Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:4][NH:5][C:6](=[O:11])[CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:3].[CH2:13]([O:17][C:18](Cl)=[O:19])[CH:14]([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[CH2:13]([O:17][C:18]([N:5]([C:6](=[O:11])[CH2:7][CH:8]([CH3:9])[CH3:10])[CH2:4][C:2]([CH3:1])([CH3:12])[NH2:3])=[O:19])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CC(=O)NCC(C)(C)N
Reactant: CC(C)COC(=O)Cl
Solvent: Cc1ccccc1
Product: CC(C)COC(=O)N(CC(C)(C)N)C(=O)CC(C)C

Procedure:
Using the same conditions as in Example 7, 5.1 parts of 2,2,7,7 -tetramethyl-1,4-diazaheptan-5-one, 30 parts of isobutylchloroformate and 150 parts of anhydrous toluene afforded 4-isobutoxycarbonyl-2,2,7,7-tetramethyl-1,4-diazaheptan-5-one of boiling point 134°C at 0.8mm pressure. The hydrochloric acid salt of this material showed a melting point of 179° -181°C and gave the following elemental analysis by weight:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][CH2:13][OH:14])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.O.[S:16](=O)(=[O:19])([OH:18])[OH:17]>>[NH2:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][CH2:13][O:14][S:16](=[O:18])(=[O:17])[OH:19])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(S(=O)(=O)NCCO)c1
Reactant: O=S(=O)(O)O
Solvent: O
Product: Nc1cccc(S(=O)(=O)NCCOS(=O)(=O)O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
216 g of 3-amino-N-(2-hydroxyethyl)-benzenesulphonamide are stirred into 0.4 liter of sulphuric acid monohydrate at 0°-5° C., whilst cooling. The mixture is subsequently stirred, first at 0°-5° C. for 1 hour and then at 15°-20° C. for 3 hours. The solution is then discharged onto about 2.5 liters of ice-water, the temperature being kept below 5° C. The resulting precipitate is allowed to settle, the sulphuric acid solution is largely distilled off, the reaction product is filled up to a volume of about 1 liter with ice-water, the mixture is neutralised by adding 45.0% strength sodium hydroxide solution dropwise, whilst cooling, and the resulting precipitate is filtered off. It is washed with a little water and can be employed in the subsequent diazotisation reaction as a moist paste. If the precipitate is dried, about 200 g of sulphuric acid mono-N-(3-amino-phenylsulphonyl)-2-aminoethyl ester are obtained. ##STR17##
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@@H:12]2[N:15]([CH3:17])[CH3:16])[C:9]=1[C:19]([O:21]CC1C=CC([N+]([O-])=O)=CC=1)=[O:20])(=[O:3])[CH3:2]>O1CCCC1.P([O-])([O-])([O-])=O.[Pt]=O>[C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:18])[C@@H:12]2[N:15]([CH3:16])[CH3:17])[C:9]=1[C:19]([OH:21])=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H](N(C)C)[C@H]2C1
Agent: O=[Pt]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CC(=O)NCCSC1=C(C(=O)O)N2C(=O)[C@H](N(C)C)[C@H]2C1
Yield: 7.1 %

