Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[N:16]O)[CH2:11][CH2:10][CH2:9]2.Cl>[Pd].CCO>[CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[CH:12]([NH2:16])[CH2:11][CH2:10][CH2:9]2
Reactant: CN(C)CCOc1ccc2c(c1)CCCC2=NO
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN(C)CCOc1ccc2c(c1)CCCC2N

Procedure:
A mixture of 6-(2-dimethylamino-ethoxy)-3,4-dihydro-2H-naphthalen-1-one oxime (0.3 g, 1.2 mmol), EtOH (12 mL), Pd/C (Aldrich, 0.13g, 0.12 mmol), and concentrated HCl (0.24 mL) was purged with H2 and connected to a H2 balloon overnight at RT. The catalyst was filtered through Celite® and washed with MeOH. The filtrate was concentrated in vacuo. The residue was added saturated NaHCO3 and extracted with CH2Cl2. The organic solution was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (5%-10% MeOH—CH2Cl2) to afford the compound as a colorless oil. MS (ESI): 235 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15](=[O:16])[NH:14][C:13]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[N:12][C:11]=1[NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.C(N(CC)CC)C.Cl[C:45]([O:47][CH3:48])=[O:46]>ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15](=[O:16])[NH:14][C:13]([CH:17]2[CH2:18][CH2:19][N:20]([C:45]([O:47][CH3:48])=[O:46])[CH2:21][CH2:22]2)=[N:12][C:11]=1[NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nc(C3CCNCC3)[nH]c(=O)c2-c2nc3ccccc3s2)C1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(c2nc(N[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)c(-c3nc4ccccc4s3)c(=O)[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.9 %

Procedure:
Into a solution of tert-butyl (3R)-3-[[5-(1,3-benzothiazol-2-yl)-6-oxo-2-(piperidin-4-yl)-1,6-dihydropyrimidin-4-yl]amino]piperidine-1-carboxylate (100 mg, 0.20 mmol, 1.00 equiv) and triethylamine (29.7 mg, 0.29 mmol, 1.50 equiv) in dichloromethane (5 ml) was added methyl chloroformate (14.8 mg, 0.16 mmol, 0.80 equiv). The resulting mixture was stirred for 2 h at room temperature. Concentration under reducing pressure gave 100 mg of the title compound as a crude product, which was used directly for next step without further purification. MS m/z [M+H]+ (ESI): 569.
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[O:8]1[CH2:11][C:10](=O)[CH2:9]1>C1COCC1.CCOC(C)=O.[Cl-].[Na+].O>[CH3:1][C:2]([S@:5]([N:7]=[C:10]1[CH2:11][O:8][CH2:9]1)=[O:6])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=C1COC1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[S@@](=O)N=C1COC1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 20.2 %

Procedure:
To a solution of Ti(OEt)4 (2.02 g, 7.53 mmol) in THF (20 mL) was added (R)-2-methylpropane-2-sulfinamide (0.854 g, 7.05 mmol) followed by oxetan-3-one (0.493 g, 6.84 mmol) in THF (5 mL) and the reaction mixture was heated to 50° C. over night. After cooling, the reaction mixture was diluted with EtOAc (50 mL) and a saturated solution of brine (20 mL) was slowly added under stirring. After 15 min, the mixture was filtered through a plug of Dicalite and washed with EtOAc. The organic phase was separated, dried over Na2SO4 and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 40% EtOAc-heptane gradient to give the title compound (0.242 g, 20%) as a light yellow oil. MS: 176.2 (M+H+).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]12[CH2:20][CH:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=31)[C:12]1[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>CCOCC.C(OCC)(=O)C>[OH:3][CH2:4][CH2:5][C:6]12[CH2:20][CH:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=31)[C:12]1[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)CC12CC(c3ccccc31)c1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: OCCC12CC(c3ccccc31)c1ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (9,10-dihydro-9,10-methano-9-anthryl)acetic acid ethyl ester (125 mg) and lithium aluminum hydride (80 mg) in ether (6 ml) was stirred at room temperature for 1 hour. Excess lithium aluminum hydride was decomposed by addition of water. The reaction mixture was diluted with ethyl acetate, dried over anhydrous sodium sulfate and evaporated to dryness to give crystals of 9-β-hydroxyethyl-9,10-dihydro-9,10-methanoanthracene. M.P. 99°-100.5° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:10][CH:9]2[N:11](C(OCC)=O)[CH:6]([CH2:7][CH2:8]2)[CH2:5]1.Cl>>[CH:9]12[NH:11][CH:6]([CH2:7][CH2:8]1)[CH2:5][CH:4]([CH2:3][CH2:2][OH:1])[CH2:10]2
Reactant: CCOC(=O)N1C2CCC1CC(CCO)C2
Agent: Cl
Product: OCCC1CC2CCC(C1)N2
Yield: 99.6 %

