Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].CO.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[CH2:19][CH3:20])=[CH:14][CH:13]=1>O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[N:2][OH:3])[CH2:19][CH3:20])=[CH:14][CH:13]=1
Reactant: CCC(=O)c1ccc(F)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCC(=NO)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
Hydroxylamine hydrochloride (7.5 g, 108 mmol) and sodium acetate (8.9 g, 108 mmol) were added to 50 mL of methanol and the resulting white slurry was stirred at room temperature for 30 min. 1-(4-Fluorophenyl)propan-1-one (15 g, 98.6 mmol) was added and the mixture was stirred at room temperature for 20 hours. Water (50 mL) was added and the mixture was stirred for 10 min. The product was extracted with EtOAc and the organic layer was washed with saturated NaHCO3 solution and dried over MgSO4. The solvent was evaporated in vacuo to give 16.4 g of the title compound. MS: (+) m/z 168.36 (M+1).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]2[C:26]([C:27]([O-:29])=[O:28])=[C:25]([CH2:30][CH3:31])[N:24]=[CH:23][N:22]=2)=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH3:10].CI>CC(CC)=O>[CH2:7]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH:20][C:21]2[C:26]([C:27]([O:29][CH3:1])=[O:28])=[C:25]([CH2:30][CH3:31])[N:24]=[CH:23][N:22]=2)=[CH:16][CH:17]=1)[CH2:8][CH2:9][CH3:10]
Reactant: O=C([O-])[O-]
Reactant: CCCCOc1ccc(CCNc2ncnc(CC)c2C(=O)[O-])cc1
Agent: [K+]
Solvent: CI
Solvent: CCC(C)=O
Product: CCCCOc1ccc(CCNc2ncnc(CC)c2C(=O)OC)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
Potassium carbonate (0.27 g, 1.95 mmol) was added to a solution of 4-(2-(4-butoxyphenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate acid (0.34 g, 0.99 mmol) in ethyl methyl ketone (20 ml), and methyl iodide (0.42 g, 2.96 mmol) was added. After stirring at 65° C. for 3 hours, the mixture was cooled to room temperature. The resulting solid was filtered off and the solvent was evaporated. The reside was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired methyl 4-(2-(4-butoxyphenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.26 g, 73%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([O:14]C)=[N:12][C:11]2[C:6]1=[N:7][C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:9][C:10]=2[NH2:16].Cl.N>CO.O1CCOCC1>[NH2:16][C:10]1[N:9]=[C:8]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[N:7]=[C:6]2[C:11]=1[NH:12][C:13](=[O:14])[N:5]2[CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCl)c2n1
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCl)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The product of step (i) (29.8 g) was dissolved in methanol (60 ml) and treated with 4M hydrogen chloride in dioxane (60 ml). The mixture was stirred at room temperature for 2 hours, cooled to 0° C. and neutralised with 3.5% aqueous ammonia solution. The solid was filtered off, washed with water then methanol and dried Yield 27.2 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]([OH:18])[CH2:10][CH2:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)[CH:5]=[CH:6][CH:7]=1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[C:22]([Si:19]([CH3:21])([CH3:20])[O:18][CH:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:10][CH2:11][CH:12]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C1CCC(CCC(O)Cc2cccc(F)c2)N1
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(F)c1
Yield: 87.6 %

Procedure:
Following the procedure described for Preparation 8, Step C, 5-[4-(3-fluoro-phenyl)-3-hydroxy-butyl]-pyrrolidin-2-one (2.23 g, 8.87 mmol) was reacted with tert-butyldimethylsilyl chloride (1.47 g, 9.76 mmol). Purification by medium pressure chromatography using a solvent gradient (1:1 hexanes:EtOAc to EtOAc to 1% MeOH in CH2Cl2 to 2% MeOH in CH2Cl2 to 4% MeOH in CH2Cl2) provided 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-fluoro-phenyl)-butyl]-pyrrolidin-2-one (2.84 g). 1H NMR (CDCl3) δ7.23 (m, 1H), 6.88 (m, 3H), 5.75 (m, 1H), 3.85 (m, 1H), 3.57 (m, 1H), 2.71 (m, 2H), 2.30 (m, 2H), 2.25 (m, 1H), 1.70-1.38 (m, 5H), 0.84 (s, 9H), 0 (s, 3H). −0.2 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:4]=2[N:5]=[C:6](/[CH:8]=C/C2C=CC=CC=2)[N:7]=1.[O:21]1CCOCC1.O>O=[Os](=O)(=O)=O>[Cl:1][C:2]1[C:3]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:4]=2[N:5]=[C:6]([CH:8]=[O:21])[N:7]=1
Reactant: C1COCCO1
Reactant: O=C1CCc2c(Cl)nc(/C=C/c3ccccc3)nc2N1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: O=Cc1nc(Cl)c2c(n1)NC(=O)CC2
Temperature: 0 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
