Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=[O:14])=[N:10][CH:9]=2)[CH2:4][CH2:3]1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[F:35][C:32]([F:33])([F:34])[C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[C:25]([NH:24][CH2:23][C:21]([NH:20][CH:18]1[CH2:19][N:16]([CH:2]2[CH2:7][CH2:6][CH:5]([C:8]3[S:12][C:11]([C:13]([OH:15])=[O:14])=[N:10][CH:9]=3)[CH2:4][CH2:3]2)[CH2:17]1)=[O:22])=[O:36]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(c2cnc(C(=O)O)s2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3cnc(C(=O)O)s3)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 5-(4-oxo-cyclohexyl)-thiazole-2-carboxylic acid (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[S:13][C:14]([C:21](Cl)=[O:22])=[C:15]([C:17]([F:20])([F:19])[F:18])[N:16]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:11][C:12]1[S:13][C:14]([C:21]([O:10][CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:22])=[C:15]([C:17]([F:18])([F:19])[F:20])[N:16]=1
Reactant: OCCOc1ccccc1
Reactant: O=C(Cl)c1sc(Cl)nc1C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(OCCOc1ccccc1)c1sc(Cl)nc1C(F)(F)F

Procedure:
6.3 g (0.045 mol) of 2-phenoxyethanol are added slowly while stirring to a solution of 11 g (0.44 mol) of 2-chloro-5-chlorcarbonyl-4-trifluoromethyl-thiazole in 100 ml of absolute toluene. The solution is then cooled to 0°-5° and 3.6 g (0.045 mol) of triethylamine are added dropwise while stirring. Triethylamine-hydrochloride precipitates from the reaction mixture. After everything is added, the suspension is stirred for 20 hours at room temperature and then poured onto ice-water. The organic phase is separated, dried over sodium sulfate and concentrated in a rotatory evaporator. The residue cristallizes. In order to purify it, the crystals are suspended in petrol-ether, filtered and dried. In this manner 8.7 g (57% of the theoreticl yield) of the title compound are obtained, m.p. 70°-72°.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:10]([F:17])=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH2:13].C(OC([N:25]1[CH2:29][C@H:28]([F:30])[CH2:27][C@H:26]1[C:31](O)=[O:32])=O)(C)(C)C>>[Cl:8][C:9]1[C:10]([F:17])=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH:13][C:31]([C@@H:26]1[CH2:27][C@@H:28]([F:30])[CH2:29][NH:25]1)=[O:32]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1C(=O)O
Reactant: NCc1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1cccc(Cl)c1F)[C@@H]1C[C@@H](F)CN1

Procedure:
The title compound was prepared as a TFA salt according to Scheme D5 (steps A and B) from 3-chloro-2-fluoro-benzylamine and (2S,4R)-4-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester. MS (LC-MS): 274.9 [M+H]+; tR (HPLC conditions b): 2.23 min.
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:14])[C@H:4]1[CH2:8][O:7][C:6]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(NC(C)CC(C)C)C>C1COCC1>[CH3:15][S:16]([O:1][N:2]=[C:3]([Cl:14])[C@H:4]1[CH2:8][O:7][C:6]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[O:5]1)(=[O:18])=[O:17]
Reactant: ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Reactant: CS(=O)(=O)Cl
Agent: CCNC(C)CC(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Temperature: 3 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
In a 4 neck 5 L flask was added (R)-N-hydroxy-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g, 719 mmol) in 2.5 L of THF. The material was cooled to 3° C. and methanesulfonyl chloride (56.1 ml, 719 mmol) added in 10 mL portions over 10 minutes. Next, N-ethyl-isopropylpropan-2-amine (126 ml, 719 mmol) was added through an addition funnel over 12 minutes. The reaction was stirred in the ice bath for 30 minutes and then at ambient temperature for 1 hour. The reaction was filtered and the solids washed with MTBE (about 3 L). The filtrate was concentrated and the residue was purified over silica gel (3 kg silica, 7:1 to 3:1 Hex/EtOAc) to afford an oil that slowly solidified under vacuum. The solids were ground using a mortar and pestle and washed with hexanes (about 1000 mL) and dried to afford (R)-N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (158 g, 531 mmol, 73.8% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH:13]1[CH2:16][CH2:15][CH2:14]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl>ClCCl>[N:13]1([C:7]([C:6]2[CH:10]=[C:2]([Cl:1])[C:3]([Cl:11])=[N:4][CH:5]=2)=[O:9])[CH2:16][CH2:15][CH2:14]1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.4 %

