Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[F:36])=[CH:5][C:6](=[O:27])[N:7]([CH2:9][CH2:10][C@@:11]([CH3:26])([S:22]([CH3:25])(=[O:24])=[O:23])[C:12]([NH:14][O:15]C2CCCCO2)=[O:13])[CH:8]=1.O>O1CCOCC1.C(Cl)Cl>[F:2][C:3]1[C:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[F:36])=[CH:5][C:6](=[O:27])[N:7]([CH2:9][CH2:10][C@@:11]([CH3:26])([S:22]([CH3:25])(=[O:24])=[O:23])[C:12]([NH:14][OH:15])=[O:13])[CH:8]=1
Reactant: COc1ccc(-c2cc(=O)n(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)cc2F)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(-c2cc(=O)n(CC[C@](C)(C(=O)NO)S(C)(=O)=O)cc2F)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.1 %

Procedure:
A solution of HCl (4 M in 1,4-dioxane, 4.4 mL, 17.5 mmol) was added to a solution of (2R)-4-[5-fluoro-4-(2-fluoro-4-methoxyphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (1.5 g, 2.9 mmol) in 1,4-dioxane (20 mL), DCM (20 mL), and water (5 mL) and the reaction was stirred for 20 min at rt. The reaction was concentrated under reduced pressure, isopropyl alcohol (10 mL) was added to the residue and the mixture was concentrated. Isopropyl alcohol (30 mL) was added to the residue and the solution was stirred overnight at rt to afford a precipitate. The precipitate was collected via filtration, washed with isopropyl alcohol, and dried under vacuum to afford the title compound as a light brown solid (725 mg, 58%) MS (LCMS) m/z 431.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.57 (s, 3 H) 2.07-2.25 (m, 1 H) 2.42-2.48 (m, 1 H) 3.11 (s, 3 H) 3.71-3.81 (m, 1 H) 3.83 (s, 3 H) 4.00-4.11 (m, 1 H) 6.44 (d, J=7.02 Hz, 1 H) 6.92 (dd, J=8.59, 2.54 Hz, 1 H) 7.00 (dd, J=12.39, 2.44 Hz, 1 H) 7.42 (t, J=8.49 Hz, 1 H) 8.03 (d, J=5.85 Hz, 1 H) 9.25 (br. s., 1 H) 11.10 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.Cl.[CH3:18][N:19]([CH3:30])[CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH2:20][N:19]([CH3:30])[CH3:18])=[CH:28][CH:27]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Reactant: CN(C)CCOc1ccc(N)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CCOc1ccc(N/C=C2\C(=O)NC(=O)c3ccc(Br)cc32)cc1
Yield: 81.8 %

Procedure:
(4E)-6-Bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (70 mg, 0.25 mmol) and 4-(2-dimethylamino-ethoxy)-phenylamine hydrochloride (50 mg, 0.23 mmol) were stirred in dimethylformamide (1 mL) and triethylamine (50 μL) at 70° C. The reaction mixture is quenched by the addition of water. The solid material is then collected, washed with diethyl ether, water, and methanol, and then dried under vacuum to give (4Z)-6-bromo-4-[({4-[2-(dimethylamino)ethoxy]phenyl}amino)methylene]isoquinoline-1,3(2H,4H)-dione (81 mg, 82%).
Reaction SMILES: C([N:8]1[CH2:16][C@@H:15]2[C@:10]([CH3:24])([CH2:11][CH2:12][C:13]3[C:20](/[CH:21]=[CH:22]\[CH3:23])=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)C1C=CC=CC=1.CC(Cl)OC([Cl:30])=O.CO>C1(C)C=CC=CC=1>[ClH:30].[CH3:24][C@@:10]12[CH2:9][NH:8][CH2:16][C@H:15]1[C:14]1[CH:17]=[CH:18][CH:19]=[C:20](/[CH:21]=[CH:22]\[CH3:23])[C:13]=1[CH2:12][CH2:11]2
Reactant: C/C=C\c1cccc2c1CC[C@]1(C)CN(Cc3ccccc3)C[C@@H]21
Reactant: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: C/C=C\c1cccc2c1CC[C@]1(C)CNC[C@@H]21
Product: Cl
Temperature: 160 °C
Yield: 13.6 %

