Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:14]=[C:13]([Cl:15])[C:12]([CH:16]([OH:25])[CH2:17][CH:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)=[C:11]([Cl:26])[N:10]=1>CS(C)=O>[NH2:8][C:9]1[N:10]=[C:11]([Cl:26])[C:12]([C:16](=[O:25])[CH2:17][CH:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)=[C:13]([Cl:15])[N:14]=1
Reactant: CC1(C)OCC(CC(O)c2c(Cl)nc(N)nc2Cl)O1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)OCC(CC(=O)c2c(Cl)nc(N)nc2Cl)O1
Reaction time: 2 h
Yield: 90.2 %

Procedure:
Triethylamine (5.25 mL) and a sulfur trioxide-pyridine complex (2.45 g) were added to a mixture composed of the above 1-(2-amino-4,6-dichloropyrimidin-5-yl)-2-(2,2-dimethyl-[1,3]dioxolan-4-yl)ethan-1-ol (2.32 g) and dimethyl sulfoxide (30 mL) under cooling in an ice bath. The ice bath was removed and the mixture was stirred for two hours. The reaction mixture was added dropwise to a 0.5 N hydrochloric acid solution (300 mL), followed by extraction with ethyl acetate. The organic layer was sequentially washed with water and brine and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the solvent was evaporated to obtain a crude product of the title compound (2.08 g, 90%) as a solid. The resulting compound was directly used for the next reaction without purification.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([CH2:21][OH:22])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=1)[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:30]([Si:34](Cl)([CH3:36])[CH3:35])([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[CH2:1]([NH:8][CH2:9][CH:10]([CH2:21][O:22][Si:34]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:36])[CH3:35])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=1)[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC(CNCc1ccccc1)C(O)c1ccc(Cl)c(F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC(CNCc1ccccc1)C(O)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a solution of (1RS,2SR)-2-[(benzylamino)methyl]-1-(4-chloro-3-fluorophenyl)propane-1,3-diol (44.5 g) and triethylamine (21.1 ml) in THF (416 mL) was added a solution of tert-butylchlorodimethylsilane (22.8 g) in THF (42 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (NH, hexane/ethyl acetate) to give the title compound (29.3 g).
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:20])[NH:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH2:18][CH3:19])=[N:8][CH:9]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[C:5](=[O:20])[NH:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH2:18][CH3:19])=[N:8][CH:9]=1
Reactant: CCCOc1ccccc1-c1ncc([N+](=O)[O-])c(=O)[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCOc1ccccc1-c1ncc(N)c(=O)[nH]1

Procedure:
A mixture of 5-nitro-2-(2-propoxyphenyl)-pyrimidin-4(3H)-one (4.34 g) in methanol (120 ml) was treated with hydrogen at atmospheric pressure and ambient temperature in the presence of 10% palladium on carbon (170 mg) for five hours. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure affording a dark oily residue. This was eluted from a silica column with chloroform and the combined fractions containing product were evaporated under reduced pressure to afford the crude title compound as a dark yellow solid, 1.69 g. This was recrystallised from isopropylacetate, then dissolved in boiling 2 Normal hydrochloric acid, and the filtered, cooled solution was washed with chloroform. The acidic solution was neutralised with potassium carbonate which afforded a pale yellow solid, 600 mg, which was recrystallised from acetonitrile to afford the title compound, 250 mg, m.p. 157°-158° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[N:4][CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][Si](C(C)(C)C)(C)C)[CH2:9]2)[N:7]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].O>C(Cl)Cl>[CH3:29][S:30]([O:14][C@H:10]1[CH2:11][CH2:12][CH2:13][C@@H:8]([C:6]2[CH:5]=[N:4][C:3]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:2]([Br:1])[N:7]=2)[CH2:9]1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)C(=O)Nc1ncc([C@@H]2CCC[C@H](O[Si](C)(C)C(C)(C)C)C2)nc1Br
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)C(=O)Nc1ncc([C@@H]2CCC[C@H](OS(C)(=O)=O)C2)nc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
To a mixture of (+/−)-N-(3-bromo-5-((1R,35)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)pyrazin-2-yl)pivalamide (72 mg, 0.202 mmol) in CH2Cl2 (2021 μL) at 0° C. was added TEA (56.3 μL, 0.404 mmol) and methanesulfonyl chloride (18.90 μL, 0.243 mmol). The resulting mixture was stirred at room temperature for 3h. Another TEA (56.3 μL, 0.404 mmol) and Methanesulfonyl chloride (18.90 μL, 0.243 mmol) was added, and stirred for 6h. Worked up the reaction by adding water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified with flash chromatography eluting with 0-100% EtOAc/heptane to provide 54 mg of (+/−)-(1S,3R)-3-(6-bromo-5-pivalamidopyrazin-2-yl)cyclohexyl methanesulfonate in 61.5% yield. LCMS (m/z): 436.1 (MH+), 0.75 min.
Reaction SMILES: [Cl:1][C:2]([Cl:13])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]Br.C1(C)C=CC(S([O-])(=O)=[O:21])=CC=1.[Na+].CO.O>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:13])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][OH:21]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: ClC(Cl)=COc1cccc(CBr)c1
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1cccc(OC=C(Cl)Cl)c1
Temperature: 60 °C

