Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.C(OC([NH:38][C@H:39]([C:41](O)=[O:42])[CH3:40])=O)C1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[NH2:38][C@H:39]([C:41]([N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C:4]([OH:3])=[O:10])=[O:42])[CH3:40]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Temperature: -15 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
L-proline methylester hydrochloride (16.58 g, 100 mmole) was dissolved in chloroform (300 ml), and triethylamine (10.12 g, 100 mmole), 1-hydroxybenzotriazole (13.51 g, 100 mmole) and N-benzyloxycarbonyl-L-alanine (22.32 g, 100 mmole) were added thereto under cooling to -15° C. and stirring. To the solution, while keeping the temperature to less than 0° C., a chloroform solution of N,N'-dicyclohexylcarbodiimide (20.63 g, 100 mmole) was added dropwise. After that, the mixture was stirred for 2 hours at 0° C. and then overnight at room temperature. The thus precipitated N,N'-dicyclohexylurea was separated by filtration, and the solution was washed with 10% aqueous sodium bicarbonate, water, 1N hydrochloric acid and water in the order given, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and to the residue thus obtained 1N sodium hydroxide (150 ml) was added. The mixture was stirred for 3 hours at 30° C. The thus precipitated N,N'-dicyclohexylurea was separated by filtration, and the filtrate was adjusted to pH 2.5 with 6N hydrochloric acid and was extracted twice with chloroform (200 ml). The chloroform layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The thus obtained residue was dissolved in 50% methanol (300 ml), and-hydrogen gas was passed through the solution in the presence of 2% palladium-carbon as a catalyst for 2 hours at 40° C. The catalyst was separated by filtration and the solvent was distilled off under reduced pressure The residue thus obtained was recrystallized from water and ethanol to give L-alanyl-L-proline (13.41 g; 72.0%).
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:12][O:13][CH3:14])=[C:7]([CH:10]=1)C=O.[OH:15][C:16]1C=CC(C=O)=CC=1>>[CH3:14][O:13][CH2:12][O:11][C:6]1[CH:7]=[CH:10][C:3]([CH:16]=[O:15])=[CH:4][CH:5]=1
Reactant: COCOc1ccc(OC)cc1C=O
Reactant: O=Cc1ccc(O)cc1
Product: COCOc1ccc(C=O)cc1

Procedure:
4-methoxymethoxybenzaldehyde (F3) was prepared in a similar manner for the preparation of 5-methoxy-2-methoxymethoxybenzaldehyde (F1) by using 4-hydroxybenzaldehyde (4.48 g, 40 mmol) instead of 2-hydroxy-5-methoxybenzaldehyde in 96% (6.40 g): 1H-NMR (500 MHz, CDCl3) δ3.53 (s, 1H), 5.24 (s, 2H), 7.17 (d, 1H, J=9.0 Hz), 7.35 (d, 1H, J=9.0 Hz), 10.52 (s, 1H).
Reaction SMILES: O.[OH-].[Li+].[C:4]1(/[C:10](=[N:17]/[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[O:32][N:31]=[C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:29]=3)=[CH:22][CH:21]=2)/[CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>O1CCCC1>[C:4]1(/[C:10](=[N:17]/[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[O:32][N:31]=[C:30]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:29]=3)=[CH:22][CH:21]=2)/[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2cc(-c3ccccc3)no2)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC/C(=N\OCc1ccc(OCc2cc(-c3ccccc3)no2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
Lithium hydroxide monohydrate (58.3 mg) was added to a solution of methyl E-4-phenyl-4-[4-(3-phenyl-5-isoxazolylmethoxy)benzyloxyimino]butyrate (326 mg) in tetrahydrofuran (6 ml)-water (4 ml) and stirred at room temperature for 2 hours. 1N hydrochloric acid (1.4 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-phenyl-4-[4-(3-phenyl-5-isoxazolylmethoxy)benzyloxyimino]butyric acid (306 mg, yield 97%) as colorless crystals. m.p. 96-97° C.
Reaction SMILES: O[C:2]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[OH:13])=O.C([O-])(=O)C.[Na+].Cl.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[NH:33][NH2:34]>>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[N:33]1[C:2]2[C:3](=[CH:14][CH:15]=[C:16]([OH:18])[CH:17]=2)[C:4]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=2[OH:13])=[N:34]1
Reactant: O=C(c1ccc(O)cc1O)c1ccc(O)cc1O
Reactant: NNc1cc(Cl)ccc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: Oc1ccc(-c2nn(-c3cc(Cl)ccc3Cl)c3cc(O)ccc23)c(O)c1
Yield: 20.5 %