Procedure:
Forty milligrams (0.09 mmol) of p-nitrobenzyl (5R,6R)-3-(2-acetamidoethyl)thio-6-dimethylamino-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate [35] was dissolved in 5 ml of tetrahydrofuran and 2 ml of 0.01M phosphate buffer (pH 7.2), and catalystically reduced in the presence of 50 mg of platinum oxide at room temperature under 4 atmosphere for 3 hours. The reaction mixture was filtered, and concentrated under reduced pressure. The filtrate and the washing were combined, and sodium chloride was added to a concentration of 5%. The solution was adsorbed on a column of CHP-20 (20 ml). The column was eluted with deionized water. Those fractions in the eluates which showed a UV absorption at 307 nm were lyophilized to give 2 mg of the captioned compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH3:24]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([NH2:24])=[O:8])([O-:3])=[O:2]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)cc([N+](=O)[O-])c1Oc1ccccc1
Reactant: N
Product: NC(=O)c1cc([N+](=O)[O-])c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
3-Nitro-4-phenoxy-5-sulphamyl-benzoyl chloride (4 g) was added in portions to liquid ammonia (40 ml). Then excess of ammonia was distilled off, and the residue was triturated with water (50 ml). The precipitated 3-nitro-4-phenoxy-5-sulphamyl-benzamide was isolated by filtration and recrystallized twice from aqueous ethanol. After drying in vacuo, the compound was obtained with a melting point of 255°-256°C.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[CH:18][C:19]=1[CH:20]=[O:21])[N:8]([CH2:11][CH2:12][O:13]C(=O)C)[CH2:9][CH3:10])(=O)C.[OH-].[Na+]>CO.O>[CH2:9]([N:8]([CH2:11][CH2:12][OH:13])[C:7]1[CH:17]=[CH:18][C:19]([CH:20]=[O:21])=[C:5]([OH:4])[CH:6]=1)[CH3:10]
Reactant: CCN(CCOC(C)=O)c1ccc(C=O)c(OC(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCN(CCO)c1ccc(C=O)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To a solution of 29.8 g (0.1 mole) of 3-acetoxy-N-(2-acetoxyethyl)-N-ethyl-4-formylaniline in 175 mL of methanol was added a solution of 17.5 g of sodium hydroxide in 175 mL of water. The mixture was stirred at room temperature overnight. Most of the methanol in the reaction mixture was evaporated with a rotary evaporator and the residue was diluted to 300 mL with water. The pH was adjusted to 6.5-7.0 by adding conc. HC1 (ca. 15-20 mL) slowly. The mixture was then extracted with ether (400 mL×3). The combined ether extracts were dried over MgSO4 and evaporated with a rotary evaporator to give 20.19 g (95%) of the product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1.[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:20])[C:10](=[O:12])[CH:9]([CH3:13])[CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1
Reactant: O=C([O-])[O-]
Reactant: CC1CN(C2CCCC2)c2nc(Cl)ncc2NC1=O
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC1CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Reaction time: 4 h
Yield: 92 %

Procedure:
To a solution of 46.72 g (0.166 mole) of (rac)-2-chloro-9-cyclopentyl-7-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one in 1000 mL of dimethylformamide was added 81.32 g (0.25 mole) of cesium carbonate, followed by 70.88 g (0.499 mole) of methyl iodide. After stirring four hours, the mixture filtered and then concentrated under reduced pressure. The residue was taken up in ethyl acetate and washed four times with water, once with brine and dried over anhydrous sodium sulfate. The mixture was filtered and then concentrated under reduced pressure to give 45 g of (rac)-2-chloro-9-cyclopentyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-1). This material was used subsequent steps without further purification.
Reaction SMILES: F[C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[O:22]1[CH2:23][CH2:24][N:19]([C:2]2[CH:18]=[CH:17][C:5]([C:6]([C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3)=[O:7])=[CH:4][CH:3]=2)[CH2:20][CH2:21]1
Reactant: O=C(c1ccc(F)cc1)c1ccc([N+](=O)[O-])cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(c1ccc(N2CCOCC2)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 105 °C
Yield: 91.3 %

Procedure:
A mixture containing 4-(4-fluorobenzoyl)-nitrobenzene (1.96 9, 8 mmol), morpholine (0.84 g, 9.6 mmol), and potassium carbonate (1.33 g, 9.6 mmol) in dimethyl sulfoxide (15 mL) was heated to 100-110° C. for 12 hours. The reaction mixture was cooled to room temperature and diluted with cold water, and filtered. The crude product was washed several times with water and dried to give 4-(4-morpholinobenzoyl)-nitrobenzene (2.28 g, 91%), m.p. 173-175° C., and was used in the next step without further purification.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[CH:13]([Si:15]([CH3:18])([Cl:17])[Cl:16])Cl.O=P(Cl)(Cl)Cl>[Cl-].[Al+3].[Cl-].[Cl-].CCCCCC>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:13]([Si:15]([CH3:18])([Cl:17])[Cl:16])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[F:5]
Reactant: C[Si](Cl)(Cl)C(Cl)Cl
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Product: C[Si](Cl)(Cl)C(c1ccccc1F)c1ccccc1F
Reaction time: 1 h
Yield: 65.5 %