Procedure:
A mixture of 7.5 parts of ethyl 3-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (prepared as in EP-A-0,320,032) and 127 parts of hydrochloric acid was refluxed for 1/2 hour and was then evaporated. The residue was taken up in water and the whole was basified with NaOH. The product was extracted with trichloromethane and the extract was washed, dried, filtered and evaporated, yielding 5.1 parts (99.6%) of 8-azabicyclo[3.2.1]octane-3-ethanol (interm. 40).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C(C[C@@H](N)CC([N:38]2[CH2:50][C:42]3=[N:43][N:44]=[C:45]([C:46]([F:49])([F:48])[F:47])[N:41]3[CH2:40][CH2:39]2)=O)=C(F)C=C(F)C=1F.O.OP(O)(O)=O.CCN(C(C)C)C(C)C.Cl.FC(F)(F)C1N2CCNCC2=NN=1.ClC1C=C(B(O)O)C=CC=1.C(OC(C)C)(C)C>O.C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:10][C:11](=[O:13])[N:38]1[CH2:39][CH2:40][N:41]2[C:45]([C:46]([F:49])([F:47])[F:48])=[N:44][N:43]=[C:42]2[CH2:50]1)[CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])([CH3:2])([CH3:3])[CH3:4]
Reactant: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Reactant: CC(C)(C)OC(=O)NC(CC(=O)O)Cc1cc(F)c(F)cc1F
Agent: Cl
Agent: FC(F)(F)c1nnc2n1CCNC2
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)OC(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5 g of 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)butyric acid of formula (II) was charged with 40 ml of xylene into a 500 ml 4 necked round bottom flask attached with dean stark apparatus followed by 5 ml of Hunig's base at room temperature. Then 5 g of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine HCl was charged and stirred for 5 minutes. 2.34 g of 3-chloro phenyl boronic acid was charged to the reaction mass. After 48 hours of stirring at reflux temperature, the reaction was complete. The reaction mass was cooled to room temperature and 50 ml of water was added to it. The organic layer was separated and washed twice with 25 ml of 1N HCl. The organic layer was separated and washed with 25 ml of water followed by 6% NaHCO3 and finally by 25 ml of water. The organic layer was then separated, treated with sodium sulfate and then with charcoal and filtered. The solvent was distilled out under vacuum. The solid obtained was stirred with 25 ml of diisopropyl ether for 2 hours, filtered, washed with diisopropyl ether and then dried under vacuum at 50° C. for 12-15 hours.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([C:16](C)(C)[O:17][SiH2]C(C)(C)C)[CH:15]=1)[C:11]#[N:12])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:17][CH2:16][C:14]1[CH:13]=[C:10]([CH:9]=[C:8]([CH2:7][OH:6])[CH:15]=1)[C:11]#[N:12]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(C#N)cc(C(C)(C)O[SiH2]C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1cc(CO)cc(CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of 3,5-bis-(tert-butyl-dimethyl-silanyloxymethyl)-benzonitrile (1.45 g, 3.702 mmol) in tetrahydrofuran (30 mL) at room temperature was added tetrabutylammonium fluoride (9.255 mL, 9.255 mmol, 1 M in tetrahydrofuran). The reaction mixture was stirred at room temperature for 2 h then concentrated in vacuo. The residue was partitioned between ethyl acetate (20 mL) and water (30 mL). The layers were separated and the product was extracted with ethyl acetate (3×20 mL). The organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solid was filtered off, and the filtrate was concentrated in vacuo. Purification of the residue by flash chromatography (Biotage system, KP-Sil™ 32-63 μm, 60 Å silica gel) eluting with 75% ethyl acetate in hexanes yielded 3,5-bis-hydroxymethyl-benzonitrile (465 mg, 77%).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:13][C:14]([N:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([C@:22]([OH:35])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH2:17]1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+]=[N-].O>CO.[Pd]>[NH2:1][CH2:4][C@@H:5]([NH:13][C:14]([N:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([C@:22]([OH:35])([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH3:28])[CH2:17]1)=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=O)N[C@H](CN=[N+]=[N-])Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COCCCC[C@@](O)(c1ccccc1)[C@@H]1CCCN(C(=O)N[C@H](CN)Cc2ccccc2)C1
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
Crude (3R)—N—((S)-3-azido-1-phenylpropan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide (210.7 mg, 91% purity, 0.4 mmol) from the previous step was dissolved in MeOH (10 mL) and was added to 0.2 g of Pd/C previously wetted with a drop of H2O. After 3 vacuum/purge cycles using 12 torr vacuum and 14 psi H2, the reaction was stirred under an atmosphere of H2 at 14 psi for 30 minutes. The crude mixture was filtered through a plug of Celite and the solvent was removed. The resulting oil was dissolved in a minimal volume of 1:1 acetonitrile:H2O then separated by prep HPLC on a C-18 column using a gradient of 0.05% TFA in H2O and acetonitrile. Appropriate fractions were combined, made slightly basic with 1 N NaOH, and the solvent was removed at 50° C. and 150 torr. The residue was taken up in CH2Cl2 (50 mL) and 1 N NaOH (10 mL). The organic layer was dried (Na2SO4), decanted and stripped to afford (3R)—N—((S)-1-amino-3-phenylpropan-2-yl)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carboxamide (61.5 mg, 34% overall yield from (R)-3-((S)-1-hydroxy-5-methoxy-1-phenylpentyl)piperidine-1-carbonyl chloride) as a clear colorless film. MS ESI+ve m/z 454 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[C:60]1([C@@H:66]([NH2:68])[CH3:67])[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>CN(C=O)C.CCOC(C)=O.O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:68][C@H:66]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[CH3:67])=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)[C@H]1CC[C@@H](C)N(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.9 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the resulting mixture was stirred at room temperature for 15 minutes. (1S)-1-phenylethanamine (58 mg, 0.478 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured into water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic layer solution was concentrated, and the formed solid was recrystallized in CH3CN to afford the title compound (186 mg) as a light yellow solid. LC-MS (ES) m/z=459 [M+H]+.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[OH:7].[OH-].[Na+]>S(=O)(=O)(O)O>[C:8]1([CH:6]2[O:7][CH2:2][CH2:3][NH:4][CH:5]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCCNC(c1ccccc1)C(O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: c1ccc(C2NCCOC2c2ccccc2)cc1
Temperature: 100 °C