Procedure:
trans-2-Benzyl-3a-methyl-6-((Z)-prop-1-enyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.378 mmol, 120 mg) was dissolved in toluene (1 ml) and ACE-Cl (2.65 mmol, 291 μl) was added. The reaction mixture was heated to 160° C. for 15 minutes in a microwave reactor then MeOH (1 ml) was added. The reaction mixture was again heated in a microwave reactor at 160° C. for 5 minutes and the resulting solution was passed through an SCX cartridge and then purified by prep-HPLC. HCl in ether (1 ml) was added to the purified fractions before removal of solvent in vacuo to afford trans-3a-methyl-6-((Z)-prop-1-enyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole hydrochloride (13.6 mg), m/z: 228.1 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].Br[CH2:12][CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][OH:15])[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: OCCCBr
Reactant: CS(=O)(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(CCCO)CC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
A suspension of 1-(methylsulphonyl)piperazine (3 g, 18.3 mmol), 3-bromopropan-1-ol (3.3 g, 23.8 mmol) and potassium carbonate (3.28 g, 23.8 mmol) in acetonitrile (20 ml) was stirred at 70° C. for 4 hours. After cooling, the mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography eluting with increasingly polar mixtures of methanol and methylene chloride to give 3-(4-methylsulphonylpiperazin-1-yl)propan-1-ol (2.93 g, 72%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[S:16][C:15]([S:17]([N:20]2[CH:24]=[CH:23][CH:22]=[CH:21]2)(=[O:19])=[O:18])=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[S:16][C:15]([S:17]([N:20]3[CH:24]=[CH:23][CH:22]=[CH:21]3)(=[O:18])=[O:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2ccc(S(=O)(=O)n3cccc3)s2)cc1

Procedure:
N-[5-(4-methylphenyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 1 3C using 4-methyl-phenylboronic acid and N-(5-bromothiophenesulfonyl)pyrrole. Purification by column chromatography using 2% ethyl acetate/hexanes gave N-[5-(4-methylphenyl)-thiophene-2-sulfonyl]pyrrole as a pale yellow solid in 77% yield.
Reaction SMILES: [Cl:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:13]([O-])=O.P(Cl)(Cl)(Cl)=O.C1(C)C=CC=CC=1>[Fe].C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:9]([NH2:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH2:13]
Reactant: N#Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1cc(N)c(Cl)c(N)c1
Yield: 80 %

Procedure:
By reaction with ammonia at about 0° C. to about 20° C., 4-chloro-3,5-dinitrobenzoic acid amide is obtained which is converted into 4-chloro-3,5-dinitrobenzonitrile by reaction with phosphorus oxychloride in boiling toluene. By reduction in boiling toluene/water with iron, 4-chloro-3,5-diaminobenzonitrile (melting point about 172° C.) is obtained in about 80% yield.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]1[CH2:15][O:14][C:9]([CH2:11][CH2:12][OH:13])([CH3:10])[O:8]1>ClCCl>[CH2:7]1[CH2:15][O:14][C:9]([CH3:10])([CH2:11][CH:12]=[O:13])[O:8]1
Reactant: CC1(CCO)OCCO1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(CC=O)OCCO1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 70.8 %

Procedure:
Pyridine (7.2 g) and chromic oxide (CrO3) (4.6 g) are added in small fractions to dichloromethane (150 cc) over 10 minutes. After 15 minutes' stirring at a temperature in the region of 20° C., 2,2-ethylenedioxy-4-hydroxybutane (0.85 g, 6.4 mmol) is added quickly as a solution in dichloromethane (2 cc). After 15 minutes' stirring at 20° C., the black, viscous precipitate is separated off by filtration through silica and is washed with ether. After evaporation of the solvents, 3,3-ethylenedioxybutanal (0.59 g) is obtained (B.P.0.4 =35° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][C:12]=1[F:13].[NH3:14]>>[F:1][C:2]1[CH:3]=[C:4]([C:9]([NH2:14])=[O:10])[C:5](=[CH:11][C:12]=1[F:13])[C:6]([O-:8])=[O:7].[NH4+:14]
Reactant: N
Reactant: O=C1OC(=O)c2cc(F)c(F)cc21
Product: NC(=O)c1cc(F)c(F)cc1C(=O)[O-]
Product: [NH4+]

