Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=3)=[N:10][S:11][C:7]=2[CH:6]=1.[CH3:21][NH:22][CH2:23][CH2:24][OH:25]>>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[C:8]3[CH:19]=[CH:20][C:5]([O:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][OH:25])=[CH:6][C:7]=3[S:11][N:10]=2)=[CH:13][CH:14]=1
Reactant: BrCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CNCCO
Product: CN(CCO)CCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 4, 6-(2-Bromo-ethoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and 2-(methylamino)ethanol were converted to yield 2-[[2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-ethyl]-methyl-amino]-ethanol, MS: 408 (MH+, 1Br).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[Mg].II.[C:17](O)(=[O:19])C>O1CCCC1.CN(C=O)C>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([CH:17]=[O:19])[CH:11]=[CH:10]2
Reactant: CC(=O)O
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2cc(C=O)ccc2c1

Procedure:
To a reactor equipped with a stirrer are charged 10 grams of 2-bromo-6-methoxynaphthalene prepared as in Example 7 hereof, 1.05 grams of magnesium and 35 mL of tetrahydrofuran (THF). The reaction is initiated by addition of a crystal of iodine. After one hour of heating at reflux with stirring, 10 mL of DMF mixed with 10 mL of THF is added and the mixture is again refluxed with stirring for 1.5 hours. The reaction mixture is hydrolyzed by addition of dilute acetic acid and a precipitate of crude 6-methoxy-2-naphthaldehyde is formed. The precipitate is recovered by filtration, washed with water, and purified by crystallization from methanol.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]([CH3:32])[CH2:23][CH:24]([C:26]1[N:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[NH2:25]>>[CH3:21][CH:22]([CH3:32])[CH2:23][CH:24]([NH:25][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:26]1[N:27]=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC(C)CC(N)c1cccnn1
Product: CC(C)CC(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)c1cccnn1