Procedure:
In a 100 ml, three-necked, frame dried, round bottom flask, aluminum chloride 1.679 (12.5 mmol), fluorobenzene 37.93 ml (404 mmol), and (dichloromethyl)methyldichlorosilane 7.08 ml (50.5 mmol) were reacted for 2 hours as in EXAMPLE 1. The aluminum chloride catalyst was quenched with POCl3 1.15 ml (12.5 mmol) and then stirred for another 1 hour to complete the deactivation. Freshly distilled hexane (50 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic solution. After hexane and fluorobenzene were distilled, the reaction products were vacuum distilled to give 10.49 g of [bis(fluorophenyl)methyl]methyldichlorosilane as a mixture of isomers (bp; 103° C./0.2 torr, yield; 65%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:9](=[O:16])[NH:10][C:11](SC)=[N:12][CH:13]=2)[CH:2]=1.[CH3:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH2:23][S:24][CH2:25][CH2:26][CH2:27][NH2:28]>>[CH3:17][C:18]1[NH:22][CH:21]=[N:20][C:19]=1[CH2:23][S:24][CH2:25][CH2:26][CH2:27][NH:28][C:11]1[NH:10][C:9](=[O:16])[C:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:13][N:12]=1
Reactant: Cc1[nH]cnc1CSCCCN
Reactant: CSc1ncc(Cc2cccnc2)c(=O)[nH]1
Product: Cc1[nH]cnc1CSCCCNc1ncc(Cc2cccnc2)c(=O)[nH]1

Procedure:
An intimate mixture of 5-(3-pyridylmethyl)-2-methylthio-4-pyrimidone and 3-(5-methyl-4-imidazolylmethylthio)propylamine is heated at 130°-135° for 7 hours. The cool mixture is triturated with hot water and treated with dilute ethanolic HCl to give the trihydrochloride of the title compound.
Reaction SMILES: C([O:3][C:4](=[O:33])[C@@H:5]([O:30][CH2:31][CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:18]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH2:31]([O:30][C@@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14]/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:18]=2)=[CH:9][CH:8]=1)[C:4]([OH:33])=[O:3])[CH3:32]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C/c2cccc(Oc3ccccc3)c2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCO[C@@H](Cc1ccc(OC/C=C/c2cccc(Oc3ccccc3)c2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.4 %

Procedure:
(E)-(S)-2-Ethoxy-3-{4-[3-(3-phenoxy-phenyl)-allyloxy]-phenyl}-propionic acid ethyl ester (example 25) (150 mg, 0.34 mmol) was dissolved in ethanol (7 mL) and sodium hydroxide (1N, 4.4 mL, 4.4 mmol) added. The mixture was heated slightly to obtain a clear solution and then stirred at room temperature for 1.5 h. The ethanol was evaporated in vacuo and the mixture acidified to pH 1 with 1N hydrochloric acid. The product was isolated by extraction with ethyl acetate (40 mL×2). The combined organic phases were dried (MgSO4), filtered and evaporated to give 130 mg (91%) of the title compound as an oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][S:8][CH2:9][CH2:10]O.SC(O)C.[Br:16]CCC1OCCO1.[H-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br>C(#N)C>[Br:16][CH2:10][CH2:9][S:8][CH2:7][CH2:6][CH:2]1[O:3][CH2:4][CH2:5][O:1]1
Reactant: BrCCC1OCCO1
Reactant: OCCSCCC1OCCO1
Agent: BrC(Br)(Br)Br
Agent: CC(O)S
Agent: [H-]
Solvent: CC#N
Product: BrCCSCCC1OCCO1
Reaction time: 4 h