Procedure:
Following the procedure of Example 1B, the 4,5-difluorophthalic anhydride product was reacted with ammonia to form the ammonium 4,5-difluorophthalamate.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[CH2:3][CH2:4][CH:5]=[CH2:6].[CH:15]1[CH:20]=[CH:19][C:18]([CH2:21][O:22][C:23](Cl)=[O:24])=[CH:17][CH:16]=1.CCOCC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:23]([NH:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[CH2:3][CH2:4][CH:5]=[CH2:6])([O:22][CH2:21][C:18]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1)=[O:24]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=CCCC(N)c1ccccc1OC
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: C=CCCC(NC(=O)OCc1ccccc1)c1ccccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a solution of crude 5-amino-5-(2-methoxyphenyl)-1-pentene (1.63 g) in CH2Cl2 (10 mL) at 0° C. was added DMAP (1.15 g, 9.38 mmol) followed by Cbz-Cl (1.34 mL, 9.38 mmol) and the resulting solution was stirred at room temperature overnight. Ether was added, the aqueous layer was extracted with diethyl ether (x4), and the combined organic layers was washed with brine, dried over MgSO4 and evaporated in vacuo. The crude product was purified by silica gel flash chromatography (5% EtOAc-95% hexanes) to provide the title compound as a white solid (1.84 g). 1H NMR (CDCl3, 400 MHz) δ: 3.82 (3H, s, OMe), 2.0 (4H, m).
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.N([O-])=O.[Na+].[ClH:18]>C(O)(=O)C.O>[Cl:18][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCOc1ccc2nc(N)sc2c1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOc1ccc2nc(Cl)sc2c1
Temperature: 30 °C
Reaction time: 0.33 h
Yield: 61.7 %

Procedure:
20 g (0.103 mol) of 2-amino-6-ethoxy-benzothiazole are dissolved in 100 ml of glacial acetic acid and 52 ml of concentrated hydrochloric acid and whilst cooling with ice the mixture is diazotised with 7.4 g (0.108 mol) of sodium nitrite in 15 ml of water. Then the solution of the diazonium salt is added batchwise to a suspension of 13.6 g (0.137 mol) of copper-I-chloride in 65 ml of concentrated hydrochloric acid and stirred for 20 minutes at 30° C. Then the mixture is diluted with 800 ml of ice water and the crystals formed are suction filtered. To purify them they are chromatographed on silica gel (eluant: petroleum ether/ethyl acetate=6:1). Yield: 61.7% of theory, Melting point: 60-61° C.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9](Cl)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N:13]1[CH:18]=[C:17](B(O)O)[CH:16]=[N:15][CH:14]=1.[NH2:22][C:23]1[N:24]=[C:25]([CH3:28])[S:26][CH:27]=1>>[CH3:28][C:25]1[S:26][CH:27]=[C:23]([NH:22][C:9]2[N:10]=[CH:11][C:2]([C:17]3[CH:18]=[N:13][CH:14]=[N:15][CH:16]=3)=[C:3]3[C:8]=2[N:7]=[CH:6][CH:5]=[CH:4]3)[N:24]=1
Reactant: OB(O)c1cncnc1
Reactant: Cc1nc(N)cs1
Reactant: Clc1ncc(Br)c2cccnc12
Product: Cc1nc(Nc2ncc(-c3cncnc3)c3cccnc23)cs1