Procedure:
In analogy to the procedure described in Example 293, 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 69 b) and 3-methyl-1-(pyridazin-3-yl)butan-1-amine were condensed to the title product. MS (EI): m/e=432.4 [M+H]+.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[F:10][C:11]([F:33])([F:32])[C:12]1[CH:31]=[CH:30][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([NH2:29])=[N:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>C1COCC1>[F:33][C:11]([F:10])([F:32])[C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[C:24]4=[N:29][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:25]4[CH:26]=[CH:27][CH:28]=3)=[CH:21][CH:22]=2)=[CH:30][CH:31]=1
Reactant: Nc1ncccc1-c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccc(C(F)(F)F)cc4)cc3)C2=N1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 418 mg) in THF (dry) (25 mL) was added 2-chloroethanesulfonyl chloride (0.659 mL) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(4-(4-(trifluoromethyl)phenoxy)phenyl)pyridin-2-amine (690 mg) in THF (dry) (40 mL) was added at 0° C. and the mixture was stirred at room temperature overnight. The mixture was quenched with water at 0° C. Water, EtOAc and THF were added and the extracted organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was washed with IPE/EtOAc, dried in vacuo to give 9-{4-[4-(trifluoromethyl)phenoxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (579.1 mg) as a slightly yellow solid. Platinum(IV) oxide (30 mg) was added to a solution of 9-{4-[4-(trifluoromethyl)phenoxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (505 mg) in THF (dry) (15 mL) and MeOH (15 mL) and the mixture was stirred at room temperature under hydrogen for 6 hr. Platinum(IV) oxide (30 mg), MeOH (15 mL) and THF (dry) (15 mL) were added and the mixture was stirred at 50° C. under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (297.2 mg) as colorless crystals.
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:12]([NH:15][CH:16]([CH3:21])[CH2:17][CH2:18][CH:19]=[CH2:20])[CH:13]=[CH2:14].C(N(CC)CC)C>C(Cl)Cl>[CH2:4]([O:3][C:1](=[O:2])[N:15]([CH2:12][CH:13]=[CH2:14])[CH:16]([CH3:21])[CH2:17][CH2:18][CH:19]=[CH2:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C=CCCC(C)NCC=C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCCC(C)N(CC=C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
Carbobenzyloxy chloride (9.56 g, 8 ml) was added dropwise to a stirred solution of allyl-(1-methyl-pent-4-enyl)-amine (7 g, 50 mmol), triethylamine (5.5 g, 8.0 ml, 57.5 mmol) in CH2Cl2 (100 ml) at 0 C. The reaction mixture was warmed to RT, then was stirred for 2 h. The reaction mixture was diluted with CH2Cl2 (100 ml), then was extracted with water, then brine. The combined organics were dried with MgSO4, filtered, concentrated in vacuo by rotary evaporation, then was chromatographed (silica gel, 4% EtOAc/hexanes) to give the title compound (8.9 g, 65% yield): Liquid Chromatgraphy/Electrospray mass spec: M+H+=274.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:40][NH:41][C@H:42]([CH2:61][C:62]1[CH:71]=[CH:70][C:69]2[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH:63]=1)[C:43]([N:45]([CH3:60])[C@@H:46]([CH2:53][N:54]([CH3:59])[S:55]([CH3:58])(=[O:57])=[O:56])[CH2:47][C:48]1[S:49][CH:50]=[CH:51][CH:52]=1)=[O:44].C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:41]([CH3:40])[C@@H:42]([C:43](=[O:44])[N:45]([CH3:60])[C@@H:46]([CH2:53][N:54]([CH3:59])[S:55]([CH3:58])(=[O:57])=[O:56])[CH2:47][C:48]1[S:49][CH:50]=[CH:51][CH:52]=1)[CH2:61][C:62]1[CH:71]=[CH:70][C:69]2[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=2)[CH:63]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1cccs1)CN(C)S(C)(=O)=O
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C)[C@H](Cc1cccs1)CN(C)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid (158 mg, 0.65 mmol) was dissolved in N,N-dimethylformamide (3 ml) and dichloromethane (3 ml). 1-Hydroxy-7-azabenzotriazole was added. The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (88 mg, 0.65 mmol) was added. The reaction mixture was stirred for 15 min at 0° C. A solution of (2R)-2-Methylamino-N-methyl-N-((1R)-1-((N-methyl-N-(methylsulfonyl)amino)methyl)-2-(2-thienyl)ethyl)-3-(2-naphthyl)propionamide in dichloromethane (3 ml) and ethyldiisopropylamine (0.12 ml, 0.65 mmol) were added successively. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was diluted with ethyl acetate (50 ml) and washed with 10% aqueous sodium hydrogen sulfate solution (50 ml). The aqueous phase was extracted with ethyl acetate (2×50 ml). The organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified on silica (120 g), using ethyl acetate/heptane 2:1 (250 ml) and successively ethyl acetateiheptane 3:1 as eluent, to give 282 mg of ((3E)-1,1-dimethyl-4-(N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-((N-methyl-N-(methylsulfonyl) amino)methyl)-2-(2-thienyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamoyl)but-3-enyl)carbamic acid tert-butyl ester.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[NH:9][CH2:10][CH2:11][OH:12].F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.O>CN(C=O)C>[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[NH:9][CH2:10][CH2:11][O:12][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: OCCNc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCNc2ncccn2)cc1
Temperature: 80 °C

Procedure:
Sodium hydride (1.2 g; 60% dispersion in oil) was added portionwise to a stirred solution of 2-(2-pyrimidinyl amino)ethanol (4 g) in DMF (140 ml) under an atmosphere of nitrogen. After the vigorous reaction had subsided 4-fluorobenzaldehyde (5.35 g) was added and the solution heated to 80° C. for 20 hours. After cooling the mixture was added to water (500 ml) and extracted with diethyl ether (3×300 ml). The organic extracts were washed with brine (2×200 ml), dried (MgSO4), filtered and evaporated to dryness. Chromatography of the residue on silica gel in 2% methanol in dichloromethane afforded the title compound, which was used in the next stage without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][NH2:9])[N:3]=1.CCOCC.Cl.[N:16]([O-])=O.[Na+]>O>[N:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[N:3]=1)=[N+:9]=[N-:16]
Reactant: NNc1cccc(Cl)n1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: [N-]=[N+]=Nc1cccc(Cl)n1
Reaction time: 2 h

