Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:10][C:11]([CH3:17])([CH3:16])[CH2:12][C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(Cl)(=O)C([Cl:21])=O>C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([S:10][C:11]([CH3:17])([CH3:16])[CH2:12][C:13]([Cl:21])=[O:14])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(SC(C)(C)CC(=O)O)cc1F
Solvent: c1ccccc1
Product: COc1ccc(SC(C)(C)CC(=O)Cl)cc1F
Reaction time: 3 h
Yield: 88.2 %

Procedure:
To a solution of 3-(3-fluoro-4-methoxy-phenylsulfanyl)-3-methyl-butyric acid (Compound 201, 3.00 g, 11.6 mmol) in 40 mL of benzene at room temperature was added a solution of oxalyl chloride (2.21 g, 17.4 mmol) in 5 mL of benzene over 30 minutes. After 3 hours, the solution was washed with ice cold 5% aqueous NaOH (CAUTION: a large volume of gas is released during this procedure), followed by ice cold H2O, and finally saturated aqueous NaCl. The solution was dried (Na2SO4) and concentrated under reduced pressure to give 2.83 g of a clear yellow oil. This material was used without further purification in the next step. 1H NMR (300 MHz, CDCl3)δ: 7.27 (2H, m), 6.96 (1H, t, J=8.4 Hz), 3.93 (3H, s), 3.13 (2H, s), 1.42 (6H, s).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.[CH3:5][N:6]1[C:10]([C:11](=[O:27])[NH:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([N:19]=[C:20]([C:22]4[N:23]=[CH:24][S:25][CH:26]=4)[N:21]=3)[CH:18]=2)=[C:9]([C:28](O)=[O:29])[CH:8]=[N:7]1>>[N:1]1([C:28]([C:9]2[CH:8]=[N:7][N:6]([CH3:5])[C:10]=2[C:11]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[N:17]([N:19]=[C:20]([C:22]4[N:23]=[CH:24][S:25][CH:26]=4)[N:21]=3)[CH:18]=2)=[O:27])=[O:29])[CH2:4][CH2:3][CH2:2]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(-c3cscn3)nn2c1
Reactant: C1CNC1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccc2nc(-c3cscn3)nn2c1

Procedure:
Using azetidine and 1-methyl-5-(2-(thiazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. Light brown solid (25 mg, 18%). MS: m/z=409.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[C:12]([C:11]1[C:3]([C:2]([F:14])([F:1])[F:15])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:6]=[CH:5]2)#[N:13]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Product: CC(C)(C)OC(=O)Cn1ccc2c(C(F)(F)F)c(C#N)ccc21

Procedure:
Synthesized as described in Example 4 using 4-(trifluoromethyl)-1H-indole-5-carbonitrile and 1,1-dimethylethyl bromoacetate: MS (ES) m/z 325 (M+1).
Reaction SMILES: O=[C:2]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][C:4]#[N:5].[CH2:12]([O:14][CH:15]([O:19][CH2:20][CH3:21])[CH2:16][NH:17][NH2:18])[CH3:13].Cl>C(O)C.C(OCC)(=O)C>[CH2:12]([O:14][CH:15]([O:19][CH2:20][CH3:21])[CH2:16][N:17]1[C:4]([NH2:5])=[CH:3][C:2]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)=[N:18]1)[CH3:13]
Reactant: N#CCC(=O)c1cccnc1
Reactant: CCOC(CNN)OCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(Cn1nc(-c2cccnc2)cc1N)OCC

Procedure:
With gentle heating, 125 g (812 mmol, purity 95%) of 3-oxo-3-(pyridin-3-yl)propionitrile [lit. for example: P. Seneci et al., Synth. Commun. 1999, 29 (2), 311-341; also available commercially] were dissolved in 1.25 liters of ethanol. 126 g (853 mmol) of (2,2-diethoxyethyl)hydrazine and 4.1 ml (4.06 mmol) of 1 M hydrochloric acid were then added. The reaction mixture was heated under reflux for 4 h, and all volatile components were then substantially removed on a rotary evaporator. The residue obtained was taken up in ethyl acetate, and the solution was washed with water and dried over anhydrous magnesium sulphate. After filtration, the mixture was evaporated to dryness. The residue that remained was triturated with diisopropyl ether at RT. The resulting solid was then filtered off with suction and dried under high vacuum. This gave 153 g (65% of theory, purity 96%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[Br:31][CH2:10][CH2:9][CH2:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCCC1CCCCC1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCCC1CCCCC1
Reaction time: 3 h
Yield: 89.8 %