Procedure:
β-[(2-Hydroxyethyl)amino]-α-phenylbenzeneethanol erythro isomer, 7.1 g (0.027 mole) was added to 20 ml of 70% sulfuric acid at 0° C. The mixture was heated at 100° C. for 3 hr and poured into ice and neutralized with 25% sodium hydroxide. The neutralized mixture was extracted with diethyl ether and the extract was dried and the solvent evaporated to give 5.8 g (54%), m.p. 70°-72° C. of solids. The solids were recrystallized from ethanol water mixture followed by low boiling petroleum ether, m.p. 82°-84° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:12][C:11]3[C:13]([C:16]4[N:17](C(OC(C)(C)C)=O)[CH:18]=[CH:19][CH:20]=4)=[CH:14][S:15][C:10]=3[C:9](=[O:28])[CH:8]=2)[CH2:3][CH2:2]1>Cl>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[O:12][C:11]3[C:13]([C:16]4[NH:17][CH:18]=[CH:19][CH:20]=4)=[CH:14][S:15][C:10]=3[C:9](=[O:28])[CH:8]=2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)n1cccc1-c1csc2c(=O)cc(N3CCOCC3)oc12
Agent: Cl
Product: O=c1cc(N2CCOCC2)oc2c(-c3ccc[nH]3)csc12
Reaction time: 8 h