Procedure:
To a 250 ml round-bottom flask equipped with a mechanical stirrer, a Claisen head and an addition funnel were added 2-chloro-6-hydrazinopyridine (4.00 g, 27.9 mmol), Et2O (20 mL) and concentrated hydrochloric acid (12 mL, 146 mmol). A solution of sodium nitrite (2.211 g, 32.0 mmol) in water (28 mL) was added dropwise to the cooled (0° C.) reaction mixture. The insoluble starting material gradually dissolved. After 2 h, the aqueous phase was extracted with ether (2×50 mL). The combined organic phase was dried over MgSO4, and concentrated in vacuo to provide the title compound as yellow crystals: LCMS m/z 155.14 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:9](OC(=O)C)(=[O:11])[CH3:10].C(OC(C)C)(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:11])[CH3:10]
Reactant: OCCCCCCBr
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: CC(=O)OCCCCCCBr
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
20.1 g (0.16 mol) of DMAP were added to 297.4 g (1.64 mol) of 6-bromo-1-hexanol in 1500 ml of THF. A solution of 184.4 g (1.81 mol) of acetic anhydride in 300 ml of THF was added dropwise in such a way that the reaction temperature did not exceed 30° C. After completion of the addition, the mixture was stirred for a further 30 minutes. The reaction mixture was mixed with 500 ml of diisopropyl ether and extracted successively with 700 ml each of water, 2× saturated NaHCO3 solution and water. After drying over sodium sulfate, the solvent was removed in vacuo. 352.8 g (1.58 mol, 96%) of 6-bromohexyl acetate were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1F)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([NH:29][CH3:30])[CH3:28]>>[C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:29]([CH2:27][CH3:28])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1F)C(=O)OC(C)(C)C
Reactant: CCNC
Product: CCN(C)c1ccc([N+](=O)[O-])cc1CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 42 %

Procedure:
Using the compound obtained in Example 263 as a starting material and also using ethylmethylamine as a reagent, the same procedure of Example 264 gave the titled compound (yield, 42%).
Reaction SMILES: N[C@H:2]([C:10]([OH:12])=[O:11])CC1C=CC=CC=1.[NH2:13][C@H:14]([C:16]([OH:18])=[O:17])[CH3:15]>>[NH2:13][C@H:14]([C:16]([OH:18])=[O:17])[CH2:15][CH2:2][C:10](=[O:11])[OH:12]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C[C@H](N)C(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
1.02 His: 0.99 Phe: 0.96 Ala: 0.98
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH:7]1S[C:11]2[S:13][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:15][C:10]=2[CH:9]([NH:20][C:21](=[O:24])[CH2:22][CH3:23])[CH2:8]1.OO.[O-][S:28]([O-:30])=[O:29].[Na+].[Na+]>CCOC(C)=O.O>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH:7]1[S:28](=[O:30])(=[O:29])[C:11]2[S:13][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:15][C:10]=2[CH:9]([NH:20][C:21](=[O:24])[CH2:22][CH3:23])[CH2:8]1
Reactant: CCC(=O)NC1CC(COCCOC)Sc2sc(S(N)(=O)=O)cc21
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(=O)NC1CC(COCCOC)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 98.5 %

Procedure:
To a solution of 10 (37.3 g, 0.095 mol) in EtOAc (1 l ) under N2 stirred at r.t. was added NaWO4 ·2H2O (2.9 g, 0.009 mol) in H2O (45 mol). After 15 min., 30% H2O2 (27 ml, 0.26 mol) was added dropwise. After addition, the solution was heated at 40° C. After 3.5 h, Na2SO3 (12 g, 0.095 mol) in H2O (12.5 ml) was added until a negative starch iodide test was observed. The layers were separated, extracted with EtOAc (1×) and the organic layers were washed with saturated NaCl, dried, filtered and concentrated to dryness to yield 39.9 g (98%) of 11.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14](OCC)=[O:15])=[CH:12][N:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[Li+].[BH4-]>C1COCC1>[OH:15][CH2:14][C:13]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:10]=[N:11][CH:12]=1
Reactant: CCOC(=O)c1cnnn1-c1ccc(C#N)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(-n2nncc2CO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.3 %