Procedure:
To a stirred cooled (<0°) solution of 2-[2-[1,3-dioxolan-2-yl]ethylthio]ethanol (13.6 g, prepared by the condensation between mercaptoethanol and 2-[2-bromoethyl]-1,3-dioxolane employing sodium hydride) in dry acetonitrile (150 ml) was added triphenylphosphine (20 g) and carbon tetrabromide (38 g). The solution was stirred for 4 hours. The solvent was removed under reduced pressure and the residue pre-absorbed onto silica. The material was flash chromatographed over silica using 10% ethylacetate/petroleum ether as eluant to afford the subtitled compound as a clear oil (4.45 g). The material was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:30][C:29](=O)[CH:28]=[C:27]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)[O:26]1>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][C:9]=1[NH:22][C:29](=[O:30])[CH2:28][C:27](=[O:26])[C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)c2ccccc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccs2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)c2ccccc2)cc1NC(=O)CC(=O)c1cccs1
Yield: 25.8 %

Procedure:
Prepared from (2-amino-4-benzoyl-phenyl)-carbamic acid tert.-butyl ester (Example G24) (259 mg, 0.5 mmol) and 2,2-dimethyl-6-thiophen-2-yl-[1,3]dioxin-4-one (Example J1) (135 mg, 0.55 mmol) according to the general procedure K. Obtained as a light yellow solid (60 mg).
Reaction SMILES: ClC(OCC(C)C)=O.C[N:10]1CCOCC1.[C:16]([C:19]1[N:20]=[CH:21][N:22]2[C:27](=[O:28])[N:26]([CH2:29][CH2:30][C:31]([OH:33])=O)[N:25]=[N:24][C:23]=12)(=[O:18])[NH2:17].N.C(N(CC)CC)C>CN(C)C=O.CCOCC>[C:16]([C:19]1[N:20]=[CH:21][N:22]2[C:27](=[O:28])[N:26]([CH2:29][CH2:30][C:31]([NH2:10])=[O:33])[N:25]=[N:24][C:23]=12)(=[O:18])[NH2:17]
Reactant: CN1CCOCC1
Reactant: NC(=O)c1ncn2c(=O)n(CCC(=O)O)nnc12
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)CCn1nnc2c(C(N)=O)ncn2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isobutyl chloroformate (1 M in toluene, 0.218 mL, 0.218 mmol) then N-methyl morpholine (0.024 mL, 0.218 mmol) were added to a stirred mixture of 3-(8-carbamoyl-oxoimidazo[5,1-d][1,2,3,5]tetrazin-3(4H)-yl)propanoic acid (0.05 g, 0.198 mmol) in dimethylformamide (1.25 mL) under nitrogen at −10° C. to −15° C. The reaction mixture was stirred for one hour at this temperature then ammonia (0.5 M solution in 1,4-dioxane, 792 μL, 0.396 mmol) and triethylamine (27.5 μL, 0.198 mmol) in dimethylformamide (0.1 mL) were added. The reaction mixture was stirred at −10° C. to −15° C. for one further hour then allowed to warm to room temperature. After 16 hours, ether (2 mL) was added and the resulting precipitate was washed with ether (10 mL), acetonitrile (10 mL) and water to afford the title compound as a white solid. Yield 12 mg, 0.048 mmol, 24%. LCMS (ES+), m/z 252 (M+H)+ at the solvent front. 1H NMR (400 MHz, d6-DMSO) δ: 8.82 (1H, s), 7.77 (1H, br s), 7.65 (1H, br s), 7.45 (1H, br s), 6.92 (1H, br s) 4.45 (2H, t), 2.64 (2H, t).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[N:16]=[C:15]([NH2:17])[C:14]([N+:18]([O-])=O)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.C(O)(=O)C>CO.[Zn]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10][C:11]2[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[CH:13][CH:12]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(COc2ccc([N+](=O)[O-])c(N)n2)cc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(COc2ccc(N)c(N)n2)cc1
Yield: 90.9 %