Procedure:
Prepared according to Method B from 2,2′,4,4′-tetrahydroxybenzophenone (0.4 g, 1.6 mmol), sodium acetate (0.27 g, 3 mmol) and 2,5-dichlorophenylhydrazine hydrochloride (0.45 g, 2.5 mmol) to give 0.127 g of product as a beige solid (mp 78–80° C.).
Reaction SMILES: [CH2:1]([NH:3][C:4](=S)[NH:5][NH2:6])[CH3:2].[Cl:8][CH:9]([C:15]([CH3:17])=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11]>Cl>[ClH:8].[CH2:1]([NH:3][C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:15]([CH3:17])[NH:6][N:5]=1)[CH3:2]
Reactant: CCNC(=S)NN
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Product: CCNc1n[nH]c(C)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25.1 %

Procedure:
A mixture of 47.68 g (0.4 mole) of 4-ethyl-3-thiosemicarbazide and 65.8 g (0.4 mole) of ethyl 2-chloracetoacetate was stirred under nitrogen atmosphere for 1.5 hr at ambient temperature then treated with 200 mL of 2N ethanolic hydrogen chloride. The mixture was stirred for ~72 hr, filtered to remove the amorphous sulfur, and the solvent was removed in vacuo to give a deep amber oil which solidified. Recrystallization from acetone gave 27 g of crude product which was recrystallized from benzene/petroleum ether to give 23.5 g of fine white crystals, mp 140°-148° C. Rework of the filtrate gave an additional 17.5 g of crude product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH2:10])=[O:4].[C:17]([OH:23])([C:19](F)(F)F)=O.C([SiH]([CH2:29][CH3:30])CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH:10][CH:30]1[CH2:29][CH2:9][CH:8]([O:23][CH:17]2[CH2:19][CH2:3][O:2][CH2:1]2)[CH2:7][CH2:11]1)=[O:4]
Reactant: CC[SiH](CC)CC
Reactant: O=C(O)C(F)(F)F
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N
Solvent: ClCCl
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CCC(OC2CCOC2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.2 %

Procedure:
A mixture of 3-amino-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (2.62 g, 11.06 mmol), 4-(tetrahydro-furan-3S-yloxy)-cyclohexanone (1.7 g, 9.22 mmol), TFA (2.84 mL, 36.9 mmol) and triethylsilane (2.94 mL, 18.44 mmol) in CH2Cl2 (15 mL) was stirred for 24 h at room temperature. The reaction was concentrated in vacuo to remove volatiles and the crude oil was dissolved in toluene (50 mL) and concentrated (repeat) to give a yellow solid. The crude solid was purified by column chromatography (hexane/ethylacetate) to give 5-(3,3-dimethyl-but-1-ynyl)-3-[4-(tetrahydro-furan-3-yloxy)-cyclohexylamino]-thiophene-2-carboxylic acid methyl ester (1.35 g, 3.33 mmol) as a single isomer.
Reaction SMILES: [C:1]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=1[O:18][CH2:19][C:20](O)=[O:21])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:24][O:25][C:26](=[O:32])[C@H:27]([CH:29]([CH3:31])[CH3:30])[NH2:28].N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O.C(Cl)Cl>[CH3:24][O:25][C:26](=[O:32])[C@H:27]([CH:29]([CH3:31])[CH3:30])[NH:28][C:20](=[O:21])[CH2:19][O:18][C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[C:1]([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CC(C)(C)OC(=O)c1ccc2ccccc2c1OCC(=O)O
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)[C@@H](NC(=O)COc1c(C(=O)OC(C)(C)C)ccc2ccccc12)C(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 85 %