Procedure:
A mixture 3(2,2-dichlorovinyloxy)benzyl bromide (2.8 g), sodium p-toluene sulphonate (2.0 g) and methanol (20 ml) is warmed to 50° C for 1 hour, after which water (20 ml) and toluene (20 ml) is added with agitation. The toluene layer is separated, washed with water and concentrated by evaporation of the solvent under reduced pressure. The concentrate is then added dropwise to a 15% (w/v) aqueous solution of potassium hydroxide (100 ml) and the mixture warmed to 60° C for 1 hour, cooled to the ambient temperature and extracted with a mixture of toluene (10 ml) and methyl iso-butylketone (10 ml), the extracts dried over anhydrous magnesium sulphate and the solvents evaporated under reduced pressure to yield 3(2,2-dichlorovinyloxy)benzyl alcohol as a residual pale yellow oil.
Reaction SMILES: B([O-])[O-].[CH3:4][C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:10]=1)([CH3:8])[C:6]#[N:7].[I-].I[C:26]1[C:31]([CH3:32])=[CH:30][N:29]=[C:28]2[NH:33][N:34]=[CH:35][C:27]=12.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC#N.O>[CH3:8][C:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:26]2[C:31]([CH3:32])=[CH:30][N:29]=[C:28]3[NH:33][N:34]=[CH:35][C:27]=23)[CH:10]=1)([CH3:4])[C:6]#[N:7]
Reactant: Cc1cnc2[nH]ncc2c1I
Reactant: CC(C)(C#N)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: C1COCCO1
Solvent: O
Product: Cc1cnc2[nH]ncc2c1-c1cccc(C(C)(C)C#N)c1
Temperature: 150 °C
Reaction time: 0.17 h
Yield: 106.5 %