Procedure:
A 20 mL vial was charged with a magnetic stirring bar, tert-butyl 2-(5-morpholino-7-oxo-7H-thieno[3,2-b]pyran-3-yl)-1H-pyrrole-1-carboxylate (94) (50 mg, 124 μmol), and hydrochloric acid (4.0 M in dioxane, 10 mL). The reaction mixture was magnetically stirred overnight at room temperature, concentrated in vacuo, and purified via reverse phase high-pressure liquid chromatography to give 5-morpholino-3-(1H-pyrrol-2-yl)-7H-thieno[3,2-b]pyran-7-one (97).
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]2[CH2:13][C:14]3[CH:20]=[C:19]([CH:21]([OH:25])[CH:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:15]=3[O:16][C:8]=12>CC(C)=O>[O:2]=[C:13]1[C:9]2[C:8](=[N:7][CH:12]=[CH:11][CH:10]=2)[O:16][C:15]2[CH:17]=[CH:18][C:19]([CH:21]([OH:25])[CH:22]([CH3:23])[CH3:24])=[CH:20][C:14]1=2
Reactant: CC(C)C(O)c1ccc2c(c1)Cc1cccnc1O2
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)C(O)c1ccc2oc3ncccc3c(=O)c2c1
Reaction time: 1 h

Procedure:
15 g of potassium permanganate is added in small portions to a solution of 11 g of 1(5H-[1]benzopyrano[2,3-b]pyridin-7-yl)-2-methyl-1-propanol in 200 ml of acetone, while the temperature is kept at 10°C. Then the mixture is allowed to stand at 20°C for 1 hour. The reaction mixture is filtered, and the crystalline residue is washed with chloroform. The filtrate and washings are concentrated, and the residue is purified by column chromatography on silica gel with chloroform as eluent, and further by recrystallization from ethanol to give 1-(5-oxo-5H-[1]-benzopyrano[2,3-b]-pyridin-7-yl)-2-methyl-1-propanol melting at 160°C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([NH2:8])[S:5][N:4]=1)[CH3:2].C1C(=O)N([Br:16])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:16][CH:1]([C:3]1[N:7]=[C:6]([NH2:8])[S:5][N:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1nsc(N)n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1nsc(N)n1
Temperature: 80 °C

Procedure:
3-Ethyl-5-amino-1,2,4-thiadiazole, 1.1 eq NBS and a small amount of AIBN were dissolved in CCl4 and refluxed at 80° C. over-night. Standard work up followed by purification on silica gel with DCM as mobile phase gave the 3-(1-bromoethyl)-5-amino-1,2,4-thiadiazole. Subsequently, 0.9 eq of NaI were dissolved in dry acetone and 3-(1-bromoethyl)-5-amino-1,2,4-thiadiazole. 1 eq of Na2CO3 and 1 eq of 3-fluorothiophenol were then added and the reaction was stirred at room temperature over-night. The reaction was quenched with water and worked up and purified using standard procedures.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:17]=[N:18][C:19](=[O:30])[N:20]([CH2:22][CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)[CH:21]=4)[S:15][C:8]=23)=[C:4]([F:33])[CH:3]=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:43](=[O:48])[CH2:44][C:45](O)=[O:46].C1C=CC2N(O)N=NC=2C=1.Cl>CN(C=O)C.C(Cl)CCl>[F:33][C:4]1[CH:3]=[C:2]([NH:1][C:45](=[O:46])[CH2:44][C:43]([NH:42][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[O:35][CH3:34])=[O:48])[CH:32]=[CH:31][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:17]=[N:18][C:19](=[O:30])[N:20]([CH2:22][CH2:23][N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[CH:21]=3)[S:15][C:8]=12
Reactant: Nc1ccc(Oc2ccnc3cc(-c4cnc(=O)n(CCN5CCOCC5)c4)sc23)c(F)c1
Reactant: COc1ccccc1NC(=O)CC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cnc(=O)n(CCN5CCOCC5)c4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.3 %