Procedure:
To a solution of (2-carbo-tert-butoxy-1-naphthyloxy)acetic acid (1.20 g, 3.97 mmol, see Example 165, Part A) and valine methyl ester hydrochloride (0.932 g, 5.56 mmol) in N-methylpyrrolidone(7.5 mL)-CH2Cl2(7.5 mL) at room temperature under nitrogen was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophate (2.11 g, 5.56 mmol) and diisopropylethylamine (2.42 mL, 13.9 mmol). After stirring at room temperature for 3.5 hrs, the mixture was partitioned between EtOAc-water. The organic phase was washed with water, 5% KHSO4, saturated NaHCO3 and saturated NaCl solutions, dried over anhydrous Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with EtOAc-hexane (1:9 to 3:7) to give the title compound (1.40 g, 85%) as a colorless oil. TLC(EtOAc-hexane; 1:1) Rf=0.76.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+].[F:14][C:15]([F:24])([F:23])[C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].[F:25][C:26](I)([F:31])[C:27]([F:30])([F:29])[F:28]>CN(C=O)C.C(OCC)(=O)C.O>[F:25][C:26]([F:31])([C:21]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([C:15]([F:23])([F:24])[F:14])[CH:22]=1)[C:27]([F:30])([F:29])[F:28]
Reactant: FC(F)(F)C(F)(F)I
Reactant: Nc1ccccc1C(F)(F)F
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(C(F)(F)C(F)(F)F)cc1C(F)(F)F
Temperature: -30 °C
Reaction time: 9 h
Yield: 20.7 %

Procedure:
To 40 ml of an aqueous solution of 7.04 g (40.4 mmol) of 85% sodium hydrosulfite and 3.40 g (40.4 mmol) of sodium hydrogen carbonate were added 13.6 g (33.7 mmol) of 2-(trifluoromethyl)aniline and 40 ml of DMF. To this reaction liquid was added 50 ml of a solution of 11.2 g (45.5 mmol) of 1,1,2,2,2-pentafluoroethyliodide in DMF (DMF was cooled to −30° C., and 1,1,2,2,2-pentafluoroethyl iodide was dissolved therein), and placed in an autoclave, followed by stirring at 110° C. for 9 hours. After being left to stand at room temperature overnight, water and ethyl acetate were added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine. The organic layer was dried over anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=10:1→5:1) to prepare 1.95 g (yield 21%) of a target compound.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:6]([CH2:7][F:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.C(O)(C(F)(F)F)=O.[Br:26][C:27]1[N:28]=[C:29]2[C:34](Cl)=[C:33]([C:36]([NH2:38])=[O:37])[CH:32]=[N:31][N:30]2[CH:39]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:26][C:27]1[N:28]=[C:29]2[C:34]([NH:1][C@H:2]3[C@@H:6]([CH2:7][F:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:10])[CH2:3]3)=[C:33]([C:36](=[O:37])[NH2:38])[CH:32]=[N:31][N:30]2[CH:39]=1
Reactant: N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CF
Reactant: NC(=O)c1cnn2cc(Br)nc2c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cnn2cc(Br)nc2c1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1CF
Yield: 98 %

Procedure:
A solution of (3S,4S)-benzyl 3-amino-4-(fluoromethyl)pyrrolidine-1-carboxylate, TFA (468 mg, 1.278 mmol) and 2-bromo-8-chloroimidazo[1,2-b]pyridazine-7-carboxamide (352 mg, 1.278 mmol), DIEA (1116 μl, 6.39 mmol) in DMA (5110 μl) was heated at 80° C. for 7 hrs. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate solution was washed with saturated NaCl, dried with sodium sulfate, filtered, and concentrated to yield a brown oil. The crude product was purified by flash column (ISCO 12 g, 0-100% EtOAc/hexane) to afford (3S,4S)-benzyl 3-((2-bromo-7-carbamoylimidazo[1,2-b]pyridazin-8-yl)amino)-4-(fluoromethyl)pyrrolidine-1-carboxylate (615.6 mg, 1.253 mmol, 98% yield) as a faint yellow solid. ESI-MS (analytical LCMS Method B): m/z 493.2 ([M+H]+). HPLC (analytical HPLC Method B) Rt: 3.148 min.
Reaction SMILES: [C:1]([NH2:13])(=[O:12])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:14]([O-:17])(=O)[CH3:15].[Na+].[C:19](OO)(=O)[CH3:20].S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[CH2:1]([NH:13][C:14](=[O:17])[CH2:15][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:19]=[CH2:20])[CH2:2][CH2:3][NH:13][C:1](=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: CC(=O)OO
Reactant: CC(=O)[O-]
Reactant: CCCCCCCCC=CC(N)=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C=CCCCCCCCCC(=O)NCCCNC(=O)CCCCCCCCC=C
Temperature: 15 °C