Procedure:
To a suspension of 6-({[4-(methyloxy)phenyl]methyl}oxy)-3-nitro-2-pyridineamine (4.8 g, 17.5 mmol) and zinc (11 g, 175 mmol) in methanol (200 mL) was added dropwise acetic acid (5 mL) at rt. After 0.5 h the reaction was filtered through celite and then the solvent was evaporated. The residue was partitioned between water (500 mL) and ethyl acetate (500 mL), the phases were separated and the water extracted with ethyl acetate (5×500 mL). The combined organic phases were dried, filtered and evaporated to afford 3.9 g of the title compound as a black solid (91%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]([CH2:14][CH3:15])[NH:12][C:11](=[O:16])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][C@@H:9]1[CH2:10][C:11](=[O:16])[N:12]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:27])([F:29])[F:28])[CH:19]=2)[C@H:13]1[CH2:14][CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(I)cc1C(F)(F)F
Reactant: CC[C@@H]1NC(=O)C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC[C@H]1[C@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Using (4R,5S)-4-(tert-butyldimethylsilyloxy)-5-ethylpyrrolidin-2-one (1.00 g), 4-iodo-2-trifluoromethylbenzonitrile (1.46 g), cesium carbonate (2.08 g), tris(dibenzylideneacetone)dipalladium(0) (193 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (490 mg), and in the same manner as in Reference Example 3, the title compound was obtained as a colorless solid (yield: 1.32 g, 78%).
Reaction SMILES: O=CC[C@@H]([C@@H](CO)O)O.C[O:11][C@@H:12]1[C@H:16]([OH:17])[C@@H:15]([CH2:18][OH:19])[O:14][C@H:13]1[N:20]1[CH:27]=[CH:26][C:24](=[O:25])[NH:23][C:21]1=[O:22].C(Cl)(=O)C.C1(C)C=CC(C(Cl)=O)=CC=1.N1C=CC=CC=1.C([SiH](CC)CC)C.B(F)(F)F>C(O)C.CO>[C@@H:13]1([N:20]2[CH:27]=[CH:26][C:24](=[O:25])[NH:23][C:21]2=[O:22])[O:14][C@H:15]([CH2:18][OH:19])[C@@H:16]([OH:17])[C@H:12]1[OH:11]
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O
Agent: CC[SiH](CC)CC
Agent: Cc1ccc(C(=O)Cl)cc1
Agent: FB(F)F
Solvent: c1ccncc1
Solvent: CCO
Solvent: CC(=O)Cl
Product: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1

Procedure:
Referring to FIG. 17, commercially available 2-deoxyribose is converted to compound 1 in a two step process. In the first step, 2-deoxyribose is treated with a mixture of acetyl chloride and methanol. In the second step, the reaction mixture is treated with p-toluoyl chloride/pyridine mixture to yield 1. Compound 1 is incubated with a mixture of triethyl silane and boron trifluoride in ethanol to yield compound 2. Treatment of 4 with sodium methylate in methanol yield compound 3. Reacting 3 with t-butyl-diphenyl-silyl chloride in pyridine yields compound 4. The 3'-end of 4 is tritylated using 4,4'-dimethoxytrityl chloride in pyridine to yield compound 5. The 5'-protecting group in 5 can be removed using a mixture of triethylamine/hydrogen fluoride/DCM to yield 6.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:16]O>>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: CO
Reactant: CS(=O)(=O)c1ccc(O)c(C(=O)O)c1
Agent: Cl
Product: COC(=O)c1cc(S(C)(=O)=O)ccc1O
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution of 2-hydroxy-5-(methylsulfonyl)benzoic acid (5.80 g, 26.8 mmol, prepared using procedure in J. Chem. Soc., Perkin Trans 1 1978, 6, 633-638) in MeOH (150 ml) at 0° C. was saturated with HCl (g). The solution was warmed to r.t. and heated to reflux for 3 h. The solid which formed upon cooling was filtered and dried to afford the title compound (4.40 g, 19.1 mmol, 71%).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([F:26])=[C:16]([CH:18]([O:21][Si](C)(C)C)C#N)[CH:17]=1.[CH3:27][O:28][CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1.Cl>C(#N)C.C1COCC1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([F:26])=[C:16]([C:18]([C:32]2([OH:35])[CH2:33][CH2:34][CH:29]([O:28][CH3:27])[CH2:30][CH2:31]2)=[O:21])[CH:17]=1
Reactant: C[Si](C)(C)OC(C#N)c1cc(Br)ccc1F
Reactant: COC1CCC(=O)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCOC1
Product: COC1CCC(O)(C(=O)c2cc(Br)ccc2F)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 18.6 %

