Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=1[Cl:24])=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[Cl:24][C:14]1[CH:15]=[C:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:18][C:13]=1[C:12]1[O:11][N:10]=[C:9]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:8]=1[C:6]([OH:7])=[O:5]
Reactant: COC(=O)Cc1ccc(-c2onc(-c3ccccc3)c2C(=O)OC(C)(C)C)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1ccc(-c2onc(-c3ccccc3)c2C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(2-Chloro-4-methoxycarbonylmethyl-phenyl)-3-phenyl-isoxazole-4-carboxylic acid tert-butyl ester 59 (25 mg, 0.06 mmol) is dissolved in trifluoroacetic acid (1 mL) and stirred at room temperature for 2 hours. Then the solvent is evaporated and the remainder is dried on high vacuum to afford 5-(2-Chloro-4-methoxycarbonylmethyl-phenyl)-3-phenyl-isoxazole-4-carboxylic acid 60 as a white solid: 1H-NMR (400 MHz, CDCl3) δ=7.62 (m, 2H), 7.38 (m, 5H), 7.24 (m, 1H), 3.64 (s, 3H), 3.59 (s, 2H). MS calculated for C19H15ClNO5 (M+H+) 372.1, found 372.1.
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.O[CH2:31][CH2:32][CH2:33][S:34][CH:35]1[CH2:39][CH2:38][O:37][C:36]1=[O:40]>C(Cl)Cl>[F:15][C:12]([F:13])([F:14])[S:9]([O:8][CH2:31][CH2:32][CH2:33][S:34][CH:35]1[CH2:39][CH2:38][O:37][C:36]1=[O:40])(=[O:10])=[O:11]
Reactant: O=C1OCCC1SCCCO
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Solvent: ClCCl
Product: O=C1OCCC1SCCCOS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Triflic anhydride (0.544 ml, 3.23 mmol) was added to a pre-cooled (0° C.) solution of 2,6-di-tert-butylpyridine (1.61 ml, 7.15 mmol) in methylene chloride (16 mL). A solution of 3-(3-hydroxypropylthio)-dihydrofuran-2(3H)-one (0.600 g, 3.41 mmol) dissolved in methylene chloride (2.5 mL) was added dropwise. The reaction was stirred at 0° C. for 15 minutes. The product was utilized in the subsequent step without isolation.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH:17](=O)[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20].C(Cl)Cl>CO>[N+:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[CH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[OH:20])[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)Cc1ccccc1-2
Reactant: O=Cc1ccccc1O
Solvent: CO
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)C(=Cc1ccccc1O)c1ccccc1-2
Temperature: 72 °C
Reaction time: 6 h

Procedure:
To a solution of 2-nitrofluorene (250 mg, 1.18 mmol) and salicylaldehyde (159 mg, 1.30 mmol) in 10 mL of methanol was added KF—Al2O3 (170 mg, 1.06 mmol). The resulting mixture was stirred at 72° C. After 6 hrs, TLC indicated that the starting material was gone. 40 mL of CH2Cl2 was added into the reaction mixture. The insoluble solid was filtrated, and the filtrate was concentrated under vacuum to give a yellow solid, which was purified by silica gel column; eluting with 11% EtOAc in hexane afforded 125 mg of CYD-1-87 as a yellow solid. 1H-NMR (600 MHz, CDCl3) δ 10.05 (br s, 1H), 8.39 (s, 1H), 8.27 (dd, 1H, J=2.4 Hz, 8.4 Hz), 8.16 (d, 1H, J=8.4 Hz), 8.09 (m, 2H), 8.04 (s, 1H), 7.52 (m, 3H), 7.37 (m, 1H), 7.05 (d, 1H, J=8.4 Hz), 6.96 (t, 1H, J=7.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[O:5][C:6]1[C:7]([CH2:23][CH3:24])=[N:8][N:9]([CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[CH2:11][OH:12].[CH2:29](I)[CH3:30]>[Ag-]=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[C:26]([Cl:28])[CH:27]=1)[O:5][C:6]1[C:7]([CH2:23][CH3:24])=[N:8][N:9]([CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])[C:10]=1[CH2:11][O:12][CH2:29][CH3:30]