Procedure:
To a 100 mL, three-necked round bottom flask (fitted with a reflux condenser, addition funnel, and stir bar) was added undecenamide according to the above formula (10) (4.07 g, 10.0 mmol, 20.0 mmol double bonds) and methylene chloride (50 mL). To the addition funnel was added a solution of sodium acetate (0.17 g) in 32 wt % peracetic acid (5.05 mL of 32 wt %, 5.71 g of 32 wt %, 1.83 g peracetic acid, and 24.0 mmol peracetic acid). The peracetic acid solution was added dropwise over 20 minutes to the suspension of formula (10) in methylene chloride, which had been cooled to 15° C. The reaction mixture was stirred at 25° C. for one hour, during which time the amide dissolved/reacted. The reaction mixture was then heated at reflux for 15 hours. The reaction mixture was then cooled to 15° C. in an ice bath, after which a solution of sodium sulfite (3.02 g, 24.0 mmol) in water (30 mL) was added dropwise to the reaction mixture. The organic and aqueous layers were then separated. The organic solution was washed consecutively with equal volumes of water, 5% (w/v) NaCl (twice), and 5% (w/v) NaHCO3 (twice). The organic layer was then dried over MgSO4, filtered, and solvent was removed under reduced pressure to yield a white solid. The crude product was recrystallized from acetone (100 mL) to which water (1 mL) had been added. The recrystallized product was dried in vacuo at 25° C. for 4 hours. The thus obtained polyepoxy amide is represented by formula (11) shown below. Yield: 1.65 g (38%). M.P. 119-122° C. Epoxide equivalent weight (EEW): 224.6 g/mol epoxide (calculated EEW=219.3).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[C:13]#[N:14].CC(C)([O-])C.[K+].Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].Cl>CN(C=O)C.C1(C)C=CC=CC=1.CCCCCCC>[NH2:14][C:13]1[C:12]2[C:11](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]([C:8]#[N:9])([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:26]=1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]
Reactant: N#CCc1ccccc1
Reactant: N#Cc1ccccc1Cl
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C1=C(N)c2ccccc2C1(C#N)c1ccccc1
Yield: 46 %

Procedure:
A mixture of 2-phenylacetonitrile (5.86 g, 50 mmol) and 2-chlorobenzonitrile (7.22 g, 1.05 eq) in DMF (15 mL) was added to a solution of potassium t-butoxide (13.0 g, 2.2 eq, 95%) in DMF (30 mL) cooled with an ice-water bath at a rate such that the internal temperature not exceeding 25° C. 30 min after completion of addition, t-butyl bromoacetate (8.86 mL, 1.2 eq) was added dropwise. The resultant mixture was stirred at room temperature for 24 h, then poured to a mixture of 0.1 N HCl (200 mL), heptane (30 mL) and toluene (15 mL). No solid precipitate was formed. The mixture was extracted with ether (3×150 mL). The combined extracts were washed with water, brine, dried (MgSO4) and concentrated to about 50 mL of total volume to give a precipitate. The solid was collected by filtration, and washed with hexane, and ethyl acetate-hexane mixture (1:1) to give the desired tert-butyl 3-amino-1-cyano-1-phenyl-1H-indene-2-carboxylate (7.65 g, 46%). MS Found: (M+H)+=333.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[O:12][C@@H:11]([N:23]2[C:41]3[N:40]=[CH:39][N:38]=[C:27]([O:28][C:29]4[CH:34]=[CH:33][C:32]([N+]([O-])=O)=[CH:31][CH:30]=4)[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1(OC2C3N=CN(C=3N=CN=2)[C@@H]2O[C@H](CO[Si](C(C)(C)C)(C)C)[C@@H](O[Si](C(C)(C)C)(C)C)C2)[C:46]2[CH:47]=CC=[CH:50][C:45]=2N=N1.C([O-])([O-])=O.[Cs+].[Cs+].C1(O)C2C(=CC=CC=2)C=CC=1>COCCOC>[Si:16]([O:15][C@@H:14]1[C@@H:13]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])[O:12][C@@H:11]([N:23]2[C:41]3[N:40]=[CH:39][N:38]=[C:27]([O:28][C:29]4[C:34]5[C:33](=[CH:50][CH:45]=[CH:46][CH:47]=5)[CH:32]=[CH:31][CH:30]=4)[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:19]([CH3:21])([CH3:22])[CH3:20])([CH3:17])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(Oc4ccc([N+](=O)[O-])cc4)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: Oc1cccc2ccccc12
Agent: [Cs+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(Oc4cccc5ccccc45)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 81 %

