Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[C:33]([OH:34])=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:24][C:25]1[C:33]([O:34][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCC1CCN(C)CC1
Reactant: Oc1ccc2[nH]ccc2c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3F)ncnc2cc1OCCC1CCN(C)CC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
A solution of 4-chloro-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline (300 mg, 0.9 mmol) and 4-fluoro-5-hydroxyindole (162 mg, 1 mmol), (prepared as described for the starting material in Example 242), in DMF (4.5 ml) containing potassium carbonate (185 mg, 1.3 mmol) was stirred at 90° C. for 1 hour. After cooling, the mixture was filtered and the solid was washed with DMF. The filtrate was evaporated and the residue was purified by column chromatography, eluting with methylene chloride followed by methanol/methylene chloride (1/99) followed by methanol saturated with ammonia/methylene chloride (2/98). The fractions containing the expected product were combined and evaporated. The solid was triturated with ether, filtered, washed with ether and dried under vacuum to give 4-(4-fluoroindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline (282 mg, 69%).
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)[CH:5]=[N:4][C:3]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[SH-:17].[Na+].Cl>CN(C)C=O>[CH2:15]([O:14][C:12]([C:3]1[N:4]=[CH:5][N:6]([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)[C:2]=1[SH:17])=[O:13])[CH3:16]
Reactant: [SH-]
Reactant: CCOC(=O)c1ncn(-c2nccs2)c1Cl
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn(-c2nccs2)c1S
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
8.0 g of 5-chloro-4-ethoxycarbonyl-1-(thiazol-2-yl)imidazole was dissolved in 30 ml of dimethylformamide. To the resulting solution was added 6.2 g of sodium hydrosulfide (content of 70%), followed by stirring of the resulting mixture at 60° C. for 1 hour. After completion of the reaction, the reaction mixture was poured into ice water and the resulting solution was made weakly acidic with conc. hydrochloric acid. Crystals precipitated were filtered out, washed and dried to give 7.5 g of the desired compound. m.p.: 155° to 158° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].[CH3:10][C:11]1([CH3:29])[O:15][N:14]=[C:13]([S:16][CH2:17][C:18]2[C:19]([OH:28])=[N:20][N:21]([CH3:27])[C:22]=2[C:23]([F:26])([F:25])[F:24])[CH2:12]1.O>CN(C)C=O>[CH3:10][C:11]1([CH3:29])[O:15][N:14]=[C:13]([S:16][CH2:17][C:18]2[C:19]([O:28][CH2:7][CH3:8])=[N:20][N:21]([CH3:27])[C:22]=2[C:23]([F:26])([F:25])[F:24])[CH2:12]1
Reactant: Cn1nc(O)c(CSC2=NOC(C)(C)C2)c1C(F)(F)F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1nn(C)c(C(F)(F)F)c1CSC1=NOC(C)(C)C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
0.20 g (1.3 mmoles) of anhydrous potassium carbonate and 0.20 g (1.5 mmoles) of ethyl iodide were added to a solution of 0.30 g (1.0 mmoles) of 5,5-dimethyl-3-(3-hydroxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline dissolved in 10 ml of N,N-dimethylformamide. The mixture was stirred at 50° C. for 3 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting-organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.30 g (yield: 92.0%) of intended 5,5-dimethyl-3-(3-ethoxy-1-methyl-5-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH:8]([CH2:24][CH3:25])[CH2:9][N:10]([N:19]1[CH:23]=[N:22][N:21]=[CH:20]1)[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.[OH:26][C:27]1[CH:32]=[CH:31][C:30]([SH:33])=[CH:29][CH:28]=1>CN(C=O)C.C(OCC)(=O)C>[OH:26][C:27]1[CH:32]=[CH:31][C:30]([S:33][CH2:25][CH2:24][CH2:8][CH2:9][N:10]([N:19]2[CH:23]=[N:22][N:21]=[CH:20]2)[C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:29][CH:28]=1
Reactant: CCC(Br)CN(c1ccc(C#N)cc1)n1cnnc1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(CCCCSc2ccc(O)cc2)n2cnnc2)cc1
Reaction time: 18 h

Procedure:
Potassium carbonate (500 mg) was added to a solution of 4-[(2-bromo-butyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB03001, 384 mg, 1.2 mmol) and 4-hydroxythiophenol (227 mg, 1.8 mmol) in DMF (20 mL). The mixture was stiffed for 18 hours at r.t., diluted with ethyl acetate (100 mL) and extracted with water (two times 30 mL) and brine (30 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate, Rf: 0.30). The resulting oil was dissolved in a small amount of ethyl acetate and the product was precipitated by addition of hexane. Yield: 289 mg (66%). 1H-NMR (400 MHz, d6-DMSO) δ=1.48-1.64 (m, 4H) 2.81 (t, J=6.6 Hz, 2H), 3.81 (t, J=6.8 Hz, 2H), 6.62 (d, J=9.0 Hz, 2H), 6.72 (d, J=8.6 Hz, 2H), 7.19 (d, J=9.0 Hz, 2H), 7.72 (d, J=9.0, 2H), 8.94 (s, 2H), 9.56 (s, 1H, —OH). LRMS (FAB+): 366.1 (100, [M+H]+).