Procedure:
Commercially available 5,6-dichloronicotinic acid (200 mg, 1.04 mmol) was dissolved in dichloromethane (5.0 mL), and azetidine hydrochloride (125 mg, 1.34 mmol), HATU (440 mg, 1.16 mmol) and N,N-diisopropylethylamine (0.45 mL, 2.58 mmol) were added, followed by stirring at room temperature for 5 hours under nitrogen atmosphere. 0.5N hydrochloric acid (30 mL) was added, and extraction was carried out with dichloromethane (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-80%) to afford the desired compound (162 mg, yield 67%) as a colorless liquid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[S:52][C:18]2[N:19]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[C:44]([C:49]#[N:50])=[CH:45][CH:46]=[CH:47][CH:48]=4)=[CH:39][C:38]=3[CH3:51])[C:20](=[O:35])[N:21]([CH2:24][C:25]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]>C(Cl)(Cl)Cl>[CH2:13]([C:15]1[S:52][C:18]2[N:19]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:49]4[NH:3][C:4](=[O:7])[O:5][N:50]=4)=[CH:39][C:38]=3[CH3:51])[C:20](=[O:35])[N:21]([CH2:24][C:25]([C:27]3[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3C)c2s1
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3C)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
A mixture of hydroxylammonium chloride (0.68 g), sodium hydrogencarbonate (1.02 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[6-ethyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}-3′-methylbiphenyl-2-carbonitrile (0.67 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in methylene chloride (40 mL). N,N′-Carbonyldiimidazole (0.2 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.32 g, 44%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH:7]=[O:8].[CH3:19][Mg]Br>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:13][CH:14]=2)[S:5][C:6]=1[CH:7]([OH:8])[CH3:19]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 g 4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbaldehyde were dissolved in 100 ml tetrahydrofuran. At 0° C. 3.38 ml of an one molar solution of methylmagnesium bromide in tetrahydrofuran were added dropwise. The cooling bath was removed and the reaction mixture stirred at room temperature for one hour. Then the reaction mixture was poured on 100 ml ice cold saturated NH4Cl solution and extracted five times with portions of 80 ml ethyl acetate. The combined organic layers were washed with 100 ml brine then dried over MgSO4. The solvent was evaporated to obtain 2.7 g crude 1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol as pale yellow solid which was used without further purification.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH2:28][CH:29]([CH3:31])[CH3:30])=[N+:11]([O-:27])[C:12]([O:25][CH3:26])=[C:13]([CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[N:14]=1)C1C=CC=CC=1.[H][H].ClCCl>CO.[C].[Pd]>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([CH2:15][C:13]2[NH:14][C:9](=[O:8])[C:10]([CH2:28][CH:29]([CH3:31])[CH3:30])=[N+:11]([O-:27])[C:12]=2[O:25][CH3:26])=[CH:17]1
Reactant: COc1c(Cc2c[nH]c3ccccc23)nc(OCc2ccccc2)c(CC(C)C)[n+]1[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COc1c(Cc2c[nH]c3ccccc23)[nH]c(=O)c(CC(C)C)[n+]1[O-]
Reaction time: 0.33 h
Yield: 92 %

Procedure:
In 140 ml of methanol was dissolved 2.69 g of 3-benzyloxy-5-(indol-3-yl)methyl-2-isobutyl-6-methoxypyrazine 1-oxide, thereto was added 10% palladium-carbon, and the mixture was stirred for 1 hour at room temperature in a hydrogen gas atmosphere. 150 Milliliters of dichloromethane was added, and the mixture was stirred for 20 minutes, then the catalyst was removed by filtration, and the filtrate was subjected to recrystallization from methanol-chloroform to obtain 1.94 g of the title compound as pale yellow prism-like crystals having a melting point of 222°-224° C.
Reaction SMILES: [N:1]([CH:4]([CH3:22])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([CH2:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])=[C:9]2[C:8]([O:20][CH3:21])=[N:7]1)=[N+]=[N-].[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[CH3:21][O:20][C:8]1[C:9]2[C:10](=[CH:11][C:12]3[C:17]=2[CH2:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[N:6]([CH2:5][C@@H:4]([NH2:1])[CH3:22])[N:7]=1
Reactant: COC1=C2C=c3c(c(OC)nn3CC(C)N=[N+]=[N-])=C2CC=C1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Solvent: CO
Solvent: CCO
Product: COC1=C2C=c3c(c(OC)nn3C[C@H](C)N)=C2CC=C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.8 %