Procedure:
LiHMDS (1.0 M, 165 mL, 165 mmol) was added dropwise to a solution of 2-(5-bromo-2-fluorophenyl)-2-((trimethylsilyl)oxy)acetonitrile (Intermediate 12 Step 1, 45.80 g, 150 mmol) in acetonitrile (250 mL) at −78° C. The reaction mixture was stirred for 1.5 h and a solution of 4-methoxycyclohexanone (Lee, C. K.; Lee, I.-S. H.; Noland, W. E. Heterocycles, 2007, 71, 419-428) (20.3 g, 150 mmol) in THF (30 mL) was added slowly and the stirring at −78° C. was continued for 3 h. 1M HCl aq. (300 mL) was added at −78° C., and the mixture was allowed to warm slowly to r.t. and stirred overnight. The phases were separated and the aqueous layer was extracted with EtOAc (2×500 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford 57 g of the crude material. A portion of the crude product (30 g) was purified by flash chromatography using a gradient of 0 to 50% EtOAc in EtOAc in hexanes to afford 9.24 g of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[CH:6][CH:7]=1.[CH:17]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:19][CH2:18]1.[NH4+].[Cl-]>CCCCO>[CH:17]1([N:20]2[CH2:25][CH2:24][N:23]([C:2]3[N:3]=[N:4][C:5]([C:8]4[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=4)=[CH:6][CH:7]=3)[CH2:22][CH2:21]2)[CH2:19][CH2:18]1
Reactant: O=[N+]([O-])c1cccc(-c2ccc(Cl)nn2)c1
Reactant: C1CN(C2CC2)CCN1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCO
Product: O=[N+]([O-])c1cccc(-c2ccc(N3CCN(C4CC4)CC3)nn2)c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 5.2 %

Procedure:
To a solution of 3-chloro-6-(3-nitro-phenyl)-pyridazine (10.0 g, 424 mmol) in n-BuOH (150 mL) was added 1-cyclopropyl-piperazine (8.55 g, 678 mmol) and NH4Cl (2.27 g, 424 mmol) and the mixture was stirred for 48 h at 80° C. The solvent was removed under reduced pressure, and the residue was diluted with water. After alkalization with ammonia, the mixture was extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated to give 7.2 g of crude 3-(4-cyclopropyl-piperazin-1-yl)-6-(3-nitro-phenyl)-pyridazine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[OH-].[CH2:15]([N+](C)(C)C)[C:16]1[CH:21]=CC=[CH:18][CH:17]=1.ClC(C)(C)C#C>ClCCl.O>[CH3:15][C:16]([O:11][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)([CH3:21])[C:17]#[CH:18]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: C#CC(C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: C#CC(C)(C)Oc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 264 h

Procedure:
4-t-Butylphenol (10 g) and sodium hydroxide (3.99 g) were added to a stirred mixture of water (60 ml) and dichloromethane (60 ml) followed by benzyltrimethylammonium hydroxide (40% solution in methanol, 150 ml) and 3-chloro-3-methyl-butyne (13.65 g). After stirring at ambient temperature for 11 days, the layers were separated and the aqueous layer extracted with chloroform. The combined organic extracts were concentrated in vacuo and the residue dissolved in diethyl ether. The solution was washed with water, 10% sodium hydroxide solution, then brine, and dried over magnesium sulphate. Removal of drying agent and solvent gave 3-methyl-3-(4-t-butylphenoxy)-but-1-yne as a yellow oil (13.35 g).