Reaction SMILES: Cl.[C:2]1([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].C(N(CC)CC)C.[Br:23][CH2:24][C:25](Br)=[O:26]>ClCCl>[Br:23][CH2:24][C:25]([N:13]1[CH2:14][CH2:15][N:10]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=2[CH3:9])[CH2:11][CH2:12]1)=[O:26]
Reactant: O=C(Br)CBr
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(N2CCN(C(=O)CBr)CC2)c1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-(2,3-Xylyl)piperazine hydrochloride (5 g; 25 mmol) is suspended in dichloromethane and triethylamine (7.6 ml; 54 mmol) is added. The mixture is cooled to 0° C. and bromoacetyl bromide (2.4 ml; 27 mmol) is added dropwise. The reaction is stirred for 30 minutes and then diluted in dichloromethane, washed with half-saturated sodium bicarbonate solution and dried over magnesium sulfate. The final product is purified by flash chromatography with a gradient of eluents (30/70 to 50/50; EtOAc-Pet. ether).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[CH2:10][CH:9]=[CH:8][NH:7]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([N:7]1[CH2:8][CH:9]=[CH:10][NH:6]1)(=[O:4])=[O:3]
Reactant: C1=CNNC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC=CN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
114.5 g of methanesulphonic acid chloride were added dropwise to 70 g of pyrazoline and 101 g of triethylamine in 300 ml of methylene chloride at room temperature. The mixture was subsequently stirred at room temperature for 3 hours and was filtered. The filtrate was washed with water, dried over sodium sulphate and concentrated. 114 g (77% of theory) of methanesulphonylpyrazoline of melting point 62° C. were obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([OH:20])=[O:19].CON(C)[C:24](=[O:26])[CH3:25]>C1COCC1>[C:24]([C:17]1[O:13][C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH:16]=1)(=[O:26])[CH3:25]
Reactant: CON(C)C(C)=O
Reactant: O=C(O)c1ccco1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(=O)c1ccc(C(=O)O)o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
To a solution of diisopropylamine (27.5 mL, 0.20 mol) in 200 mL of THF at 0° C. was added n-butyllithium (78.5 mL, 0.196 mol; 2.5M in hexanes). The solution was stirred 30 min and was cooled to -78° C. A solution of furoic acid (10.0 g, 0.089 mol) in 100 mL of THF was added and the solution stirred 30 min. To this mixture was added N-methoxy- N-methyl-acetamide (13.8 g, 0.134 mol) in 50 mL of THF. The reaction mixture was warmed to room temperature and stirred 1 h. The mixture was quenched with saturated ammonium chloride solution and the aqueous layer was washed with ether (3×50 mL) to remove impurities. The aqueous layer was acidified with 2M HCl and extracted with ethyl acetate (3×100 mL). The combined organic extract was washed with brine, dried over MgSO4, filtered and evaporated to yield 11.1 g (81%) of 2-acetyl-fur-5-yl carboxylic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[S:18](Cl)(=[O:20])=[O:19].O>ClCCl>[F:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[S:18]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:19])=[O:20]
Reactant: COc1cc(F)c(S(=O)(=O)Cl)cc1OC
Reactant: C1CCNCC1
Solvent: O
Solvent: ClCCl
Product: COc1cc(F)c(S(=O)(=O)N2CCCCC2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Piperidine (4.15 ml, 42.02 mmol) was slowly added to a cooled (ice-bath) solution of 2-fluoro-4,5-dimethoxy-benzenesulfonyl chloride (5 g, 19.63 mmol) in dichloromethane (110 mL). The mixture was stirred overnight at room temperature, diluted with dichloromethane and poured into water. The aqueous phase was extracted with dichloromethane and the combined organic phases washed with brine, dried over magnesium sulfate and evaporated. The crude product was used without further purification.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[Cl:18])=[N:15][C:14]([O:19][CH3:20])=[CH:13][CH:12]=2)=[O:7])C>O1CCCC1.O>[Cl:18][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[N:15]=2)[N:10]=[CH:9][C:8]=1[C:6]([OH:7])=[O:5]