Procedure:
1.11 g (3.71 mmol) of (RS)-1-(2-azido-propyl)-3,7-dimethoxy-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 60 ml of anhydrous ethanol were hydrogenated over 110 mg of platinum oxide for 1.5 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 50 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 430 mg (3.71 mmol) of fumaric acid in 5 ml of methanol. The mixture was stirred at room temperature for 15 hours and the beige crystals were subsequently filtered off. 0.56 g (46%) of (S)-2-(3,7-dimethoxy-1,4-dihydroindeno[2,1-c]pyrazol-1-yl)-1-methyl-ethylamine fumarate (1:05) with m.p. 209° was obtained.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[CH2:15][O:14][NH:13][C:12]2=[O:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:25]1([C:31]([O:33][CH3:34])=[O:32])[CH:29]=[CH:28][C:27](=[O:30])[O:26]1>ClCCl>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[CH2:15][O:14][N:13]([C:25]3([C:31]([O:33][CH3:34])=[O:32])[CH:29]=[CH:28][C:27](=[O:30])[O:26]3)[C:12]2=[O:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N[C@@H]1CONC1=O
Reactant: COC(=O)C1(Cl)C=CC(=O)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(N2OC[C@@H](NC(=O)Cc3ccccc3)C2=O)C=CC(=O)O1
Yield: 43.3 %

Procedure:
In 8 ml of dichloromethane was suspended 110 mg of (4R)-4-phenylacetamido-3-isoxazolidinone. To the suspension were added, under ice-cooling and stirring, 0.14 ml of triethylamine and 2 ml of dichloromethane solution dissolving 106 mg of the Compound (27) obtained in Example (27). The reaction solution was stirred at room temperature for 40 minutes, washed with water and dried (Na2SO4). The solvent was then evaporated off. The residue was subjected to a silica gel column chromatography, followed by elution with hexane-ethyl acetate (2:3) to give 78 mg of the subject Compound (30) as colorless oil.
Reaction SMILES: C1C(=O)N([O:8][C:9]([O:11][CH2:12][CH:13]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=O)C(=O)C1.[NH2:26][C@@H:27]([CH2:31][CH2:32][CH2:33][CH2:34][N:35]([C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52])[CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[C:28]([OH:30])=[O:29].C([O-])([O-])=O.[Na+].[Na+].Cl>CN(C=O)C>[CH2:44]([O:43][C:41]([NH:40][CH2:39][CH2:38][CH2:37][CH2:36][N:35]([C:51]([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52])[CH2:34][CH2:33][CH2:32][CH2:31][C@H:27]([NH:26][C:9]([O:11][CH2:12][CH:13]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=2[C:20]2[C:25]1=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:8])[C:28]([OH:30])=[O:29])=[O:42])[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: N[C@@H](CCCCN(CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCCCCN(CCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 58.4 %

Procedure:
A solution of 9-fluorenylmethyl N-succinimidyl carbonate (143 mg, 0.42 mmol) in DMF (1.60 mL) was added to a solution of 9 (135 mg, 0.278 mmol) in 9% Na2CO3 (655.9 mg, 0.557 mmol) at 0° C. and stirred at room temperature for 21 hours under argon. The pH was adjusted to 7.0 with 0.1 N HCl. The mixture was concentrated to an oil and purified by flash chromatography (CHCl3, then 95% CHCl3MeOH) to give 10 (115 mg, 58%) as a colorless oil: 1H NMR (19.2° C.) δ1.22-1.92 (m, 10 H), 3.08 (m, 2 H), 3.16-3.30 (m, 4 H), 4.12 (m, 1 H), 4.21 (t, 1 H, J=6.9), 4.30-4.45 (m, 2 H), 5.04(s, 2H), 5.08 (s, 2 H), 7.22-7.42 (m, 14 H), 7.66 (m, 2 H), 7.78 (d, 2 H, J=7.5); HRMS m/z calcd for C41H46N3O8 708.3285, found 708.3284. [δ]22D=+9.3°(c 1.00, CHCl3).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[C:19]([Cl:25])[CH:18]=1.I[CH2:28][CH:29]1[CH2:33][CH2:32][C:31]2([O:38][CH2:37][CH2:36][CH2:35][O:34]2)[CH2:30]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:26])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[C:19]([Cl:25])[CH:18]=1)[CH2:28][CH:29]1[CH2:33][CH2:32][C:31]2([O:34][CH2:35][CH2:36][CH2:37][O:38]2)[CH2:30]1
Reactant: COC(=O)Cc1ccc(SC)c(Cl)c1
Reactant: ICC1CCC2(C1)OCCCO2
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(CC1CCC2(C1)OCCCO2)c1ccc(SC)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 56.2 %