Procedure:
4-Cyclohexyl-1-butanol (5.00 g) was dissolved in methylene chloride (100 ml), triphenylphosphine (9.15 g) and N-bromosuccinimide (6.21 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (100 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (6.30 g) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:8][N:7]=1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([O:11][CH2:12][C:13]([F:15])([F:16])[F:14])=[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:8]([CH2:25][C:26](=[O:27])[NH:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Reactant: CCOC(=O)c1n[nH]c(C(=O)OCC)c1OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(CC(=O)Nc2ccc(Cl)cn2)c(C(=O)OCC)c1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 260 mg 4-(2,2,2-Trifluoro-ethoxy)-1H-pyrazole-3,5-dicarboxylic acid diethyl ester in 4 ml absolute DMF 33.5 mg of a 60% suspension of NaH in mineral oil were added under an argon atmosphere. The mixture was stirred for 15 min at RT. Then 209 mg 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide were added and the mixture stirred for 2 h at RT. After concentration in vacuo the residue was directly subjected to the next reaction step without further purification.
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[F:16])=[O:5].[OH2:18].[OH-].[Na+]>CO>[F:16][C:10]1[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=1[CH:7]1[CH2:8][CH:6]1[C:4]([OH:18])=[O:5]
Reactant: CON(C)C(=O)C1CC1c1cc(F)ccc1F
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CC1c1cc(F)ccc1F
Temperature: 25 °C

Procedure:
A mixture of 2-(2,5-difluoro-phenyl)-cyclopropanecarboxylic acid methoxy-methyl-amide (9.6 g), water (20 mL), and NaOH (3.2 g) in MeOH (40 mL) was refluxed for 3 h. The reaction mixture was cooled down to room temperature and concentrated in vacuo. The residue was acidified by 6 N HCl followed by extraction with CH2Cl2. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (7.8 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:25](I)([CH3:27])[CH3:26].O1CCOCC1>C(OCC)(=O)C.CN(C=O)C.O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:25]([CH3:27])[CH3:26])=[C:4]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[N:3]=1
Reactant: Fc1ccc(Nc2nc(Cl)nc3nc[nH]c23)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(C)n1cnc2c(Nc3ccc(F)cc3)nc(Cl)nc21

Procedure:
A mixture comprising 1 g (3.3 mmol) of 2-chloro-6-(4-fluoro-phenyl-amino)-purine, 2.1 g (6.6 mmol) of caesium carbonate and 2 ml of isopropyl iodide is stirred in 32 ml of a mixture comprising dioxane, water and DMF in a ratio of 2:3:7 at 100° C. for 20 h. Thereafter, the reaction mixture is diluted with ethyl acetate and the organic phase is washed with water. After drying over sodium sulfate and removal of the solvent, the residue is chromatographed over silica gel (mobile phase: ethyl acetate:hexane=4:1). On concentration, 2-chloro-9-isopropyl-6-(4-fluoro-phenyl-amino)-9H-purine is obtained as a crystalline compound. m.p. 154° C.; FAB-MS: (M+H)+=306; Rf=0.2 (ethyl acetate:hexane=4:1).
Reaction SMILES: [NH2:1][C:2]1([C:9]2[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=2[F:16])[CH2:6][O:5][CH2:4][CH:3]1[CH2:7][OH:8].C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.[C:32]([N:40]=[C:41]=[S:42])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1.C(OCC)(=O)C>[Br:15][C:13]1[CH:12]=[CH:11][C:10]([F:16])=[C:9]([C:2]2([NH:1][C:41]([NH:40][C:32](=[O:39])[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[S:42])[CH:3]([CH2:7][OH:8])[CH2:4][O:5][CH2:6]2)[CH:14]=1
Reactant: NC1(c2cc(Br)ccc2F)COCC1CO
Reactant: O=C(N=C=S)c1ccccc1
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NC(=S)NC1(c2cc(Br)ccc2F)COCC1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a solution of racemic ((3RS,4SR)-4-amino-4-(5-bromo-2-fluorophenyl)tetrahydrofuran-3-yl)methanol (75 g, 259 mmol) in tetrahydrofuran (1.3 L) at 25° C. under a nitrogen atmosphere is added dropwise bis(trimethylsilyl)trifluoroacetamide (76.3 mL, 259 mmol) keeping the internal temperature below 30° C. The reaction is stirred at 25° C. for 30 minutes. Benzoyl isothiocyanate (38.4 mL, 284 mmol) is added over 10 minutes keeping internal temperature below 35° C. and the reaction is stirred at 25° C. for 30 min. The reaction mixture is diluted with ethyl acetate (500 mL) and is washed three times with 1 N HCl (3×500 mL), followed by water and brine. The solution is dried over magnesium sulfate and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using a linear gradient of 25% to 50% ethyl acetate in hexanes to give the title compound (110 g, 94%). ES/MS m/e (79Br/81Br) 453, 455 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]([C:7]([NH:6][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])=[O:8])[S:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-:31])=[O:30])=[CH:19][CH:20]=1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: O=[N+]([O-])c1ccccc1SNc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(NC(=O)N(Sc1ccccc1[N+](=O)[O-])c1ccc(Cl)cc1)c1c(F)cccc1F
Temperature: -5 °C
Reaction time: 8 h