Procedure:
The title compound, MS: m/e=321.2 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 5-bromo-8-chloro-[1,7]naphthyridine (Example H), 5-pyrimidineboronic acid and 4-amino-2-methylthiazole (Example F).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[C:15](=[O:18])[CH2:16][CH3:17].Cl.[N:20](OCCCC)=[O:21]>C(OCC)C>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[C:15](=[O:18])[C:16](=[N:20][OH:21])[CH3:17]
Reactant: CCC(=O)c1cc(OC)c2ccccc2c1OC
Reactant: CCCCON=O
Agent: Cl
Solvent: CCOCC
Product: COc1cc(C(=O)C(C)=NO)c(OC)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.9 %

Procedure:
The product from Step A (1.28 g, 5.24 mmol) was dissolved in ethyl ether (50 mL), anhydrous hydrogen chloride gas was added through this solution at moderate rate for 5 min. Butyl nitrite (0.68 mL, 5.77 mmol) was then added dropwise. Hydrogen chloride bubbling was continued for an additional 10 min. after addition of butyl nitrite was completed, the reaction mixture was then stirred at room temperature for 4 hr. The volatiles were removed by evaporation under vacuum and the residue was purified by flash chromatography (silica gel, ethyl acetate/hexane: 0.5/9.5) to give an oil (0.8 g): MS 274 (M+1).
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:45])[CH2:7][C:8]1([CH2:11][CH2:12][CH:13](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=2)[CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)C>C1COCC1.O>[C:6]([CH2:7][C:8]1([CH2:11][CH2:12][CH:13](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][C:34]2[CH:35]=[CH:36][C:37]([O:40][C:41]([F:42])([F:44])[F:43])=[CH:38][CH:39]=2)[CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)([OH:45])=[O:5]
Reactant: CCOC(=O)CC1(CCC(/C=C/c2ccccc2OCc2ccc(OC(F)(F)F)cc2)Cc2ccc(C(=O)O)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC1(CCC(/C=C/c2ccccc2OCc2ccc(OC(F)(F)F)cc2)Cc2ccc(C(=O)O)cc2)CC1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
4 mg (0.17 mmol) of lithium hydroxide are added to a solution of 50 mg (0.08 mmol) of 4-[(3E)-2-{2-[1-(2-ethoxy-2-oxoethyl)cyclopropyl]ethyl}-4-(2-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)-but-3-en-1-yl]benzoic acid (enantiomer 1) in 2 ml of THF and 1 ml of water, and the mixture is stirred at 50° C. for 12 hours. After cooling, the THF is removed under reduced pressure, and the aqueous phase is adjusted to pH 4 using 1 M hydrochloric acid. The product precipitates out and is filtered off, washed with water and dried. This gives 38 mg (79% of theory) of a slightly white solid.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:16]([F:17])=[CH:15][C:10]3[NH:11][C:12](=[S:14])[NH:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1.[CH2:24]1COCC1.CI>C(N(CC)CC)C>[C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:16]([F:17])=[CH:15][C:10]3[NH:11][C:12]([S:14][CH3:24])=[N:13][C:9]=3[CH:8]=2)=[CH:3][CH:2]=1
Reactant: C1CCOC1
Reactant: Fc1cc2[nH]c(=S)[nH]c2cc1-c1ccc(-c2ccccc2)cc1
Solvent: CI
Solvent: CCN(CC)CC
Product: CSc1nc2cc(-c3ccc(-c4ccccc4)cc3)c(F)cc2[nH]1
Temperature: 40 °C