Procedure:
A solution of diisopropylamine (1.9 mL, 13.64 mmol) in dry tetrahydrofuran (19.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (6.5 mL) cooled to −78° C. under nitrogen was treated with a 2.5M solution of n-butyllithium in hexanes (5.5 mL, 13.64 mmol). The reaction mixture was stirred at −78° C. for 45 min and then treated dropwise with a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (prepared as in Example 4, 2.42 g, 10.49 mmol) in dry tetrahydrofuran (19.5 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (6.5 mL). The reaction mixture turned bright yellow. The reaction mixture was allowed to stir at −78° C. for 15 min, then at 0° C. for an additional 30 min, and then re-cooled to −78° C. At this point, a solution of 2-iodomethyl-6,10-dioxa-spiro[4.5]decane (prepared as in Example 43, 3.85 g, 13.64 mmol) in dry tetrahydrofuran (10 ML) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (3 mL) was added dropwise. The reaction mixture stirred at −78° C. for 30 min and was then allowed to warm to 25° C., where it was stirred for 24 h. The reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The aqueous residue was diluted with ethyl acetate (200 mL), and the organic layer was washed with a saturated aqueous lithium chloride solution (2×200 mL), water (200 mL), and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 25% ethyl acetate/hexanes) afforded the 2-(3-chloro-4-methylsulfanyl-phenyl)-3-(6,10-dioxa-spiro[4.5]dec-2-yl)-propionic acid methyl ester (2.27 g, 56%) as a yellow oil: EI-HRMS m/e calcd for C19H25ClO4S (M)+ 384.1162. found 384.1181.
Reaction SMILES: O.[CH3:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:6]([NH:8][NH2:9])=[O:7].C(N(CC)CC)C.[CH3:23][C:24]([CH3:29])([CH3:28])[C:25](Cl)=[O:26]>ClCCl>[CH3:23][C:24]([CH3:29])([CH3:28])[C:25]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:12]([N+:13]([O-:15])=[O:14])=[C:3]([CH3:2])[CH:4]=1)=[O:26]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(C(=O)NN)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)NNC(=O)C(C)(C)C)ccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
Water is added to a mixture consisting of 3-methyl-4-nitrobenzhydrazide (3.9 g), triethylamine (3 ml) and 2,2-dimethylpropanoyl chloride (2.6 ml) in dichloromethane (120 ml) stirred for 2 h. After drying, evaporation and trituration of the organic phase in petroleum ether, N′-(2,2-dimethylpropanoyl)-3-methyl-4-nitrobenzhydrazide is obtained in the form of a precipitate.
Reaction SMILES: CC1C(=O)NC(=O)N(C2OC(COC(C3C=CC(OC)=CC=3)(C3C=CC(OC)=CC=3)C3C=CC=CC=3)C(O)C2)C=1.COP(Cl)[Cl:44].[N:46]1[C:51]([CH3:52])=[CH:50][C:49]([CH3:53])=[CH:48][C:47]=1[CH3:54].N1C=NN=N1>O1CCCC1>[ClH:44].[N:46]1[C:51]([CH3:52])=[CH:50][C:49]([CH3:53])=[CH:48][C:47]=1[CH3:54]
Reactant: COP(Cl)Cl
Agent: COc1ccc(C(OCC2OC(n3cc(C)c(=O)[nH]c3=O)CC2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: c1nnn[nH]1
Solvent: Cc1cc(C)nc(C)c1
Solvent: C1CCOC1
Product: Cl
Reaction time: 0.25 h