Procedure:
Boronate-2-methyl-2-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanenitrile (200 mg, 0.7376 mmol), iodide-4-iodo-5-methyl-1H-pyrazolo[3,4-b]pyridine (191.1 mg, 0.7376 mmol), Na2CO3 (1.106 mL of 2 M, 2.213 mmol) and Pd(PPh3)4 (85.23 mg, 0.07376 mmol) were placed in a microwave tube and dry Dioxane (5.000 mL) was added. The resulting suspension was stirred at 150° C. in the microwave (using a 10 minute ramp and nitrogen cooling) for 60 minutes. The reaction mixture was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc (3×20 mL) and the combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give an oil. The mixture was purified by column chromatography (10-100% EtOAc in hexanes, ˜100 mL silica, loaded in DCM) to give an oil which was lyophilised from MeCN/H2O to give a solid (217 mg, 57% Yield).
Reaction SMILES: [C:1]([C@@:3]1([CH2:32][CH3:33])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[N:17][N:18]([CH:20]4[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]4)[CH:19]=3)[N:9]=2)[C:4]1=[O:31])#[N:2].[ClH:34]>C(OCC)(=O)C>[ClH:34].[ClH:34].[NH:22]1[CH2:23][CH:20]([N:18]2[CH:19]=[C:15]([NH:14][C:10]3[N:9]=[C:8]([N:5]4[CH2:6][CH2:7][C@:3]([CH2:32][CH3:33])([C:1]#[N:2])[C:4]4=[O:31])[CH:13]=[CH:12][N:11]=3)[CH:16]=[N:17]2)[CH2:21]1
Reactant: CC[C@]1(C#N)CCN(c2ccnc(Nc3cnn(C4CN(C(=O)OC(C)(C)C)C4)c3)n2)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC[C@]1(C#N)CCN(c2ccnc(Nc3cnn(C4CNC4)c3)n2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 3-(4-((4-((3R)-3-cyano-3-ethyl-2-oxopyrrolidin-1-yl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)azetidine-1-carboxylate (170 mg) obtained in Example 184 was added a solution of 4 M hydrogen chloride in ethyl acetate (6.0 mL), and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, and the residue was recrystallized (ethanol/ethyl acetate) to give the title compound (120 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:16]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]([F:24])=[CH:13][C:12]=3[N:11]3[CH2:25][CH2:26][CH:27]([CH2:28][C:29]([OH:31])=[O:30])[C:10]=23)=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:16]([CH:18]([OH:23])[C:19]([F:21])([F:22])[F:20])=[CH:15][C:14]([F:24])=[CH:13][C:12]=3[N:11]3[CH2:25][CH2:26][CH:27]([CH2:28][C:29]([OH:31])=[O:30])[C:10]=23)=[CH:4][CH:3]=1
Reactant: O=C(O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(C(=O)C(F)(F)F)cc(F)cc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(C(O)C(F)(F)F)cc(F)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
To a solution of (+/−)-[9-[(4-chlorophenyl)sulfanyl]-6-fluoro-8-(trifluoroacetyl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetic acid (Example 11, 78 mg) in MeOH (5 mL) at r.t. was added 50 mg of NaBH4. The reaction mixture was stirred at r.t. for 3 hours and 1N HCl was slowly added The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with EtOAc/Hexanes/AcOH (20:30:1) to provide 60 mg of the title compound as a white solid.
Reaction SMILES: [OH-].[Na+].O1CCCC1.C[O:9][C:10]([C@@:12]12[CH2:20][N:19]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:18][C@@H:17]1[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11]>CO>[CH2:24]([O:23][C:21]([N:19]1[CH2:20][C@:12]2([C:10]([OH:11])=[O:9])[C@@H:17]([CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:18]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)[C@]12CCCC[C@H]1CN(C(=O)OCc1ccccc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1C[C@@H]2CCCC[C@]2(C(=O)O)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.6 %

Procedure:
A 1 mol/L sodium hydroxide solution (70.8 mL) and tetrahydrofuran (78.8 mL) were added to a solution of [(1R*,6R*)-8-benzyloxycarbonyl-8-azabicyclo[4.3.0]nonan-1-yl]carboxylic acid methyl ester (7.50 g, 23.6 mmol) in methanol (78.8 mL) in a nitrogen atmosphere, and the mixture was stirred at room temperature for three days. The reaction solution was concentrated under reduced pressure and then washed with diethyl ether (50 mL×2). The aqueous layer was made acidic with 3 mol/L hydrochloric acid (28 mL) under ice-cooling, followed by extraction with ethyl acetate (100 mL×2). The organic layer was washed with brine (250 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 6.70 g of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([CH2:15][CH3:16])[C:13]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[C:18]([F:21])[CH:19]=[CH:20][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:15]([N:14]1[C:13]2[C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[C:18]([F:21])[CH:19]=[CH:20][C:12]=2[N:11]=[C:10]1[C@@H:8]([NH2:7])[CH3:9])[CH3:16]
Reactant: CCn1c([C@H](C)NC(=O)OC(C)(C)C)nc2ccc(F)c(-c3ccccn3)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1c([C@H](C)N)nc2ccc(F)c(-c3ccccn3)c21
Yield: 86.9 %