Procedure:
A solution of 1.8 g of 2,6-difluorobenzoyl isocyanate in 15 ml of dry toluene was added over 15 minutes to a stirred solution of 2.8 g of N-(4-chlorophenyl)-2-nitrobenzenesulphenamide in 35 ml of the same solvent at room temperature. After stirring overnight, the reaction was incomplete. A few drops of triethylamine were added, and after a further 24 hours, the reaction mixture was cooled to -5° C. and filtered, and the pale yellow product was washed with cold toluene. Traces of toluene were removed by drying under reduced pressure at about 40° C. for 3 days, to give 5, as a solid, m.p.: 176°-178° C.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:35])(=[O:34])[NH:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:36])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[Cl:36][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:20]=[CH:21][C:22]([S:25](=[O:34])(=[O:35])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)Nc3ccc(F)cc3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)Nc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.6 %

Procedure:
Lithium hydroxide monohydrate (0.012 g, 0.28 mmol) was added to a stirred solution of {6-chloro-4-[4-(4-fluoro-phenylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.035 g, 0.07 mmol) in a 3:1 mixture of THF—H2O mixture (5 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane afforded {6-chloro-4-[4-(4-fluoro-phenylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid (0.03 g, 88%) as a solid. 1H NMR (DMSO-d6) δ: 12.50 (br. s, 1H), 10.25 (br. s, 1H), 7.75-8.06 (m, 5H), 7.32-7.56 (m, 3H), 7.13 (d, J=6.4 Hz, 4H), 6.81 (s, 1H), 3.84 (s, 3H), 2.01 (s, 3H). MS calcd. for C25H18ClFNO4S [(M−H)−] 482, obsd. 481.8.
Reaction SMILES: C[Mg]I.[Mg].[CH3:5]I.[O:7]=[C:8]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])/[CH:9]=[CH:10]/[CH:11]1[CH2:13][C:12]1([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH4+].[Cl-]>CCOCC.O.C(OCC)(=O)C.C1C=CC=CC=1>[OH:7][C:8]([CH3:5])([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])/[CH:9]=[CH:10]/[CH:11]1[CH2:13][C:12]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCCCCC(=O)/C=C/C1CC1(C(=O)OCC)C(=O)OCC
Reactant: CI
Agent: C[Mg]I
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCCCCC(C)(O)/C=C/C1CC1(C(=O)OCC)C(=O)OCC
Reaction time: 1.25 h