Procedure:
5'-O-Dimethoxytritylthymidine (1.6 g, 2.9 mmol) in anhydrous tetrahydrofuran (5 ml) was added dropwise to a well stirred solution at -78° of CH3OPCl2 (0.33 ml, 2.5 mmol) and collidine (1.86 ml, 14.1 mmol) in anhydrous tetrahydrofuran (5 ml). A white precipitate formed during the addition. The mixture was stirred for 15 min at -78° and then filtered through a sintered glass funnel to remove collidine hydrochloride. The collidine hydrochloride was washed with dry tetrahydrofuran (1 ml). The filtrate was then diluted with dry toluene and concentrated to a gum. After dry argon had been bled into the apparatus, a solution (6 ml) containing toluene:tetrahydrofuran (2:1) was added and the gum was allowed to dissolve completely in this solution. Solvent was removed by concentration in vacuo. This reconcentration using a solution of toluene and tetrahydrofuran was repeated three times. After the final concentration, the gum was dissolved in dry tetrahydrofuran (3 ml), cooled to -78° and a solution of tetrazole (0.18 g, 2.6 mmol) in dry tetrahydrofuran (3 ml) was added dropwise. A white precipitate of collidine hydrochloride formed during the addition. The mixture was stirred additional 10 min at -78° and then transferred using positive argon pressure and a cannula to a centrifuge tube filled with argon. The supernatant recovered after centrifugation contained the tetrazolylphosphite product which can be used directly for synthesis of deoxyoligonucleotides. Alternatively, the tetrazolylphosphite can be stored as a precipitate and reconstituted as needed.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][C:6]([CH2:7][O:8][N:9]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]([O:22]C)=[O:21])=[N:16][CH:17]=2)[CH3:11])=[CH:5][CH:4]=1.CO.O.[OH-].[Li+]>C1COCC1>[F:26][C:2]([F:1])([F:27])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][N:9]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]([OH:22])=[O:21])=[N:16][CH:17]=2)[CH3:11])=[CH:24][CH:25]=1
Reactant: COC(=O)COc1ccc(C(C)=NOCc2ccc(C(F)(F)F)cc2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(=NOCc1ccc(C(F)(F)F)cc1)c1ccc(OCC(=O)O)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
To a solution of the product of step 3 (2.0 gm, 5.2 mmoles) in a mixture of THF (12 mL), methanol (4 mL) and water (4 mL), lithium hydroxide (440 mg, 10.5 mmoles) was added and the reaction mixture was stirred at ambient temperature for 4 hours. The solvents were evaporated under reduced pressure. The residue was dissolved in water, acidified with 1N HCl and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evapourated under reduced pressure to yield 1.7 gm (88%) of title product as white solid.
Reaction SMILES: [Cl-].O[NH3+].[C:4](=[O:7])([O-])[OH:5].[Na+].[CH2:9]([C:11]1[S:42][C:14]2[N:15]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:30][CH:29]=3)[C:16](=[O:26])[N:17]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]=2[CH:12]=1)[CH3:10].[N:43]12CCCN=C1CCCCC2>C(Cl)(Cl)Cl.C(Cl)Cl.CS(C)=O>[CH2:9]([C:11]1[S:42][C:14]2[N:15]([CH2:27][C:28]3[CH:29]=[CH:30][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]4[NH:43][C:4](=[O:7])[O:5][N:41]=4)=[CH:32][CH:33]=3)[C:16](=[O:26])[N:17]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:13]=2[CH:12]=1)[CH3:10]
Reactant: CCc1cc2c(s1)n(Cc1ccc(-c3ccccc3C#N)cc1)c(=O)n2CCc1ccccc1
Reactant: C1CCC2=NCCCN2CC1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [NH3+]O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(s1)n(Cc1ccc(-c3ccccc3-c3noc(=O)[nH]3)cc1)c(=O)n2CCc1ccccc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
A mixture of hydroxylammonium chloride (0.71 g), sodium hydrogencarbonate (1 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C. for 30 min, 4′-{[5-ethyl-2-oxo-1-(2-phenylethyl)-1,2-dihydro-3H-thieno[2,3-d]imidazol-3-yl]methyl}biphenyl-2-carbonitrile (0.58 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained by silica gel column chromatography was dissolved in methylene chloride (20 mL), N,N′-carbonyldiimidazole (0.22 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (0.23 g, 36%).