Procedure:
[(S)-1-(1-Ethyl-6-fluoro-7-pyridin-2-yl-1H-benzoimidazol-2-yl)ethyl]-carbamic acid tert-butyl ester (0.65 g, 1.7 mmol) was added to 20% TFA in DCM (10 mL) and the resultant solution stirred at 20° C. for 1 hour. The reaction mixture was concentrated in vacuo and the residue loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH then concentrated in vacuo to give title compound as a light yellow gum (0.42 g, 88%). LCMS (Method B): RT 1.65 min [M+H]+ 285.1
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:10]2[C:25](=[O:26])[C:14]3[CH:15]=[N:16][C:17]4[C:18]([O:23][CH3:24])=[CH:19][CH:20]=[CH:21][C:22]=4[C:13]=3[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])[CH:7]=[CH:8][CH:9]=1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:30]1[CH2:31][CH2:32][CH:27]([N:12]2[C:13]3[C:22]4[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH3:24])[C:17]=4[N:16]=[CH:15][C:14]=3[C:25](=[O:26])[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=3)[C:11]2=[O:33])[CH2:28][CH2:29]1)(=[O:36])[CH3:35]
Reactant: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCNCC3)c12
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCN(C(C)=O)CC3)c12

Procedure:
1-(1-Acetyl-piperidin-4-yl)-3-(3-chloro-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (45 mg) was prepared according to general procedure H from 3-(3-chloro-phenyl)-7-methoxy-1-piperidin-4-yl-1H-pyrimido[5,4-c]quinoline-2,4-dione.dihydrochloride (50 mg, 0.1 mmol) and acetyl chloride. LCMS: m/z 479 [M+1]+. 1H NMR (400 MHz, CDCl3): δ 9.59 (s, 1H), 7.58 (m, 1H), 7.52 (m, 1H), 7.42 (m, 1H), 7.24 (m, 1H), 7.10-7.18 (m, 2H), 6.48 (m, 1H), 5.18 (m, 1H), 4.82 (m, 1H), 4.12 (s, 3H), 3.95 (m, 1H), 3.20 (m, 1H), 3.58-3.78 (m, 3H), 2.08 (s, 3H), 1.78 (m, 2H) ppm.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:40]1[C:45]([F:46])=[CH:44][CH:43]=[CH:42][N:41]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:40]5[C:45]([F:46])=[CH:44][CH:43]=[CH:42][N:41]=5)=[CH:27][CH:28]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
Reactant: Fc1cccnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ncccc5F)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 2-chloro-3-fluoropyridine (201 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (359 mg, 68%) as a black oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.C([Li])CCC.CN([CH:22]=[O:23])C1C=CC=CC=1.S(=O)(=O)(O)O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:22]=[O:23]
Reactant: CN(C=O)c1ccccc1
Reactant: Fc1cccc(F)c1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c(F)cccc1F
Temperature: -50 °C
Reaction time: 1.5 h
Yield: 58.2 %

Procedure:
1,3-Difluorobenzene (25 g., 0.22 mole) was dissolved in 150 ml. of tetrahydrofuran and cooled to -50° C. Butyl lithium (99 ml. of 2.3 M in hexane, 0.228 mole) was added over 20 minutes, maintaining the temperature at -50° C. After 1.5 hours of stirring at the same temperature, N-methylformanilide (29.7 g., 0.22 mole) in 50 ml. of tetrahydrofuran was added over 20 minutes at -50° C. After an additional 1.5 hours of stirring at -50° C., the reaction mixture was poured slowly into 1 liter of cold 1 N sulfuric acid, and extracted with three portions of ether. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The oil was distilled. Middle cuts were combined to yield 2,6-difluorobenzaldehyde (18.2 g., 58%; b.p. 72°-74°/12 mm.).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>O1CCOCC1.O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([S:18]([NH:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)[C@@H](N)C(=O)O
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)(C)C)c1
Yield: 93.4 %