Procedure:
To a solution of 5 (2.23 g, 6.9 mmol) in 40 ML of THF was added triethylamine (2.2 mL) followed by the dropwise addition of methyliodide (0.43 mL, 6.9 mmol). The reaction mixture was heated to 40° C. for 2 h. The solvent was then removed in vacuo and the residue was taken up in EtOAc and washed two times with 100 mL portions of saturated aqueous ammonium chloride and one 100 mL portion of brine. The combined organic layers were dried over MgSO4 filtered and concentrated to dryness in vacuo. Then 150 mL of CH2Cl2 were added and the resulting precipitate was collected by vacuum filtration to give title compound 6.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]([OH:25])=[O:24].CN1CCOCC1.Cl[C:34]([O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:35]>ClCCl>[C:34](=[O:35])([O:24][C:23](=[O:25])[CH2:22][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:2]1=[O:1])[O:36][CH2:37][CH:38]([CH3:40])[CH3:39]
Reactant: CC(C)COC(=O)Cl
Reactant: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)COC(=O)OC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of (2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)acetic acid (0.30 g, 0.88 mmol) in dichloromethane (12.5 mL) was added N-methylmorpholine (0.09 g, 0.88 mmol) and iso-butyl chloroformate (0.12 g, 0.88 mmol) dropwise at 0° C. The mixture was stirred at 0° C. for 1.5 h and at ambient temperature for 3 h. This mixture was used as a mixed anhydride for the next step amide formation.
Reaction SMILES: ClCCl.[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>O>[CH3:23][S:24]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])(=[O:26])=[O:25]
Reactant: COC(=O)CCCCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CCCCCCCCOS(C)(=O)=O
Temperature: 0 °C
Yield: 68 %

Procedure:
Dichloromethane (20 mL) was added with methyl 9-hydroxynonanoate (2.1 g) and pyridine (1.8 g), stirred at 0° C., added with methanesulfonyl chloride (1.3 mL), gradually warmed to room temperature and stirred for one day. The reaction solution was added with water and then extracted twice with dichloromethane. The resulting organic layer was washed with 1 N hydrochloric acid and saturated sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed. The resulting residue was purified by silica gel column chromatography to obtain methyl 9-(methanesulfonyloxy)nonanoate (2.1 g, yield: 68%).
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[CH2:3][CH:4]([C:9](=[O:32])[NH:10][C@H:11]1[CH2:29][C:28]2=[CH:30][N:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=32)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:31])[CH2:5][C:6]([OH:8])=O.O.OC1C=CC2NN=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:56]([O:63][NH2:64])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>CN(C=O)C>[CH2:56]([O:63][NH:64][C:6](=[O:8])[CH2:5][CH:4]([C:9](=[O:32])[NH:10][C@H:11]1[CH2:29][C:28]2=[CH:30][N:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=32)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:12]1=[O:31])[CH2:3][CH:2]([CH3:1])[CH3:33])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: CC(C)CC(CC(=O)O)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCCNC1=O
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1ccc2[nH]nnc2c1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CC(CC(=O)NOCc1ccccc1)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCCNC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the less polar stereoisomer of (11S)-5-methyl-3-(10-oxo-1,9-diazatricyclo[11.6.1.014,19 ]eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanoic acid (210 mg) and 5-hydroxybenzotriazole monohydrate (109 mg) in anhydrous DMF (20 mL) under argon was cooled to 0° C. (ice bath). To this mixture was added EDCI (282 mg) and stirring was continued for 0.5 hours. O-benzylhydroxylamine (0.27 mL) was added to the solution and the reaction mixture was left to warm to room temperature overnight. All volatiles were removed under reduced pressure. The residue was taken up in CH2 Cl2 (100 mL) and 20% HCl (100 mL) and transferred to a separatory funnel. The organic phase was isolated and the aqueous phase washed (2×100 mL) with CH2Cl2. The organic materials were then washed consecutively with 5% NaHCO3, brine, dried (MgSO4), filtered and concentrated to provide (11S)-N-benzyloxy-5-methyl-3-(10-oxo-1,9-diazatricyclo[11.6.1.014,19 ]eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl) hexanamide as a crystalline product. The product was further purified by column chromatography on silica gel followed by crystallization from hot ethyl acetate/CH2Cl2, to provide the more polar stereoisomer of the compound having a melting point at 232°-233° C. m.p., and the less polar stereoisomer of the compound having a melting point at 251°-253° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH2:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].COC1C=CC2N=C(N[C:29](=O)[CH2:30][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)SC=2C=1>>[CH2:16]([O:15][P:11]([CH:9]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH2:10][CH:30]([CH3:29])[C:31](=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:18])[O:12][CH2:13][CH3:14])[CH3:17]
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reactant: COc1ccc2nc(NC(=O)CC(=O)c3ccccc3)sc2c1
Product: CCOP(=O)(OCC)C(CC(C)C(=O)c1ccccc1)P(=O)(OCC)OCC