Procedure:
To a solution of the amine 416 (0.16 mmol) in DMF (1 mL) was added acid 27 (38 mg, 0.18 mmol), HOBT (24 mg, 0.18 mmol) and EDC×HCl (46 mg, 0.24 mmol). The mixture was stirred at room temperature for 16 h. The solvent was evaporated, then the residue was purified by flash chromatography with gradient of methanol (0-5%) in dichloromethane, followed by preparative HPLC purification with gradient of methanol (20-100%) in water to give title compound 412 (14 mg, 13% yield). MS (m/z): 659.1 (M+H). 1H NMR (DMSO-d6) δ (ppm): 10.59 (s, 1H), 9.64 (s, 1H), 9.16 (d, J=3.3 Hz, 1H), 8.69 (d, J=3.3 Hz, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.07 (d, J=7.4 Hz, 1H), 7.98 (s, 1H), 7.88 (dd, J=13, 2.3 Hz, 1H), 7.51 (t, J=9.0 Hz, 1H), 7.43 (dd, J=8.8, 1.6 Hz, 1H), 7.11-7.05 (m, 2H), 6.94-6.90 (m, 1H), 6.67 (d, J=4.7 Hz, 1H), 4.05 (t, J=6.5 Hz, 2H), 3.86 (s, 3H), 3.64 (s, 2H), 3.55-3.50 (m, 4H), 2.63 (t, J=5.5 Hz, 2H), 2.46-2.42 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1([OH:9])[CH2:4][CH:3]1[Si:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][C:2]1([O:9][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:4][CH:3]1[Si:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(O)CC1[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(OS(C)(=O)=O)CC1[Si](C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.2 g of a trans and cis mixture of 1-methyl-1-hydroxy-2-(trimethylsilyl)cyclopropane, prepared in Section 1, was dissolved in 15 mL of dichloromethane, and 1.7 g of triethylamine was added to the resulting solution. The reaction mixture was cooled to 0° C., 1.8 g of methanesulfonylchloride was gradually added thereto and the mixture was vigorously stirred for 1 hour. 5 mL of a saturated NaHCO3 solution was added to the reaction mixture, thereby terminating the reaction. An organic layer was separated, dried over anhydrous magnesium sulfate (MgSO4), and concentrated by low vacuum distillation at a low temperature of less than 30° C. Although it may be used directly without any further purification, the concentrate was finely purified by vacuum distillation (65-70° C./0.1 mmHg). As a result, 2.8 g of 1-methyl-1-(methanesulfonyloxy)-2-(trimethylsilyl)cyclopropane was obtained as a mixture of cis and trans isomers in a ratio of 3 to 4:1. Results of 1H-NMR and 13C-NMR for the major isomer (trans isomer) of the mixture are given below.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:27])[C@H:10]([CH2:16][NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:11](OCC)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(C)C=C(C)C=C(C)C=1[Mg]Br>O1CCCC1>[Si:1]([O:8][C@@H:9]([C@@H:10]1[CH2:16][N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:11]1=[O:12])[CH3:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H](CNCc1ccc(OC)cc1)[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: Cc1cc(C)c([Mg]Br)c(C)c1
Solvent: C1CCOC1
Product: COc1ccc(CN2C[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C2=O)cc1
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
To a solution of ethyl (2S,3R)-3-(t-butyldimethylsilyloxy)-2-(4-methoxybenzylaminomethyl)butanoate (7.91 g, crude) in tetrahydrofuran (200 ml) was added dropwise mesitylmagnesium bromide (29 ml) at room temperature. After stirring for 30 minutes, the mixture was quenched with 0.2N hydrochloric acid (250 ml) ethyl acetate (200 ml). The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate, water and an aqueous sodium chloride in turn, and then dried over magnesium sulfate. The resultant solution was evaporated, and the residue was purified by column-chromatography to give (3S)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-1-(4-methoxybenzyl)azetidin-2-one (3.55 g).
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([C:6]([N:8]2C=N[CH:10]=[CH:9]2)=[O:7])[CH:2]=1.[N:13]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:18]CC(N)[CH2:15][CH2:14]1>C(Cl)Cl>[N:13]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:18][CH2:10][CH:9]([NH:8][C:6]([N:3]2[CH:2]=[CH:1][N:5]=[CH:4]2)=[O:7])[CH2:15][CH2:14]1
Reactant: NC1CCN(c2ccccn2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(NC1CCN(c2ccccn2)CC1)n1ccnc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of CDI (1.1 g, 6.77 mmol) in DCM (100 ml) is treated with 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylamine (WO 99/65895, EP 21973) (1 g, 5.64 mmol in 50 ml of DCM) added dropwise over 30 minutes. The reaction mixture is stirred at room temperature for 15 minutes to yield the titled compound as a 10 mg/ml solution in DCM.