Reactant: CCI
Reactant: CCc1nn(CCNC(=O)OC(C)(C)C)c(CO)c1Oc1cc(Cl)cc(Cl)c1
Agent: O=[Ag-]
Product: CCOCc1c(Oc2cc(Cl)cc(Cl)c2)c(CC)nn1CCNC(=O)OC(C)(C)C
Temperature: 40 °C

Procedure:
Silver(I)oxide (210 mg, 0.900 mmol) was added in one portion to a stirred solution of the alcohol of Example 135 (129 mg, 0.300 mmol) in ethyl iodide (1.75 ml) at room temperature under nitrogen. The reaction was heated at 40° C. for 1 day and then cooled to room temperature. The mixture was filtered and the residual solid was washed with dichloromethane (10 ml). The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (99:1, by volume) to provide the title compound (60 mg) as a colourless oil.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]=1[NH:19][C:20]([NH:22][CH3:23])=[O:21])([OH:8])[C:4]([F:7])([F:6])[F:5].[C:26](Cl)(=[O:28])[CH3:27]>>[C:26]([O:8][C:3]([C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]=1[NH:19][C:20]([NH:22][CH3:23])=[O:21])([C:4]([F:6])([F:5])[F:7])[C:2]([F:24])([F:25])[F:1])(=[O:28])[CH3:27]
Reactant: CNC(=O)Nc1c(C(O)(C(F)(F)F)C(F)(F)F)ccc2c1CCCC2
Reactant: CC(=O)Cl
Product: CNC(=O)Nc1c(C(OC(C)=O)(C(F)(F)F)C(F)(F)F)ccc2c1CCCC2

Procedure:
Reaction of the compounds of formulae (Ia) and (Ib) wherein Z is hydroxy with the appropriate acid chloride affords the corresponding alkanoyloxy derivative. For instance, reaction of N-[2-(hexafluoro-2-hydroxy-2-propyl)-5,6,7,8-tetrahydro-1-naphthyl]-N'-methylurea with acetyl chloride yields N-[2-(2-acetoxyhexafluoro-2-propyl)-5,6,7,8-tetrahydro-1-naphthyl]-N'-methylurea.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][C:11]([N+:14]([O-])=[O:15])([CH3:13])[CH3:12].C(O)(=O)C>C(O)C.[Zn]>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[N+:14]([C:11]([CH3:13])([CH3:12])[CH3:10])[O-:15]
Reactant: O=Cc1ccccc1F
Reactant: CC(C)(C)[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)[N+]([O-])=Cc1ccccc1F

Procedure:
To a suspension of 2-fluorobenzaldehyde (332.3 mg, 2.68 mmol), 1,1-dimethylnitroethane (547.5 mg, 5.31 mmol) and zinc (514.6 mg, 7.87 mmol) in ethanol (3.0 ml) was added acetic acid (940.2 mg, 15.7 mmol) dropwise at 5° C. while stirring. The mixture was stirred at room temperature for 6.5 hours. Zinc acetate in the mixture was filtered off and the filtrate was concentrated and purified by silica gel chromatography (hexane/ethyl acetate=4/1 to 2/1).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:21])[CH:27]=2)=[CH:13][CH:12]=1)[C:18]([OH:20])=[O:19])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)cc1)C(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Temperature: 85 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