Procedure:
As described for the synthesis of 3′,5′-bis-O-(tert-butyldimethylsilyl)-O6-(4-nitrophenyl)-2′-deoxyinosine, this naphthyl derivative was prepared by a reaction between O6-(benzotriazol-1-yl)-3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (26) (59.8 mg, 0.100 mmol), Cs2CO3 (65.2 mg, 0.200 mmol) and 1-naphthol (15.9 mg, 0.110 mmol) in dry DME (1.0 mL) at 85° C. for 2 h. Chromatographic purification (SiO2, elution with 20% EtOAc in hexanes) afforded 49.2 mg (81% yield) of the title compound as a yellowish-white foam. Rf (20% EtOAc in hexanes)=0.37. 1H NMR (500 MHz, CDCl3): δ 8.44 (s, 1H, Ar—H), 8.41 (s, 1H, Ar—H), 7.93 (d, 1H, Ar—H, J=8.8), 7.91 (d, 1H, Ar—H, J=8.3), 7.81 (d, 1H, Ar—H, J=8.3), 7.54 (t, 1H, Ar—H, J=7.8), 7.50 (t, 1H, Ar—H, J=7.6), 7.42 (t, 1H, Ar—H, J=7.6), 7.39 (d, 1H, Ar—H, J=7.3), 6.56 (t, 1H, H-1′, J=6.4), 4.67 (m, 1H, H-3′), 4.06 (q, 1H, H-4′, J=3.4), 3.92 (dd, 1H, H-5′, J=11.2, 4.4), 3.82 (dd, 1H, H-5′, J=11.2, 2.9), 2.71 (quint, 1H, H-2′, J=6.3), 2.50 (ddd, 1H, H-2′, J=12.9, 5.9, 4.1), 0.94, 0.93 (2 s, 18H, tert-Bu), 0.12 (s, 12H, SiCH3). 13C NMR (126 MHz, CDCl3): δ 160.7, 152.7, 152.1, 148.6, 141.7, 134.9, 127.9, 127.3, 126.4, 126.2, 125.9, 125.5, 122.0, 121.9, 118.1, 88.1, 84.7, 71.9, 62.8, 41.4, 25.9, 25.7, 18.4, 18.0, −4.7, −4.8, −5.4, −5.5. FAB HRMS calcd for C32H47N4O4Si2 (M++H) 607.3136. found 607.3120.
Reaction SMILES: [Cl:1][O-].[Na+].[Cl:4][C:5]1[N:10]=[CH:9][C:8]2[CH:11]=[N:12][NH:13][C:7]=2[CH:6]=1.O.S([O-])([O-])=O.[Na+].[Na+]>CCO>[Cl:1][C:11]1[C:8]2[CH:9]=[N:10][C:5]([Cl:4])=[CH:6][C:7]=2[NH:13][N:12]=1
Reactant: Clc1cc2[nH]ncc2cn1
Reactant: [O-]Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Clc1cc2[nH]nc(Cl)c2cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.8 %