Reactant: CCOC(=O)c1cnc2ccc(OC)nc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2ncc(C(=O)O)c(Cl)c2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96.1 %

Procedure:
Sodium hydroxide (5.86 g, 140.6 mmol, 2.5 eq) is added protionwise at room temperature to a stirred solution of 4-chloro-6-methoxy-[1,5]naphthyridine-3-carboxylic acid ethyl ester (15.0 g, 56.25 mmol, 1.0 eq) in tetrahydrofuran (150 mL) and water (80 mL). After 15 hours stirring at room temperature, tetrahydrofuran is removed, the aqueous layer is cooled down to 0° C. and the pH is adjusted to 3 by the addition of a 2N hydrochloric acid aqueous solution. The resulting precipitate is collected by filtration, washed with water and dried under high vacuum to afford 4-chloro-6-methoxy-[1,5]naphthyridine-3-carboxylic acid as a light red solid (12.9 g, 96% yield).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:32]=[CH:31][C:15]2[NH:16][C:17]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][C:14]=2[CH:13]=1)[C:3]([OH:5])=O.[CH:33]([N:36](C(C)C)[CH2:37]C)(C)C.CNC>CN(C=O)C>[CH3:33][N:36]([CH3:37])[C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:32]=[CH:31][C:15]2[NH:16][C:17]([CH2:19][O:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=3)=[N:18][C:14]=2[CH:13]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)C(O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Agent: CNC
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Reaction time: 12 h
Yield: 88 %

Procedure:
To a solution of hydroxy-{2-[2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazol-5-yl]-phenyl}-acetic acid (0.030 g, 0.0678 mmol) in DMF (0.5 mL) was added (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (0.033 g, 0.0745 mmol), diisopropylethylamine (DIPEA) (0.05 mL, 0.272 mmol), and dimethylamine (0.05 mL, 0.102 mmol, 2.0M solution in THF). After stirring for 12 hours, the crude product was purified by chromatography (silica, CH2Cl2: MeOH, 5:1) to afford the title compound as a white solid (0.028 g, 83%). 1H NMR (400 MHz, CD3OD) δ (ppm): 7.71-7.67 (m, 2H), 7.63 (d, 2H, J=8.4 Hz), 7.41-7.37 (m, 5H), 7.25 (d, 2H, J=8.8 Hz), 5.46 (s, 2H), 5.24 (s, 1H), 2.85 (s, 3H), 2.36 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H23F3N3O3: 470.5 (M+H), Found 470.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:30])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:52])(=O)=O)=CC=1>O1CCCC1>[C:1]([O:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]([F:52])[C:16]([C:22]3[CH:23]=[C:24]([Cl:29])[CH:25]=[C:26]([Cl:28])[CH:27]=3)([C:18]([F:20])([F:19])[F:21])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2F)ccc1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 38.5 %

Procedure:
To a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (preparation of similar compounds described in, for example, EP 1,731,512) (500 mg) in tetrahydrofuran (6 ml) that was stirred at −78° C. for 15 minutes under argon, was slowly added lithium bis(trimethyl-silyl)amide (“LiHMDS”) (1M in hexane) (1.1 ml). The reaction mixture was stirred at −78° C. for 1.5 hours. Then N-fluorobenzenesulfonimide (“NFSI”) (433 mg) was added quickly and the reaction mixture was stirred at −78° C. for 2 hours. The reaction was quenched by addition of aqueous ammonium chloride (saturated) at −78° C. tent-Butyl methyl ether (“TBME”) was added and the phases were separated. The organic layer was washed successively with aqueous ammonium chloride (saturated) and brine, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/heptane 1:2) to give 4-[5-(3,5-dichloro-phenyl)-4-fluoro-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (200 mg) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.C[Si]([P:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(C)C>C1(C)C=CC=CC=1.CC#N.CC#N.Cl[Pd]Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[P:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Brc1ccccc1I