To a solution of Boc-4-bromo-L-phenylalanine (15 g, 43.6 mmol) in DME (180 ml) at room temperature was added 3-chlorobenzeneboronic acid (8.52 g, 54.5 mmol) followed by aq. Na2CO3 (32.7 ml, 65.4 mmol) and Pd(PPh3)4 (1.511 g, 1.307 mmol). The mixture was stirred at 85° C. for 3 hours. The reaction mixture was filtered and added EtOAc and acidified by 1M HCl to pH˜5. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (silica gel, 5 to 20% EtOAc/Heptane) and gave the title compound: 12.0 g (yield: 66%). LCMS (condition A): 374.2 (M−1); retention time=1.57 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:21][CH3:22])=[C:6]([CH:8]2[C:14](=[O:15])[CH:13]3[C:16](C)(C)[C:10]([CH3:19])([CH2:11][CH2:12]3)[C:9]2=[O:20])[CH:7]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.[F-].[Cs+]>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[CH:4][C:5]([CH2:21][CH3:22])=[C:6]([CH:8]3[C:14](=[O:15])[CH:13]4[CH2:16][CH2:19][CH:10]([CH2:11][CH2:12]4)[C:9]3=[O:20])[CH:7]=2)=[CH:26][CH:25]=1
Reactant: CCc1ccc(Br)cc1C1C(=O)C2CCC(C)(C1=O)C2(C)C
Reactant: OB(O)c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: COCCOC
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C2CCC(CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-(5-bromo-2-ethyl-phenyl)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.035 g, 0.1 mmol) and 4-chlorophenylboronic acid (0.022 g, 0.14 mmol) in anhydrous dimethoxyethane (2 ml) is stirred at room temperature under an atmosphere of nitrogen. The reaction mixture is then evacuated and flushed with nitrogen (degassing cycle repeated 4 times). Cesium fluoride (0.046 g, 0.30 mmol) is added, and the suspension is stirred at room temperature for 1 hour. Next [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.012 g, 0.015 mmol) is added in one portion, and the reaction mixture is heated at 80° C. for 5.5 hours. After cooling to room temperature the suspension is filtered through diatomaceous earth, then washed with 2M hydrochloric acid (5 ml) and dichloromethane (5 ml). The organic phase is separated, and the aqueous phase is extracted with dichloromethane (5 ml×2). All organics are combined, dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to give a brown gum. The crude product is purified by flash column chromatography on silica gel (100% to 40% hexane/ethyl acetate eluant ratio), then further purified by preparative reverse-phase HPLC to afford to afford 3-(4′-chloro-4-ethylbiphen-3-yl)bicyclo[3.2.2]nonane-2,4-dione.
Reaction SMILES: IC.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([I:27])[CH:22]=4)[CH:18]=3)[NH:13][C:12](=[O:29])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1.[CH3:30]COC(C)=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.[OH-].[Na+].C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([I:27])[CH:22]=4)[CH:18]=3)[N:13]([CH3:30])[C:12](=[O:29])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(C)=O
Reactant: O=C(c1cccc(I)c1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1c(=O)cc(-c2cccc(Cl)c2)c2cc(C(=O)c3cccc(I)c3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
Benzyltriethylammonium chloride (0.00267 mol) and iodomethane (0.053 mol) were added to a solution of intermediate (74) (0.0267 mol) in concentrated sodium hydroxide (150 ml) and THF (150 ml). The mixture was stirred at room temperature for 4 hours and poured out into ice water. EtOAc was added. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from EtOAc/2-propanone. The precipitate was filtered off and dried, yielding 6 g (45%) of 4-(3-chlorophenyl)-6-(3-iodobenzoyl)-1-methyl-2(1H)-quinolinone, melting point 235° C. (intermediate 75).