Procedure:
A solution of the lower alkyl magnesium halide, methyl magnesium iodide, prepared from 24.31 g of magnesium turnings and 157 g of methyl iodide in 1000 ml of ether, is cooled to -70°. Diethyl trans-2-(3-oxo-1-octenyl)cyclopropane-1,1-dicarboxylate (124.2 g); described in Example 3, in 600 ml ether is added slowly taking care that reaction mixture temperature does not exceed -45°. The mixture is stirred 75 min. at the temperature range -50° to -45°. Aqueous saturated NH4Cl solution is added slowly keeping the temperature of the reaction mixture below -55°. The mixture is diluted with water and extracted with 1500 ml ether. The ether layer is washed with saturated NaCl solution twice, then with 10% sodium thiosulfate solution twice, again with saturated NaCl solution, dried (NaSO4) and concentrated to give a greenish yellow oil. The oil is dissolved in ethyl acetate-benzene (3:17) and poured through a column of silica gel. The eluate is concentrated to yield the title compound, nmr (CDCl3) δ 0.88 (+, J = 5, 3H), 2.45 (q, 2H), 4.13 (q, 2H), 5.14 (2xd, J = 16.8, 1H), 5.72 (d, J = 16, 1H).
Reaction SMILES: [F:1][CH:2]([F:16])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]2[N:10]=[C:11]([N+:13]([O-])=O)[CH:12]=[C:6]2[CH2:5]1.[H][H]>C(O)C.[Pd]>[F:16][CH:2]([F:1])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]2[N:10]=[C:11]([NH2:13])[CH:12]=[C:6]2[CH2:5]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc2n(n1)CCN(CC(F)F)C2
Agent: [Pd]
Solvent: CCO
Product: Nc1cc2n(n1)CCN(CC(F)F)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
A solution of 135a (370 mg, 1.59 mmol) in ethanol (20 mL) was added Pd/C (about 200 mg). The reaction was charged with hydrogen gas (via balloon) and stirred at room temperature for 2 h. After reaction was complete, the mixture was filtered through a plug of CELITE®. The filtrate was concentrated reduced pressure to afford 135b as a yellow solid (293 mg, 91%), which was used in the next step without further purification. MS-ESI: [M+H]+ 203.2
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[C:18]2[C:13](=[N:14][C:15]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=3[Cl:33])=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH:17]=2)[N:12]([CH3:34])[C:11](=[O:35])[C:10]=1[C:36](=[O:38])[CH3:37])=[O:7])(=O)C.C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl.CO.CCOC(C)=O>[C:36]([C:10]1[C:11](=[O:35])[N:12]([CH3:34])[C:13]2[C:18]([C:9]=1[NH:8][C:6](=[O:7])[CH2:5][OH:4])=[CH:17][C:16]([C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)=[C:15]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=1[Cl:33])[N:14]=2)(=[O:38])[CH3:37]
Reactant: CC(=O)OCC(=O)Nc1c(C(C)=O)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)c1c(NC(=O)CO)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To the product of EXAMPLE 33 (77 mg) in CH2Cl2 (2 mL) was added Cs2CO3 (43.7 mg) in methanol (1 mL). The reaction stirred at room temperature for 2.5 hours before diluting with EtOAc. The reaction was washed with brine and 10% aqueous NaHSO4 solution. The concentrated residue was purified by flash chromatography on silica gel gradient eluted with 0-65% EtOAc in hexane affording the title compound. HPLC/MS: 530.1 (M+1), 532.1 (M+3); Rt=3.85 min.
Reaction SMILES: Br[Si](C)(C)C.C[O:7][P:8]([CH2:12][P:13]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH2:28])([O:15]CC)=[O:14])(=[O:11])[O:9]C.C(N(CCCC)CCCC)CCC.[Na+:42].[I-].CC(C)=O>CO>[Na+:42].[Na+:42].[Na+:42].[CH2:18]([P:13]([CH2:12][P:8](=[O:7])([O-:11])[O-:9])([OH:15])=[O:14])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH2:28]
Reactant: C=CCCCCCCCCCP(=O)(CP(=O)(OC)OC)OCC
Agent: C[Si](C)(C)Br
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCN(CCCC)CCCC
Solvent: CC(C)=O
Product: C=CCCCCCCCCCP(=O)(O)CP(=O)([O-])[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
Bromotrimethylsilane (0.8 mL, 6.06 mmol) was added dropwise to ((10-undecenyl)-ethoxyphosphinyl) methylphosphonic acid dimethyl ester (0.250 g, 0.68 mmol) in a 3 mL vial. This solution was stirred for 14–16 hours at ambient temperature. Excess bromotrimethylsilane was removed by passing a steady stream of dry nitrogen over the solution for 2 hours. The residue was then placed under high vacuum for 3 hours to remove residual bromotrimethylsilane. Tributylamine (0.57 g, 3.08 mmol) and methanol (3 mL) was then added to the residue resulting in a clear solution. This mixture was added dropwise to a 0.5 M solution of NaI in acetone (10 mL, 5.0 mmol). A white solid precipitated immediately. The solid was collected by centrifugation and the acetone solution was discarded. The solid was then washed by suspension in clean acetone (20 mL), centrifugation and removal of acetone supernatant. After this washing procedure was completed 3 times, the solid was placed under vacuum for a period of 12–16 hours providing the desired product (0.19 g, 74% yield). 