Reactant: C[Si](C)(C)P(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Solvent: Cc1ccccc1
Solvent: CC#N
Product: Brc1ccccc1P(c1ccccc1)c1ccccc1

Procedure:
According to the method described in a literature (S. E. Tunney and J. K. Stille, J. Org. Chem., 1987, 52, 748), (2-bromophenyl)diphenylphosphine was obtained by reacting 2-bromoiodobenzene and (trimethylsilyl)diphenylphosphine in toluene in the presence of dichlorobis(acetonitrile)palladium. Into a four-necked flask was weighed 10.00 g (29.3 mmol) of (2-bromophenyl)diphenylphosphine obtained in the above. The atmosphere of the reaction vessel fitted with a thermometer, a condenser tube, and a dropping funnel with a pressure-equalizing tube was completely replaced with nitrogen, and 100 mL of anhydrous tetrahydrofuran (hereinafter referred to as THF) was added thereto. Thereto was added dropwise 18.3 mL of n-butyllithium-hexane (1.6 M) solution at −78° C. over a period of 30 minutes, followed by 1 hour of stirring at the same temperature. The resulting mixed solution was added dropwise to a 25 mL THF solution of 4.83 g (29.3 mmol) of diethyl chlorophosphite (manufactured by Aldrich) at −78° C. over a period of 30 minutes. After the dropwise addition, a cooling bath was removed and the whole was further stirred at room temperature for 1 hour. After the reaction, THF was removed by evaporation, the residue was dissolved in 50 mL of diethyl ether, and insoluble matter was removed by filtration. The solvent was removed by evaporation and the residue was purified by active alumina column chromatography (eluent: hexane/ethyl acetate=2/1) to obtain the title compound (10.30 g, a pale yellow oily substance). Yield 92%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:22][CH2:23][OH:24])[CH2:10][C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:22][CH2:23][O:24][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:10][C:11]([N:13]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH3:14])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)CC(CCO)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)CC(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1
Yield: 91.1 %

Procedure:
3,4-Dichloro-beta-(2-hydroxyethyl)-N-(4-chlorophenyl)-N-methylbenzenepropanamide (2.1 g) in CH2Cl2 (40 mL) was cooled to -5° to -10° C. and treated sequentially with Et3N (0.69 g), and methanesulfonyl chloride (0.78 g). After two hours the reaction mixture was washed with water(3×50 mL) and the organic layer separated, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound (2.3 g).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])[CH2:17][N:16]2[C:28](OC(C)(C)C)=[O:29])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:75]([O:79][C:80]([NH:82][C:83](C)([CH3:87])[C:84](O)=O)=[O:81])([CH3:78])([CH3:77])[CH3:76]>CN(C=O)C>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])[CH2:17][N:16]2[C:28](=[O:29])[C:83]([NH:82][C:80](=[O:81])[O:79][C:75]([CH3:76])([CH3:78])[CH3:77])([CH3:87])[CH3:84])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(Cl)ccc2F)=CC1c1cccc(O[Si](C)(C)C(C)(C)C)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N1CC(c2cc(Cl)ccc2F)=CC1c1cccc(O[Si](C)(C)C(C)(C)C)c1

Procedure:
A solution of tert-butyl 2-(3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-4-(5-chloro-2-fluorophenyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (17-2,276 mg, 0.683 mmol, 1 equiv), triethylamine (277 mg, 2.73 mmol, 4 equiv), PYBOP (711 mg, 1.37 mmol, 2 equiv) and 2-[(tert-butoxycarbonyl)amino]-2-methylpropanoic acid (278 mg, 1.37 mmol, 2 equiv) in in DMF (10 mL) was warmed at 60° C. for 18 hours. The solution was concentrated and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography. Elution with 10% ethyl acetate/hexanes to 20% ethyl acetate/hexanes gave tert-butyl 2-[2-(3{[tert-butyl(dimethyl)silyl]oxy}phenyl)-4-(5-chloro-2-fluorophenyl)-2,5-dihydro-1H-pyrrol-1-yl]-1,1-dimethyl-2-oxoethylcarbamate (17-3) as a pale yellow gum. LRMS m/z (M+H) 588.9 found, 589.0 required.