Reaction SMILES: O1C=C(CN)N=C1.[CH3:8][N:9]1[C:13]([CH3:14])=[C:12]([CH2:15][NH2:16])[C:11]([CH3:17])=[N:10]1.[F:18][C:19]1[CH:40]=[CH:39][C:22]([CH2:23][N:24]2[CH2:28][CH2:27][N:26]([C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][N:37]=3)[C:32](O)=[O:33])[C:25]2=[O:38])=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][N:24]2[CH2:28][CH2:27][N:26]([C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][N:37]=3)[C:32]([NH:16][CH2:15][C:12]3[C:11]([CH3:17])=[N:10][N:9]([CH3:8])[C:13]=3[CH3:14])=[O:33])[C:25]2=[O:38])=[CH:39][CH:40]=1
Reactant: Cc1nn(C)c(C)c1CN
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Agent: NCc1cocn1
Product: Cc1nn(C)c(C)c1CNC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 67 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace oxazol-4-ylmethanamine with (1,3,5-trimethyl-1H-pyrazol-4-yl)methanamine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid, 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-N-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)isonicotinamide was obtained as a colorless solid in 67% yield: mp 179-181° C.; 1H NMR (300 MHz, CDCl3) δ 8.48 (s, 1H), 8.33 (d, J=5.1 Hz, 1H), 7.37 (dd, J=5.1 Hz, 1.2 Hz, 1H), 7.25-7.21 (m, 2H), 7.03-6.97 (m, 2H), 6.35 (br s, 1H), 4.40-4.36 (m, 4H), 4.01 (t, J=8.1 Hz, 2H), 3.68 (s, 3H), 3.34 (t, J=8.1 Hz, 2H), 2.21 (s, 3H), 2.19 (s, 3H); MS (ES+) m/z 436.8 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[C:6]([NH:14][C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])[CH:5]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[N+:28]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1)([O-:30])=[O:29].O>CN(C=O)C.[Cl-].[Na+].O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:35][C:34]2[CH:37]=[CH:38][C:31]([N+:28]([O-:30])=[O:29])=[CH:32][CH:33]=2)=[O:12])=[C:6]([NH:14][C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)Nc1cc(C(C)=O)ccc1CC(=O)O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)Nc1cc(C(C)=O)ccc1CC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
To (4-acetyl-2-{[(allyloxy)carbonyl]amino}phenyl)acetic acid (10.9 g) prepared by step g) and triethylamine (11 mL) in DMF (100 mL) was added at room temperature p-nitrobenzyl bromide (17.0 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added saturated brine (500 mL) and water (300 mL), and the mixture was extracted with ethyl acetate (200 mL, 2×100 mL). The organic layers were combined, washed with saturated brine (100 mL), dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The residue was purified with column chromatography (SiO2 300 g, hexane/ethyl acetate/chloroform=3:1:4˜0:1:1) to give the object compound (16.4 g, 98%) as a pale brown solid. Further the product was recrystallized from chloroform/hexane to give the object compound (10.4 g, 64%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](O)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH:11]([OH:14])([CH3:13])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH:11]([O:14][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1)[NH2:1])([CH3:13])[CH3:12]
Reactant: CC(C)O
Reactant: COc1cc(N)cc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(N)cc(OC(C)C)c1
Reaction time: 16 h
Yield: 58.3 %

Procedure:
To a solution of 3-amino-5-methoxyphenol (5.44 g, 39.1 mmol), isopropyl alcohol (3.6 ml, 47 mmol) and triphenylphosphine (12.0 g, 47 mmol) in THF, was added diethyl azodicarboxylate (7.4 ml, 47 mmol). The reaction mixture was stirred for 16 h and the solvent was removed. The residue was purified by flash chromatography on silica gel eluting with 20% EtOAc/hexanes to afford the title compound (4.13 g). MS m/z: 182 [M+H]+
Reaction SMILES: [CH:1]1([O:6][NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=2)(=[O:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[NH2:17][C:13]1[CH:12]=[C:11]([S:8]([NH:7][O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:9])=[O:10])[CH:16]=[CH:15][CH:14]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)NOC2CCCC2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(S(=O)(=O)NOC2CCCC2)c1
Yield: 100.1 %

Procedure:
A solution of N-(cyclopentyloxy)-3-nitro-1-benzenesulfonamide (2.98 g, 10.41 mmol) in 50 mL of absolute ethanol was combined with 5 wt % Palladium on barium sulfate (300 mg) and reduced under a balloon of hydrogen gas with vigorous agitation for 18 hours. The mixture was filtered, washed with ethanol, and evaporated in vacuo to a residue. The crude product was purified on flash grade silica gel eluting with 4:1 hexane : ethyl acetate. Fractions containing the product were combined, evaporated in vacuo and dried under vacuum to provide 3-amino-N1-(cyclopentyloxy)-1-benzenesulfonamide (2.67 g, 100%) as an oil. Hl-NMR chloroform-D3): 1.62 (m, 8H), 3.92 (bs, 2H), 4.58 (m, 1H), 6.74 (bs, !H), 6.88 (m, 1H), 7.16 (m, 1H), 7.27 (m, 2H). MS(ESI): 257(MH+).