Procedure:
To a solution of ethyl 1-(4-cyanophenyl)-1H-1,2,3-triazole-5-carboxylate (650 mg, 2.68 mmol, 1.00 equiv) in THF (15 mL) at 0° C. was added LiBH4 (177.3 mg, 8.06 mmol, 3.00 equiv) in portions. The resulting solution was stirred at room temperature for 3 h and then quenched with 100 mL of saturated NH4Cl solution. The mixture was extracted with 3×100 mL of ethyl acetate. The combined organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-50% of ethyl acetate in petroleum ether to give 200 mg (37%) of 4-[5-(hydroxymethyl)-1H-1,2,3-triazol-1-yl]benzonitrile as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 8.12 (d, J=8.0 Hz, 2H), 7.96 (d, J=8.0 Hz, 2H), 7.90 (s, 1H), 5.60 (t, J=5.2 Hz, 1H), 4.65 (d, J=5.2 Hz, 2H) ppm. LCMS (method A, ESI): RT=1.07 min, m/z=201.0 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:21]=[CH:20][C:8]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:7][CH:6]=1)#[N:4].S(OCC)(O[CH2:26][CH3:27])(=O)=O.O>CN(C=O)C>[C:3]([C:5]1[CH:21]=[CH:20][C:8]([N:9]([CH2:26][CH3:27])[S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:7][CH:6]=1)#[N:4]
Reactant: CCOS(=O)(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C#N)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(c1ccc(C#N)cc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
To a suspension of sodium hydride (65%, 3.39 g (91.8 mmol)) in DMF (60.0 ml), 4′-cyano-p-toluenesulfonanilide (10.0 g (36.7 mmol)) was added with stirring at room temperature. To the resulting mixture, after stirring for an hour at room temperature, diethyl sulfate (12.0 ml (91.8 mmol)) was added dropwise, and the resulting mixture was heated with stirring at 75° C. for 4 hours. Then, the reaction mixture was allowed to cool to room temperature, poured into water and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with chloroform as eluent, to give 9.8 g (89%) of the title compound as white crystals.
Reaction SMILES: [CH2:1]([C:3]1([C:18]#[N:19])[CH2:7][CH2:6][N:5](C(=O)C2C=CC(F)=CC=2)[C:4]1=[O:17])[CH3:2].C(N)CCCCCCC>C1COCC1>[CH2:1]([C:3]1([C:18]#[N:19])[CH2:7][CH2:6][NH:5][C:4]1=[O:17])[CH3:2]
Reactant: CCC1(C#N)CCN(C(=O)c2ccc(F)cc2)C1=O
Solvent: C1CCOC1
Solvent: CCCCCCCCN
Product: CCC1(C#N)CCNC1=O
Temperature: 25 °C
Reaction time: 60 h
Yield: 97.6 %

Procedure:
To a solution of 3-ethyl-1-(4-fluorobenzoyl)-2-oxopyrrolidine-3-carbonitrile (11 g) in THF (80 mL) was added octylamine (8.5 mL). The reaction mixture was stirred at room temperature for 60 hr, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.7 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[NH:18][NH:17][C:16]1=[O:21])=[N+:2]=[N-:3]>C(Cl)Cl>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:16](=[O:21])[N:17]=[N:18][C:19]1=[O:20])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCOCCOCCOCCn1c(=O)[nH][nH]c1=O
Solvent: ClCCl
Product: [N-]=[N+]=NCCOCCOCCOCCN1C(=O)N=NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.7 %

Procedure:
To 4-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-1,2,4-triazolidine-3,5-dione (I-18c: 3 mg, 9.92 umol) in CH2Cl2 (1 mL) was added SiO2-HNO3 (25 mg). The mixture was stirred at room temperature for 15 minutes, then filtered, concentrated in vacuo and dried giving 4-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-3H-1,2,4-triazole-3,5(4H)-dione (I-18c: 3 mg, quantitative) as a pink oil.
Reaction SMILES: [Sn](Cl)Cl.[C:4]1([S:10]([NH:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([N+:37]([O-])=O)[CH:32]=3)(=[O:30])=[O:29])[CH:22]=2)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:12])=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(O)=O.[Na+]>C(O)C>[C:4]1([S:10]([NH:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([NH2:37])[CH:32]=3)(=[O:29])=[O:30])[CH:22]=2)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:11])=[O:12])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CC(NS(=O)(=O)c1ccccc1)c1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(NS(=O)(=O)c1ccccc1)c1cccc(NS(=O)(=O)c2cccc(N)c2)c1