4-Chloro-2-[(E)-2-phenylethenyl]-5,8-dihydropyrido[2,3-d]pyrimidin-7(6H)-one (0.18 g, 0.64 mmol) was dissolved in a 2:1 solution of 1,4-dioxane/water (6 mL) and cooled to 0° C. NalO4 (0.314 g, 1.47 mmol) and catalytic OsO4 (1 mL, 4% aq. solution) were added and the solution was then stirred at ambient temperature for 16 h. The reaction solution was concentrated under vacuum, diluted with water, and extracted with 10% MeOH/DCM (4×). The organic layers were combined, dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was then purified by column chromatography (silica gel) using a DCM/DCM-MeOH—NH4OH (90:10:1) gradient to yield the desired compound as an off-white solid (0.05 g, 44%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:6]=1[CH:7]=O)[CH:2]=[CH2:3].[CH3:14][C:15]([S:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>C1COCC1.O.C(Cl)Cl.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:6]=1[CH:7]=[N:20][S:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(Cl)cc1C=O
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCOc1ccc(Cl)cc1C=NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2-allyloxy-5-chloro-benzaldehyde (8.55 g, 43.48 mmol, 1.0 eq.) and 2-methyl-2-propanesulfinamide (6.86 g, 56.64 mmol, 1.3 eq.) in THF (200 mL), titanium (IV) ethoxide (52.3 mL, 49.84 mmol, 1.1 eq.) was added dropwise. The reaction mixture was stirred at r.t. for 18 hours. The reaction mixture was diluted with water (1000 mL) and DCM (300 mL).The reaction mixture was filtered. The layers were separated. The aq. phase was extracted with DCM (2×200 mL). The comb. org. phases were washed with water (1×250 mL), sat. aq. NaCl soln. (1×150 mL), dried over MgSO4, and concentrated in vacuo. The residue was used without further purification.
Reaction SMILES: CCOC(C)=O.[O:7]=[C:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([NH:25]C(=O)OC(C)(C)C)[CH2:21][CH2:20]3)=[CH:13][CH:14]=2)[NH:9]1.Cl.CCOC(C)=O.C(Cl)(Cl)Cl>O>[NH2:25][CH:22]1[CH2:23][CH2:24][N:19]([CH2:18][C:12]2[CH:11]=[C:10]3[C:15]([CH2:16][CH2:17][C:8](=[O:7])[NH:9]3)=[CH:14][CH:13]=2)[CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccc3c(c2)NC(=O)CC3)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: NC1CCN(Cc2ccc3c(c2)NC(=O)CC3)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an EtOAc (130 mL) solution of the compound (37.8 g) obtained in Step 1-5, 4 M HCl/EtOAc solution (263 mL) was added under ice cooling and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated under reduced pressure. The residue was suspended in EtOAc (200 mL) and filtrated to obtain a solid. To the solid, CHCl3 (200 mL) and H2O (200 mL) were added and the mixture was stirred for 15 minutes. After a water layer and an organic layer were separated, the water layer was washed with CHCl3 twice. To the water layer, a 2 M aqueous NaOH solution was added to adjust to pH 10 and thereafter the solution was extracted 30 times with CHCl3. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (Chromatorex NH, mobile phase: MeOH/CHCl3=1/4; v/v) to obtain 7-[(4-aminopiperidin-1-yl)methyl]-3,4-dihydroquinolin-2(1H)-one (17.9 g, a colorless solid).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([Cl:24])[C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.C(=O)(O)[O-].[Na+].[CH2:30]([O:37][C:38](Cl)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OCC)(=O)C>O1CCCC1.O>[Cl:24][C:4]1[C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:14])([CH3:15])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=[C:2]([NH:1][C:38]([O:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:39])[CH:3]=1
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc(N)cc(Cl)c21
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc(NC(=O)OCc3ccccc3)cc(Cl)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
12 g (0.035 mol) of 7-amino-9-chloro-5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one are dissolved in 360 ml of dry tetrahydrofuran, treated with 10 g of ground sodium bicarbonate and 8 ml of chloroformic acid benzyl ester and stirred at room temperature for 31/2 hours. The mixture is treated with ethyl acetate and water, and separated aqueous phase is extracted twice with ethyl acetate and the combined organic extracts are dried and evaporated. The residue is chromatographed on 600 g of silica gel with methylene chloride/ethyl acetate (20:1 ) as the elution agent. From ether there is obtained benzyl 9-chloro-5-(o-fluorophenyl)-2,3-dihydro-1,3,3-trimethyl-2-oxo-1H-1,4-benzodiazepine-7-carbamate of melting point 212°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[C:3]([CH:7]=O)[CH2:2]1.[C:9]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:11][CH2:12][CH3:13])=[O:10]>ClCCl>[O:1]1[CH2:6][CH2:5][CH:4]=[C:3](/[CH:7]=[CH:14]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2]1