Reaction SMILES: [CH2:1]([O:8][C:9](/[N:11]=[C:12]1/[N:13](C(OCC2C=CC=CC=2)=O)[C:14]([CH2:18][C:19](N(OC)C)=[O:20])=[CH:15][CH:16]=[CH:17]/1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:35]([Mg]Br)=[CH2:36]>C1COCC1>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19](=[O:20])[CH:35]=[CH2:36])[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)Cc1ccc/c(=N\C(=O)OCc2ccccc2)n1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: C=CC(=O)Cc1cccc(NC(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To a solution of benzyl (2E)-2-([(benzyloxy)carbonyl]imino)-6-(2-[methoxy(methyl)amino]-2-oxoethyl)pyridine-1(2H)-carboxylate (150 mg, 0.33 mmol) in 4 ml anhydrous THF cooled to −40° C. via dry ice/acetone bath under nitrogen atmosphere was added via syringe 1.0M vinylmagnesium bromide (1.5 mL, 1.5 mmol) and the resulting solution stirred for 2 hours allowing to warm to room temperature. The reaction was quenched with water and extracted with ethyl acetate (3×10 mL). The organics were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via preparative TLC plate (1000 μM) eluting with 2.5% methanol in dichloromethane to afford the title compound (64 mg, 67%). LC-MS: C17H16N2O3 calculated 296.32 found m/z (ES) 297.3 (MH)+. 1HNMR (500 MHz, DMSO) δ: 10.12 (s, 1H) 8.05 (d, J=8.5 Hz, 1H), 7.99 (d, J=2.1, 1H), 7.62 (dd, J=2.2, 8.7 Hz, 1H), 7.60-7.34 (m, 5H), 6.40 (dd, J=10.3, 17.7 Hz, 1H), 6.26 (dd, J=10.3, 18.1 Hz, 1H), 5.94 (d, J=10.3 Hz, 1H), 5.22 (s, 2H), 3.60 (s, 2H).
Reaction SMILES: C(O[CH:5]([O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)C.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[CH2:13][CH2:12][O:11][CH:5]2[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(OCCc1ccccc1OC)OC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C1OCCc2c(OC)cccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
The solution of ethyl 2-acetoxy-2-(2-methoxyphenethoxy)acetate (12.3 g) in dichloromethane (415 ml) at −20° C. was treated with AlCl3 (5.5 g), and stirred for 1 hr. AlCl3 (5.5 g) was added to the solution and stirred for 3.5 hrs, pours into ice-water (400 ml). Separation method A was applied, followed by distillation (1-2 mbar/120-130° C.) of the crude product to yield ethyl 5-methoxyisochroman-1-carboxylate (5.1 g).