1H NMR (400 MHz D2O): δ 5.8 (m, 1H), 4.9 (m, 2H), 1.9 (m, 4H), 1.6 (m, 2H) 1.2 (m, 14H).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:29][C:30]1([C:35]([N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:36])[CH2:34][CH2:33][NH:32][CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO>[CH3:29][C:30]1([C:35]([N:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:36])[CH2:34][CH2:33][N:32]([CH2:11][C:10]2[N:2]([CH3:1])[C:3]3[C:8]([N:9]=2)=[C:7]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:6]=[C:5]([N:19]2[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[C:20]2[CH3:28])[N:4]=3)[CH2:31]1
Reactant: CC1(C(=O)N2CCCC2)CCNC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C)(C(=O)N4CCCC4)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
A mixture of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.26 mmol), (3-methylpyrrolidin-3-yl)pyrrolidin-1-ylmethanone (58 mg, 0.32 mmol), trimethoxyorthoformate (0.29 mL, 2.65 mmol) and acetic acid (15 μL, 0.26 mmol) in DCE (5 mL) was stirred at room temperature for 1 hour then sodium triacetoxyborohydride (90 mg, 0.42 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours then diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was washed with MeOH and the desired product was eluted with 2M NH3 in MeOH. The solvents were removed and the residue was subjected to flash chromatography (Si—PCC, 0-20% MeOH in EtOAc) to give 396 as a white solid (107 mg, 76%). LCMS (Method G): RT 6.69 min; [M+H]+ 544. 1H NMR (400 MHz, CHCl3-d): δ 8.12-8.07 (m, 1 H); 7.74-7.70 (m, 1 H); 7.30-7.26 (m, 2 H); 4.35 (m, 4 H); 3.90 (s, 3 H); 3.87 (t, J=4.75 Hz, 5 H); 3.49 (m, 5 H); 2.96 (s, 3 H); 2.64 (s, 2 H); 2.46-2.37 (m, 2 H); 1.89 (m, 4 H); 1.81 (m, 2 H); 1.41 (s, 3 H).
Reaction SMILES: [CH2:1]([CH2:8][NH:9][CH2:10][C:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21]C)[CH:17]=2)[C:12]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.CO>ClCCl>[CH2:1]([CH2:8][NH:9][CH2:10][C:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:21])[CH:17]=2)[C:12]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)CCC(CNCCc1ccccc1)=C2c1ccccc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc2c(c1)CCC(CNCCc1ccccc1)=C2c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
To a solution of 2-(N-benzylmethylamino)methyl-6-methoxy-1-phenyl-3,4-dihydronaphthalene (0.375 g; prepared according to Process 1) in dichloromethane (15 cm3) being stirred at 0° C. under nitrogen was added a solution of boron tribromide in dichloromethane (1 M, 2.2 cm3). The resulting solution was stirred at 0° C. for 30 min and then at room temperature for 1.5 h. Methyl alcohol (5 cm3) was added and the solvents were removed under reduced pressure. The residue was treated with hydrochloric acid (6 M, 2 cm3) and dichloromethane (4 cm3) and stirred at room temperature for 30 min. The mixture was basified with potassium carbonate, diluted with water (50 cm3), and extracted with dichloromethane (3×25 cm3). The combined organic extracts were washed with brine (25 cm3), dried (MgSO4), and the solvent was removed under reduced pressure. The crude product was purified by column chromatography [silica, eluting with ethyl acetate-heptane (1:1)] to yield the title compound (0.202 g) as a brown oil.
Reaction SMILES: C([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:18])([CH3:17])[C:9]1=[O:19])C1C=CC=CC=1.C([Li])CCC.BrCCO[Si](C(C)(C)C)(C)C>C1COCC1>[CH3:17][C:10]1([CH3:18])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8][C:9]1=[O:19]
Reactant: CC1(C)C(=O)N(Cc2ccccc2)c2ccccc21
Agent: CC(C)(C)[Si](C)(C)OCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)C(=O)Nc2ccccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1-benzyl-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (4.0 g, 15.9 mmol) was dissolved in THF (75 mL) and cooled to −78° C. n-Butyl lithium (2.5 M in hexane, 7.0 mL, 17.5 mmol) was added dropwise and the mixture was warmed to 0° C. over 15 minutes. Cooled to −78° C. and (2-Bromoethoxy)-tert-butyldimethylsilane (5.2 mL, 23.9 mmol) was added and the mixture was allowed to warm to 25° C. The mixture was stirred for 2 hours then quenched with saturated aqueous ammonium chloride, diluted with ether, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 0-10% ethyl acetate in hexane) to afford 4.1 g (63%) 1-(3-{[tert-butyl)dimethyl)silyl]oxy}-1-phenylpropyl)-3,3-dimethyl-1,3-dihydro-2H-indol-2-one.