Reactant: O=CC1=CCCOC1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/C1=CCCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
To 5,6-dihydro-2H-pyran-3-carbaldehyde (5.0 g) in dry dichloromethane (150 ml) at 0° C., was added carbethoxymethylene-triphenylphosphorane (15.53 g). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was diluted with dichloromethane (150 ml) and washed with water (150 ml) and a saturated aqueous solution of brine (150 ml). The organic layer was dried by passing through a hydrophobic frit and concentrated in vacuo. to afford a yellow oil. The product was purified by silica chromatography (120 g) (ISCO) using a gradient elution of 0-10% cyclohexane:ethyl acetate to afford the title compound as a clear oil (5.59 g).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:10]([N:17]=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[OH:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Oc1ccccc1C=NCc1ccccc1

Procedure:
A mixture of 5.0 mL of 2-hydroxy-benzaldehyde, 6.3 mL of benzylamine and 0.05 g of p-toluenesulphonic acid was refluxed in toluene for 2 hours using a Dean-Stark trap to remove liberated water. The volatiles were removed in vacuo yielding 10.1 g of crude 2-(benzylimino-methyl)-phenol.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[CH:10]([C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C.C(OCC)(=O)C>[CH2:1]([N:3]([CH2:10][C:12]1[NH:13][CH:14]=[N:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=Cc1c[nH]cn1
Reactant: CCNc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCN(Cc1cnc[nH]1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
To a solution of N-ethylaniline (0.145 g, 1.2 mmol) in 1,2-dichloroethane (5 ml) were added molecular sieves (2 g, size 0.4 nM) and 4-formylimidazole (0.3 g, 3.12 mmol). After stirring the mixture for 5 min at room temperature sodium triacetoxyborohydride (1.02 g, 4.8 mmol) and acetic acid (5 drops) were added. The reaction mixture was stirred at room temperature overnight. For workup ethyl acetate (50 ml) and 1 M sodium bicarbonate solution (30 ml) were added and the mixture was shaken. The organic layer was separated, dried over magnesium sulfate and evaporated. The residue was purified using flash chromatography (column: Isolute® Flash-NH2 (Separtis); eluent: ethyl acetate/methanol=95:5) to yield a white solid (122 mg, 51%); MS (ISP): 202.0 ((M+H)+.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)([O-:3])=[O:2].C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:25]([O:14][CH:11]1[CH2:10][CH2:9][N:8]([CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:13][CH2:12]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1cccc(CN2CCC(O)CC2)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OC1CCN(Cc2cccc([N+](=O)[O-])c2)CC1)c1ccccc1
Yield: 57.7 %

Procedure:
0.5 g (0.00212 mol) of 1-(3-nitro-benzyl)-piperidin-4-ol and 0.595 ml (0.00424 mol) of triethylamine were dissolved in 15 ml of toluene, treated with 0.295 ml (0.00254 mol) of benzoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.416 g (58%) of 1-(3-nitro-benzyl)-piperidin-4-yl benzoate was obtained as yellow crystals; m.p. 54°-55°.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:9](=[O:12])[NH:10][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]2[N:4]([C:9](=[O:12])[N:10]([CH2:14][C:15]3[CH:20]=[N:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1[nH]nc2c(Br)c(Cl)ccn12
Reactant: FC(F)(F)c1ccc(CCl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2c(Br)c(Cl)ccn12
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 80.6 %

Procedure:
To a solution of 8-bromo-7-chloro-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (515 mg, 2.258 mmol) in anhydrous DMF (10 mL) was added 5-(chloromethyl)-2-(trifluoromethyl)pyridine (883 mg, 4.518 mmol), followed by solid potassium carbonate (624 mg, 4.518 mmol). The resulting suspension was stirred under argon at 80° C. for 1.5 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water, and the aqueous layer was extracted with EtOAc twice. The combined EtOAc extracts were washed with water, then saturated aqueous NaCl, dried over Na2SO4, and evaporated under reduced pressure to provide crude product as a brown solid. The crude product was purified by silica gel (40 g) column chromatography eluting with a gradient of EtOAc (0-60%) in hexanes to obtain the title compound as a beige solid (742 mg, 81%). HPLC/MS: retention time=3.17 min, [M+H]+=407. See 7,8-bis(4-chlorophenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one for data addressing the question of N vs. O-alkylation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[CH:24])=[CH:17][C:16]=2[C:25]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=2)=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[O-:36][C:37]#[N:38].