Procedure:
Tin(II) chloride (1.27 g) was added to a solution of ethyl 3-benzenesulphonylamino-3-(3-[3-nitrophenylsulphonylamino]-phenyl)-propionate from II.4c (600 mg) in 9 ml of ethanol, and the reaction mixture was heated under reflux for 2 h. After cooling, the solution was hydrolysed on ice and neutralized (pH=8) using NaHCO3 solution (5%). It was then extracted with dichloromethane, and the organic phase was washed with NaCl, dried (MgSO4) and concentrated. A yellow, viscous residue was obtained (yield: 394 mg).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C@:24]12[CH2:33][O:32][C@@H:31]([CH:34]([OH:39])[CH2:35][CH2:36][CH2:37]O)[CH2:30][C@H:29]1[CH2:28][S:27][C:26]([NH:40][C:41](=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[N:25]2.CC1C=CC=C(C)N=1>ClCCl>[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C@:24]12[CH2:33][O:32][C@@H:31]([CH:34]3[CH2:35][CH2:36][CH2:37][O:39]3)[CH2:30][C@H:29]1[CH2:28][S:27][C:26]([NH:40][C:41](=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[N:25]2
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C(O)CCCO)C[C@H]2CS1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CCCO3)C[C@H]2CS1)c1ccccc1
Temperature: 0 °C

Procedure:
Trifluoromethanesulfonic anhydride (12.5 μL, 76 μmol) was added drop-wise to a −78° C. solution of N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(1,4-dihydroxybutyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C12) (18 mg, 38 μmol) and 2,6-dimethylpyridine (17.6 μL, 152 μmol) in dichloromethane (0.65 mL), and the reaction mixture was allowed to gradually warm to 0° C. over 30 minutes. The reaction mixture was partitioned between dichloromethane (10 mL) and water (5 mL), and the organic layer was washed with water (2×5 mL) and with saturated aqueous sodium chloride solution (5 mL), then dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 60% ethyl acetate in heptane) afforded the product as an off-white foam. Yield: 14.7 mg, 32.1 μmol, 84%. LCMS m/z 459.2 [M+H+]. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ 8.23 (br d, J=7.6 Hz, 2H), 7.36-7.55 (m, 4H), 6.84-6.97 (m, 2H), 4.17 (br d, J=12 Hz, 1H), 3.76-3.94 (m, 4H), 3.63-3.70 (m, 1H), 3.11-3.20 (m, 1H), 3.03 (dd, J=12.8, 4.2 Hz, 1H), 2.65 (br d, J=13 Hz, 1H), 1.83-2.06 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[C:8]2[C:15](=[O:17])[CH3:16])=[CH:4][CH:3]=1>[Pd]>[NH2:12][C:10]1[CH:9]=[C:8]([C:15](=[O:17])[CH3:16])[N:7]([CH2:6][C:5]2[CH:18]=[CH:19][C:2]([F:1])=[CH:3][CH:4]=2)[CH:11]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])cn1Cc1ccc(F)cc1
Agent: [Pd]
Product: CC(=O)c1cc(N)cn1Cc1ccc(F)cc1
Reaction time: 24 h

Procedure:
To a 1L round bottomed flask with a stirring bar and a balloon hydrogenation adapter was added 1-[1-(4-fluorobenzyl)-4-nitro-1H-pyrrol-2-yl]ethanone AVI-1-1 (8.00 g, 30.51 mmol) absolute EtOH (640 mL) and 10% Pd-C (2.24 g, 2.11 mmol). This mixture was hydrogenated at ambient temperature 24 h. The catalyst was removed by filtration and the EtOH was removed in vacuo. The semi-solid residue was chromatographed on silica gel using EtOAc as eluant to give 1-[4-amino-1-(4-fluorobenzyl)-1H-pyrrol-2-yl]ethanone AVI-2-1 as a yellow crystalline solid. 1H NMR (CDCl3) δ 2.34 (3H, s), 3.01 (2H, br s), 5.42 (2H, s), 6.46 (1H, d, j=2.0 Hz), 6.50 (1H, d, j=2.0 Hz), 6.98 (2H, m), 7.12 (2H, m).