Reaction SMILES: Cl[C:2]1([NH2:20])[N:19]=[CH:18][N:17]=[C:16]2[C:3]1=[N:4][CH2:5][N:6]2[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[CH:21]1(N)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C>[CH:21]1([NH:20][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:16]=3[N:17]=[CH:18][N:19]=2)[C@@H:7]2[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]2[OH:9])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NC1CCCCC1
Reactant: NC1(Cl)N=CN=C2C1=NCN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NC4CCCCC4)ncnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Yield: 87.6 %

Procedure:
A solution of 6-chloroadenosine (2.58 g) and cyclohexylamine (5 g) in ethanol (20 ml) was heated at reflux for 6 hours then cooled to room temperature. The reaction mixture was concentrated in vacuo and the resultant residue was diluted with water (50 ml) and ethyl acetate (300 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with water (1×30 ml), dried over sodium sulfate, concentrated in vacuo and dried under vacuum to provide N6-cyclohexyladenosine as a white solid (2.600 g). N6-Cyclohexyladenosine (2.6 g) was diluted with acetone (30 ml) and to the resultant solution was added 2,2-dimethoxypropane (12 ml), followed by D-camphorsulphonic acid (3.01 g) and the mixture was allowed to stir at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the resultant residue was diluted with ethyl acetate (150 ml), then neutralized to pH 8.0 using saturated aqueous NaHCO3. The organic layer was separated, dried over sodium sulfate, concentrated in vacuo. The residue was purified twice on the silica gel column using MeOH—CH2Cl2 (4:96) as an eluent to provide 2′,3′-isopropylidene-N6-cyclohexyladenosine (3.16 g). 1H NMR (CDCl3): δ 1.23-1.47 (m, 9H), 1.38 (s, 3H), 1.64 (s, 3H), 1.79-1.81 (m, 1H), 2.04-2.06 (m, 1H), 3.80 (d, J=12 Hz, 1H), 3.96 (d, J=12 Hz, 1H), 4.53 (s, 1H), 5.09-5.16 (m, 2H), 5.80-5.92 (m, 2H), 7.79 (s, 1H), 8.24 (s, 1H), 8.22-8.38 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[NH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>O1CCOCC1>[Br:1][C:2]1[C:7]([NH:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: NCCN1CCOCC1
Solvent: C1COCCO1
Product: Nc1nc(NCCN2CCOCC2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine and 4-(2-aminoethyl)morpholine in dioxane. ES-MS m/e (%): 370 (M{81Br}+H+, 100), 368 (M{79Br}+H+, 97).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.CCOCC>C(Cl)Cl>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3]2=[O:19])=[O:26])=[CH:23][CH:22]=1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,3-Dihydro-3-(RS)-amino-5-phenyl-2H-1,4-benzodiazepin-2-one (500 mg, 1.98 mmole) and p-chlorobenzoyl chloride (255 μl, 2.00 mmole) were combined at room temperature in 30 ml of methylene chloride. The resulting solution was protected from moisture and stirred at room temperature overnight. The reaction mixture was diluted with 70 ml of methylene chloride and washed with sodium bicarbonate solution (sat.) and brine. The organic extracts were dried (MgSO4) and concentrated to give the crude product. Trituration with ether afforded the analytical sample as a white solid.