[Na+].C(OCC)(=O)C.O>CC(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][N:14]2[C:15]3[C:16](=[CH:17][C:18]([O:21][CH2:22][C:23]#[CH:24])=[CH:19][CH:20]=3)[C:25]([C:27]3[CH:32]=[CH:31][C:30]([CH:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=3)=[N:38][C:37]2=[O:36])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: N#C[O-]
Reactant: C#CCOc1ccc(NCCCc2ccc(OC)c(OC)c2)c(C(=O)c2ccc(C(C)C)cc2)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2CCCc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 338 mg (0.72 mmol) of the product prepared in step C in 6 ml AcOH is treated with 70 mg (1.1 mmol) sodium cyanate. The mixture is stirred for 1.5 h at rt. A yellow product results after work-up with ethyl acetate/water, which is purified by chromatography (CH2Cl2/MeOH) to afford a yellow foam.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14]([N:16]1[CH2:24][C@H:23]([O:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH:36]=[CH2:37])[CH:34]=3)[N:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:27]=2)[CH2:22][C@H:17]1[C:18]([O:20][CH3:21])=[O:19])=[O:15])[CH2:10][CH2:11][CH2:12][CH3:13])=O)(C)(C)C.Cl.CCN(C(C)C)C(C)C.[CH2:54]([S:59](Cl)(=[O:61])=[O:60])[CH2:55][CH2:56][CH:57]=[CH2:58]>CCOC(C)=O.CN(C=O)C>[CH2:54]([S:59]([NH:8][C@H:9]([C:14]([N:16]1[CH2:24][C@H:23]([O:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH:36]=[CH2:37])[CH:34]=3)[N:29]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:27]=2)[CH2:22][C@H:17]1[C:18]([O:20][CH3:21])=[O:19])=[O:15])[CH2:10][CH2:11][CH2:12][CH3:13])(=[O:61])=[O:60])[CH2:55][CH2:56][CH:57]=[CH2:58]
Reactant: C=CCCCS(=O)(=O)Cl
Reactant: C=Cc1ccc2nc(-c3ccccc3)cc(O[C@@H]3C[C@@H](C(=O)OC)N(C(=O)[C@H](CCCC)NC(=O)OC(C)(C)C)C3)c2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCCS(=O)(=O)N[C@@H](CCCC)C(=O)N1C[C@H](Oc2cc(-c3ccccc3)nc3ccc(C=C)cc23)C[C@H]1C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.4 %

Procedure:
Compound 32 (115 mg, 0.196 mmol) was dissolved in EtOAc (5 mL) cooled to 0° C. and treated with anhydrous HCl gas for 10 min. The reaction mixture was then concentrated to give a solid. The solid was dissolved in DMF (2 mL) and DIPEA (0.1 mL, 0.57 mmol) was added. The reaction was cooled to 10° C. and 4-pentenesulfonyl chloride (35 mg, 0.20 mmol) (Culshaw, P. N.; Walton, J. C., J. Chem. Soc., Perkin Trans. 2 (1991), 8, p 1201) was then added. The mixture was stirred at RT for 30 min, quenched with aqueous NaHCO3 and extracted with EtOAc. The EtOAc extract was dried over NaSO4, filtered, concentrated to an oil and chromatographed on silica to give 33 (94 mg, 78% yield) as a foam. LRMS (M+1)+=620.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([O:11][C:12](=[O:23])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[CH3:10].I[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.CN(C)P(N(C)C)(N(C)C)=O>[CH2:9]([O:11][C:12](=[O:23])[CH:13]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[CH3:10]
Reactant: ICC1CCCC1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 77.2 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (430.55 mL of a 0.3M stock solution, 129.16 mmol) cooled to −78° C. was treated with (4-nitro-phenyl)-acetic acid ethyl ester (prepared as in Example 22A, 26.32 g, 125.83 mmol) in tetrahydrofuran/hexamethylphosphoramide (312.5 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. Iodomethylcyclopentane (27.75 g, 132.1 mmol) was then added in hexamethylphosphoramide (27.75 mL). The mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 16 h. The reaction mixture was then quenched by the dropwise addition of a saturated aqueous ammonium chloride solution (250 mL). This mixture was concentrated in vacuo. The residue was diluted with water (250 mL) and extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with a saturated aqueous lithium chloride solution (2×250 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 98/2 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid ethyl ester (28.30 g, 77.2%) as a yellow oil: EI-HRMS m/e calcd for C16H21NO4 (M+) 291.1470, found 291.1470.