Procedure:
D-tert-leucine (3 g, 22.9 mmol), 3-methoxy benzenesulfonyl chloride (4.68 g, 22.6 mmol) and triethylamine (6.4 ml, 45.7 mmol) are stirred in dioxane-water (1:1, 60 ml) at ambient temperature for 20 minutes. The reaction mixture is concentrated in vacuo and the residue is re-dissolved in Ethyl Acetate and washed with 1 N HCl. The organics are separated and washed with brine. The organic layer is dried over MgSO4 and concentrated to afford the title compound as a white solid (6.36 g, 92% yield). 1H-NMR (CDCl3, 400 MHz): δ 7.49 (d, 1H, J=8), 7.39 (s, 1H), 7.32 (t, 1H, J=8.11), 7.00 (m, 1H), 5.67 (d, 1H, J=12), 3.86 (s, 3H), 3.42 (d, 2H, J=8), 1.01 (s, 9H). Mass spectrum (302.0; M+1, 300.0; M−1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17](Br)[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[CH2:21]([Zn]CC)[CH3:22]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH2:21][CH3:22])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: CC[Zn]CC
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Temperature: 70 °C
Yield: 62.1 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.400 g, 1.125 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.130 g, 0.112 mmol) were combined in THF (7 mL) and treated with diethylzinc (1 M in heptane) (2.250 mL, 2.250 mmol) with stirring under an inert atmosphere. The reaction mixture was heated to 70° C. and stirred for 2 h. The reaction mixture was concentrated to dryness and partitioned between EtOAc and saturated aqueous NaHCO3. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted successively with EtOAc and 10% CH3OH/DCM to give 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-ethylbenzonitrile (0.213 g, 0.699 mmol, 62.1% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.44-7.54 (m, 3H), 7.12-7.20 (m, 2H), 3.76 (s, 2H), 2.64 (q, J=7.60 Hz, 2H), 1.90 (br. s., 2H), 1.15 (t, J=7.55 Hz, 3H). LC-MS (ES−) m/z 303.25, 305.16 [M−1]. LC-MS (ES+) m/z 305.01, 306.98 [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]2[N:31]=[N:32][N:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]O)[N:34]=2)[CH:25]=[CH:26][C:27]=1[Cl:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1.N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][N:33]3[N:32]=[N:31][C:30]([CH2:29][C:24]4[CH:25]=[CH:26][C:27]([Cl:28])=[C:22]([Cl:21])[CH:23]=4)=[N:34]3)[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1
Reactant: OCCCCCn1nnc(Cc2ccc(Cl)c(Cl)c2)n1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n(CCCCCn2nnc(Cc3ccc(Cl)c(Cl)c3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.18 g, 0.61 mmol) in THF (5 ml) was added 5-{5-[(3,4-dichlorophenyl)methyl]-2H-tetrazol-2-yl}-1-pentanol (0.191 g, 0.61 mmol; prepared in similar fashion to Example 35), triphenylphosphine (0.36 g, 1.3 mmol) and finally dibenzylazodicarboxylate (0.40 g, 1.3 mmol). The solution was stirred for 18 h after which Pd(PPh3)4 (0.16 g, 0.137 mmol) followed by morpholine (0.75 ml, 8.3 mmol) was added and the solution stirred at ambient temperature for 6 h. The solution was loaded onto an aminopropyl SPE (5 g) and eluted with MeOH then 5% AcOH/MeOH to yield the title compound containing minor impurities. Further chromatography (silica SPE, 20 g) eluting with ether yielded the title compound as a white solid (0.061 g, 18%).