Procedure:
Sodium hypochlorite (121 mL, 195 mmol) was gradually added to a suspension of 6-chloro-1H-pyrazolo[4,3-c]pyridine (10 g, 65.1 mmol) in EtOH (100 mL) at 0° C. The reaction mixture was then stirred at room temperature for 10 minutes. Water and sodium sulfite (24.62 g, 195 mmol) were added, forming a clear solution, and the mixture was extracted with EtOAc. The organic phase was concentrated in vacuo to give 3,6-dichloro-1H-pyrazolo[4,3-c]pyridine (11.6 g, 61.7 mmol, 95% yield). MS ESI calc'd. for C6H4Cl2N3 [M+H]+ 188, found 188.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:17])=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[O:5][CH2:6][C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[Br:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH2:26]Br)[CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[Br:18][C:19]1[CH:20]=[C:21]([CH2:26][NH:1][C:2]2[C:3]([F:17])=[C:4]([CH:13]=[CH:14][C:15]=2[F:16])[O:5][CH2:6][C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8])[CH:22]=[C:23]([CH3:25])[CH:24]=1
Reactant: CC(C)OC(=O)COc1ccc(F)c(N)c1F
Reactant: Cc1cc(Br)cc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Br)cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2F)c1
Temperature: 100 °C
Yield: 31.4 %

Procedure:
To a solution of isopropyl 2-(3-amino-2,4-difluoro-phenoxy)acetate (intermediate IV(b)) (350 mg, 1.43 mmol, 1.0 eq) and 1-bromo-3-(bromomethyl)-5-methyl-benzene (528 mg, 1.99 mmol, 1.4 eq) in DMSO (15 mL) was added K2CO3 (593 mg, 4.29 mmol, 3.0 eq). The reaction was heated at 100° C. for 1 h in a microwave reactor, then diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by chromatography (petroleum ether: EtOAc, 100:1 to 80:1) to give the title compound as a light yellow oil (192 mg, 16%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[C:13]([CH2:15][NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])=[O:3].[NH3:21]>C1COCC1>[S:2]([C:5]1[CH:14]=[C:13]([CH2:15][NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:4])(=[O:3])[NH2:21]
Reactant: N
Reactant: COC(=O)c1ccc(CNS(C)(=O)=O)cc1S(=O)(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CNS(C)(=O)=O)cc1S(N)(=O)=O
Yield: 80.5 %

Procedure:
A solution of 11 g (32 mmol) of methyl 2-chlorosulfonyl-4-methanesulfonylaminomethylbenzoate in 200 ml of THF is treated at 0° C. with 1.1 g (64 mmol) of NH3 gas. For work-up, the mixture is concentrated in vacuo. Extracting the residue by stirring with water and then filtration and drying in vacuo give 8.3 g (80%) of methyl 2-sulfamoyl-4-methanesulfonylaminomethylbenzoate of melting point 185–187° C.
Reaction SMILES: C(OP([CH:9]=[C:10]1[NH:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[C:19]([C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)[CH:20]=[CH:21][C:11]1=2)(=O)OCC)C.[H-].[Na+].[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH:33]=O>O1CCCC1>[ClH:29].[ClH:29].[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH:33]=[CH:9][C:10]1=[N:16][CH2:15][CH2:14][N:13]([CH3:17])[C:12]2[CH:18]=[C:19]([C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)[CH:20]=[CH:21][C:11]1=2
Reactant: CCOP(=O)(C=C1NCCN(C)c2cc(-c3ccsc3)ccc21)OCC
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN=C(C=Cc2ccc(Cl)c(Cl)c2)c2ccc(-c3ccsc3)cc21
Product: Cl
Reaction time: 3 h
Yield: 165.2 %

Procedure:
To 105 mg (0.27 mmol) of (1-methyl-8-thiophen-3-yl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester in 2 ml of tetrahydrofuran was added 19 mg (0.47 mmol) of sodium hydride (60% dispersion in mineral oil). After 10 minutes 49 mg (0.28 mmol) of 3,4-dichlorobenzaldehyde was added and the mixture was stirred for 3 hours. The product was purified by column chromatography (20 g IST pre-packed column) eluting with 1% methanol/dichloromethane and treated with 0.15 ml of 4M hydrogen chloride in dioxan. The solvent was evaporated and the residue was recrystallized from acetone to give 75 mg of (E)-5-(3,4-dichlorostyryl)-2,3-dihydro-1-methyl-8-(3-thienyl)-1H-1,4-benzodiazepine dihydrochloride as an orange solid; MS: 412 (M+).