Reaction SMILES: [N:1]1([C:7]([C:9]2[C:10]3[CH2:27][S:26](=[O:29])(=[O:28])[C:25]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:11]=3[N:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:13]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].O>C1COCC1>[CH3:37][S:38]([N:17]1[CH2:18][CH2:19][CH:14]([N:12]2[C:11]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[S:26](=[O:29])(=[O:28])[CH2:27][C:10]=3[C:9]([C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:8])=[N:13]2)[CH2:15][CH2:16]1)(=[O:40])=[O:39]
Reactant: O=C(c1nn(C2CCNCC2)c2c1CS(=O)(=O)c1ccccc1-2)N1CCOCC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCC(n2nc(C(=O)N3CCOCC3)c3c2-c2ccccc2S(=O)(=O)C3)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-(morpholin-4-ylcarbonyl)-1-piperidin-4-yl-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (30 mg, 0.066 mmol) in THF (10 mL) is added triethylamine (40 □l, 0.26 mmol) and the reaction mass is cooled to 0° C. after which methane sulfonyl chloride (0.01 mL, 0.099 mmol) is slowly added. The reaction mixture is slowly warmed to RT then stirred for 12 h. After this time, water is added to the reaction mixture that is then extracted with EtOAc. The organic layer is separated, dried under sodium sulphate and concentrated under reduced pressure. Compound is then purified by neutral alumina column chromatography (0.2% MeOH in chloroform) to afford the title compound as an off white solid. 1H NMR (DMSO-d6, 400 MHz): δ 8.20-8.18 (d, J=7.0 Hz, 1H), 7.78-7.75 (m, 1H), 7.67-7.64 (m, 1H), 7.52-7.49 (m, 1H), 4.70 (m, 3H), 4.18 (m, 2H), 4.05 (m, 2H), 3.81 (s, 6H), 2.99-2.94 (t, J=11.4 Hz, 2H), 2.80 (s, 3H), 2.47-2.42 (m, 2H), 2.24-2.18 (m, 2H). MS (ESI+): 495.0. HPLC (max plot) 93.19%; Rt 3.18 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:25])[CH2:16][NH:17]C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:26]>CO.O1CCOCC1>[Cl:26][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:25])[CH2:16][NH2:17])[CH2:10][CH2:9]2)=[CH:3][CH:4]=1
Reactant: Cl
Reactant: CC(C)(C)OC(=O)NCC(=O)NC1CCN(Cc2ccccc2)CC1
Solvent: CO
Solvent: C1COCCO1
Product: NCC(=O)NC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 1-benzyl-4-{N-(tert-butoxycarbonyl)glycyl}aminopiperidine (6.59 g) in methanol (80 mL) was added 4 N HCl in dioxane (19 mL). The solution was stirred at room temperature for 2 h. The reaction mixture was concentrated and 2 N aqueous NaOH solution (20 mL) was added. The mixture was extracted with dichloromethane (40 mL×3), and the combined extracts were dried over anhydrous sodium sulfate and concentrated. Column chromatography (SiO2, AcOEt/MeOH/Et3N=85/12/3) gave 1-(4-chlorobenzyl)-4-(glycylamino)piperidine (3.91 g, 83%): 1H NMR (CDCl3, 400 MHz) d 1.47-1.59 (m, 2 H), 1.59 (br, 2 H), 1.76-1.96 (m, 2 H), 2.10-2.19 (m, 2 H), 2.75-2.87 (m, 2 H), 3.29 (s, 2 H), 3.50 (s, 2 H), 3.65-3.89 (m, 1 H), 7.15-7.23 (m, 1 H), 7.23-7.33 (mn, 5 H).