Reaction SMILES: [N:1]1([C:8]2[C:13]([CH2:14][NH:15][C:16]3[N:20]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])[CH:19]=[N:18][N:17]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:29][C:30]([CH3:32])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[N:20]1[CH:19]=[N:18][N:17]=[C:16]1[NH:15][CH2:14][C:13]1[C:8]([N:1]2[CH2:7][CH2:6][CH2:5][N:4]([CH:30]([CH3:32])[CH3:29])[CH2:3][CH2:2]2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)=O
Reactant: Clc1cccc(-n2cnnc2NCc2cccnc2N2CCCNCC2)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)N1CCCN(c2ncccc2CNc2nncn2-c2cccc(Cl)c2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 113A in 1,2-dichloroethane (10 ml) was added acetone (3 mL) and sodium triacetoxyborohydride (253 mg, 1.194 mmol). The reaction mixture was stirred at room temperature overnight. Saturated sodium bicarbonate was added and the layers were separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane/methanol (80:20) to give the title compound. MS (ESI+) m/z 460.6 (M+H)+; Rt=1.47. 1H NMR (DMSO-d6) δ 8,171 (s, 1H); 8,049 (d, 1H); 7,831(d, 1H); 7,586(m, 3H); 6,837 (dd, 1H); 6,521 (t, 1H); 4,353 (d, 2H); 3,377 (m, 4H); 3,289 (m, 1H); 2,862 (m, 2H); 2,642 (m, 2H); 1,773 (m, 2H); 0,949 (m, 6H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([CH2:10][NH2:11])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.S1C2C=C(C(O)=O)C=CC=2N=[CH:13]1.Cl.S1C2C=CN=CC=2C=C1CN>>[S:1]1[C:5]2[CH:6]=[C:7]([CH:10]([NH2:11])[CH3:13])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NCc1ccc2ncsc2c1
Reactant: O=C(O)c1ccc2ncsc2c1
Agent: Cl
Agent: NCc1cc2cnccc2s1
Product: CC(N)c1ccc2ncsc2c1

Procedure:
Intermediate T′ was prepared from benzo[d]thiazole-6-carboxylic acid (T-1) following similar procedures for synthesizing intermediate D′-5 from D′-1, as described above, and intermediate D from D-4 as described above. MS (m/z): 179 (M+1)+.
Reaction SMILES: [CH2:1]([O:4][N:5]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:6]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:9]([CH2:19][OH:20])[CH:8]=[C:7]1[CH2:21][O:22][CH3:23])[CH:2]=[CH2:3].I([O-])(=O)(=O)=O.[Na+].OS([O-])=O.[Na+].C(O[N:46](C(OC(C)(C)C)=O)[C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(O)=O)C=C1COC)C=C.[Cl-].[NH4+].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>CC#N.C(OCC)(=O)C.CN(C=O)C>[CH2:1]([O:4][N:5]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:6]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:9]([C:19](=[O:20])[NH2:46])[CH:8]=[C:7]1[CH2:21][O:22][CH3:23])[CH:2]=[CH2:3]
Reactant: C=CCON(C(=O)OC(C)(C)C)[C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)C=C1COC
Reactant: C=CCON(C(=O)OC(C)(C)C)[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1COC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S([O-])O
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCON(C(=O)OC(C)(C)C)[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1COC
Yield: 43.3 %

Procedure:
To a stirred solution of (2S,5R)-tert-butyl 5-(allyloxy(tert-butoxycarbonyl)amino)-2-(hydroxymethyl)-4-(methoxymethyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 72, 8.82 g, 20.58 mmol) in 100 mL MeCN at 0° C., was added sodium periodate (19.37 g, 90.56 mmol). Then 12 mL of the stock oxidation solution was added. The suspension was then stirred at rt for 2d. An additional 16 mL the above stock solution was added and stirred for 2 more days. The mixture was diluted with 150 mL ethyl acetate, 50 mL 1M pH 7 buffer, and 50 mL 2M NaHSO3. The aqueous was extracted with 20 mL ethyl acetate. The ethyl acetate layer was then washed with brine. The aqueous layer was checked by LCMS and found containing desired carboxylic acid. The aqueous layer was then extracted with 50 mL ethyl acetate and washed with brine. The combined organic layers was dried over MgSO4, filtered and concentrated to afford a yellow dry film, (crude 7.11 g, 78%) which was used directly without further purification. To a stirred solution of (2S,5R)-5-(allyloxy(tert-butoxycarbonyl)amino)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)-1,2,5,6-tetrahydropyridine-2-carboxylic acid (crude, 7.11 g, 16.07 mmol), ammonium chloride (1.719 g, 32.14 mmol), HATU (12.22 g, 32.14 mmol) in DMF (50.0 mL) at rt, was added DIPEA (8.31 g, 64.27 mmol). After stirring at rt for 1 hr, 100 mL EtOAc was added. The organic layer was washed with water, brine. The residue was purified by silica gel column (0-100% Hex/EA) to afford the desired product (3.07 g, 43.3%) as an off-white solid.