, J=7.5 Hz, 2H), 7.59-7.56 (m, 3H), 7.50-7.49 (m, 1H), 4.38 (s, 4H), 3.29 (t, J=8.0 Hz, 4H), 3.23 (q, J=5.0 Hz, 8H), 3.14 (t, J=8.0 Hz, 4H), 2.25-2.19 (m, 4H), 2.17-2.11 (m, 4H). 13C NMR (125 MHz, D2O) 142.3, 138.8, 132.1, 130.0, 129.5, 129.2, 128.4, 127.0, 50.8, 44.7, 44.6, 44.2, 36.5, 23.7, 22.7. LRMS [M+H]+441.4.
Reaction SMILES: C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5[CH:36]=[C:35]([C:37](N)=[O:38])[CH2:34][CH:33]=[CH:32]5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.[C:45]([C:53](OC)=O)(=O)[C:46]1C=CC=C[CH:47]=1.P([O-])([O-])([O-])=O.[OH-].[Na+]>C(OCC)C.CCCCCC.CC(O)C>[C:33]1([C@H:34]2[CH2:36][C@@H:35]2[CH2:37][OH:38])[CH:32]=[CH:47][CH:46]=[CH:45][CH:53]=1
Reactant: COC(=O)C(=O)c1ccccc1
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCCCCC
Solvent: CCOCC
Product: OC[C@H]1C[C@@H]1c1ccccc1
Temperature: 25 °C

Procedure:
A reaction mixture was formed by admixing (i) 50 mg NAD, (ii) 4 ml of 2-propanol and (iii) 5 mmoles of 1-carboxyaldehyde-2-phenylcyclopropane (Example 5), Compound 5, in a liquid medium containing 1 gm of lyophilized PED alcohol dehydrogenase preparation, 75 ml of 50 mM phosphate buffer, pH 7.1, and 25 ml of hexane. The pH of the reaction was maintained constant by addition of 1N NaOH. The reaction mixture was maintained at room temperature until product formation stopped. When product formation stopped, (S,S)-2-phenylcyclo-propylmethanol, Compound 5a, was isolated by removal of the hexane layer and extraction of the aqueous layer with ethyl ether (3×75 ml).
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][N:16]4[CH2:21][CH2:20][CH:19]([NH:22][C:23]([C:25]5[CH:26]=[N:27][O:28][C:29]=5[CH3:30])=[O:24])[CH2:18][CH2:17]4)[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.COC(OC)N(C)C.O.C(OCC)(=O)C>O1CCCC1>[N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][N:16]4[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:24])[CH:25]([C:26]#[N:27])[C:29](=[O:28])[CH3:30])[CH2:18][CH2:17]4)[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: Cc1oncc1C(=O)NC1CCN(Cc2ccc3c(c2)Nc2nccnc2S3)CC1
Agent: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)C(C#N)C(=O)NC1CCN(Cc2ccc3c(c2)Nc2nccnc2S3)CC1
Yield: 22 %

Procedure:
To 10 ml of a solution of 500 mg of N-[1-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-piperidin-4-yl]-5-methyl-1,2-oxazole-4-carboxamide in tetrahydrofuran was added 400 μl of N,N-dimethylformamide dimethyl acetal and the resulting mixture was heated under reflux for 4 hours. After distributing into water and ethyl acetate, the aqueous layer was extracted and washed with diethyl ether. After distilling off the organic solvent contained therein under reduced pressure, the residue was acidified with dilute hydrochloric acid and purified by high-porous gel chromatography (CHP20P, 75-150μ; manufactured by Mitsubishi Chemical Industries) (eluted with methanol/water) to thereby give 110 mg of the title compound as pale yellow crystals.