Procedure:
Ethenylidenebisphosphonic acid tetraethyl ester (I) and propiophenone (II), MS (m/e) 434, 392, 329, 297, 288, 261, 243, 152, 132 and 105; IR (neat) 2983, 1682, 1253, 1027 and 970 cm-1 ; NMR (CDCl3) 8.03, 7.57, 7.47, 4.1, 2.4, 2.0 and 1.29 δ; CMR (CDCl3) 203, 136, 133, 128.6, 128.5, 62, 38, 34, 29, 17 and 16 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[S:10][C:11]=2[C:12]2[N:16](S(N(C)C)(=O)=O)[CH:15]=[N:14][CH:13]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>Br.O.C(Cl)Cl>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[S:10][C:11]=2[C:12]2[NH:16][CH:15]=[N:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CN(C)S(=O)(=O)n1cncc1-c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Clc1ccc(Cc2nc(-c3ccncc3)sc2-c2cnc[nH]2)cc1
Yield: 88.4 %

Procedure:
A solution of 5-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (50 mg, 0.109 mmol) in 48% HBr in water (3.0 mL) was heated to 90° C. for 2.5 hours. The cooled solution was taken up in DCM (20 mL) and saturated sodium bicarbonate (20 mL). The layers were separated and the aqueous extracted with DCM (20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. To this crude material was added the 19 mg of deprotected material obtained in the previous step. The combined material was purified by silica gel chromatography (methanol/DCM=0/100→15/85) to give 34 mg of the title compound as a white solid (27% yield). LC/MS (FA) ES+ 353. 1H NMR (300 MHz, d4-MeOH) δ: 8.63-8.61 (m, 2H), 7.93-7.91 (m, 2H), 7.80 (d, 1H, J=1.1 Hz), 7.30-7.19 (m, 5H), 4.35 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH2:7])=[N:5][N:6]=1.[C:8]1(=O)[CH2:11][CH2:10][CH2:9]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH:8]1([NH:7][C:4]2[NH:3][C:2]([CH3:1])=[N:6][N:5]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: O=C1CCC1
Reactant: Cc1nnc(N)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nnc(NC2CCC2)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.9 %

Procedure:
To a solution (30 mL) of 5-methyl-4H-1,2,4-triazol-3-amine (2.5 g) and cyclobutanone (2.1 g) in acetic acid was added sodium cyanoborohydride (8.1 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with a mixed solvent of ethyl acetate and isopropyl alcohol (3:1). The obtained extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid (2.4 g, 61%).
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)=[N:8]2)=[C:4]([NH2:22])[N:3]=1.C1C(=O)N([I:30])C(=O)C1.C(O)(C(F)(F)F)=O>C(#N)C>[F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][C:12]3[CH:13]=[C:14]([O:20][CH3:21])[C:15]([O:18][CH3:19])=[CH:16][C:17]=3[I:30])=[N:8]2)=[C:4]([NH2:22])[N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc(Cc2nc3nc(F)nc(N)c3[nH]2)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1cc(I)c(Cc2nc3nc(F)nc(N)c3[nH]2)cc1OC

Procedure:
A solution of 2-Fluoro-8-(3,4-dimethoxy-benzyl)adenine (50 mg, 0.165 mmol), NIS (74 mg, 0.33 mmol), TFA (18.8 mg, 12.7 L, 0.165 mmol) in acetonitrile (120 L) was stirred at room temperature for 24 h. Following solvent removal, the product (12 mg, 16.9%) was collected through silica gel column purification (CHC13:MeOH:AcOH at 80:1:0.5 to 30:1:0.5). MS m/z 430.1 (M+H)+.