Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[NH:24]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25]1.O>C(#N)C.C(Cl)(Cl)Cl>[OH:29][CH:26]1[CH2:27][CH2:28][N:24]([CH2:2][C:3]([NH:5][C@H:6]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)=[O:4])[CH2:25]1
Reactant: OC1CCNC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)CBr)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)CN2CCC(O)C2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 77.7 %

Procedure:
A suspension of (S)-3-(2-bromoacetyl)amino-1-(tert-butoxycarbonyl)pyrrolidine (671 mg) prepared in Example 113, Step A and potassium carbonate (604 mg) in acetonitrile (6 ml) was added with 3-pyrrolidinol (190 mg, Tokyo Kasei Kogyo), and the mixture was stirred at room temperature for 22 hours. The reaction mixture was added with water and chloroform, and the organic layer was separated. Further, the aqueous layer was extracted with chloroform, and the combined organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (531 mg).
Reaction SMILES: [N:1]([C:4]1[N:11]=[CH:10][CH:9]=[C:8]([NH:12][C@H:13]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:14])[C:5]=1[C:6]#[N:7])=[N+]=[N-].O>C1COCC1.CP(C)C>[NH2:1][C:4]1[N:11]=[CH:10][CH:9]=[C:8]([NH:12][C@H:13]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:14])[C:5]=1[C:6]#[N:7]
Reactant: C[C@@H](CCc1ccccc1)Nc1ccnc(N=[N+]=[N-])c1C#N
Agent: CP(C)C
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CCc1ccccc1)Nc1ccnc(N)c1C#N
Yield: 68.4 %

Procedure:
Prepared according to the methods above using (S)-2-azido-4-((4-phenylbutan-2-yl)amino)nicotinonitrile (59.1 mg, 0.192 mmol) in THF (2.0 mL), trimethylphosphine 1.0 M in tetrahydrofuran (0.960 mL, 0.960 mmol) and water (0.017 mL, 0.960 mmol) at rt for 3.5 hours to give the desired product as a white solid (35 mg). LC/MS (267, [M+H]+); 1H NMR (400 MHz, CHLOROFORM-d) δ 7.78 (d, J=6.3 Hz, 1H), 7.35-7.26 (m, 2H), 7.26-7.19 (m, 1H), 7.19-7.11 (m, 2H), 5.83 (d, J=6.3 Hz, 1H), 5.13 (br. s., 2H), 4.70 (d, J=8.0 Hz, 1H), 3.65-3.51 (m, 1H), 2.71 (t, J=7.7 Hz, 2H), 1.98-1.80 (m, 2H), 1.32-1.23 (m, 3H).
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.[NH2:31][CH2:32][C:33]([OH:42])([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35].[OH-].[NH4+].FC(F)(F)C1(C(F)(F)F)CO1>CCCCO.CS(C)=O>[F:35][C:34]([F:36])([F:37])[C:33]([CH2:32][NH:31][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1)([OH:42])[C:38]([F:39])([F:41])[F:40]
Reactant: NCC(O)(C(F)(F)F)C(F)(F)F
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Agent: FC(F)(F)C1(C(F)(F)F)CO1
Agent: [NH4+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1cnc2c(NCc3cccnc3)nc(NCC(O)(C(F)(F)F)C(F)(F)F)nc21
Reaction time: 72 h
Yield: 23 %

Procedure:
To a stirred solution of 2-fluoro-9-isopropyl-6-[(pyridine-3-ylmethyl)-amino]purine (50 mg, 0,175 mmol) in n-BuOH/DMSO (2.5 ml, 4:1) at room temperature and under an argon atmosphere was added diisopropylethylamine (135 mg, 1.05 mmol) followed by 2-(aminomethyl)-1,1,1,3,3,3-hexafluoropropane-2-ol (prepared from the reaction of 30% ammonium hydroxide with 2,2-bis[trifluoromethyl]oxirane). The reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 3 days. The reaction was followed by LCMS and was gone by only 30%. Additional newly prepared 2-(aminomethyl)-1,1,1,3,3,3-hexafluoropropane-2-ol was added and the reaction continued. This addition was done on three more consecutive days to achieve complete conversion. After removal of solvent, the residue was purified by silica gel flash column chromatography to give the title compound as a pale brown powder (19 mg, 23%); δH (CDCl3, 500 MHz) 1.57 (6 H, d, J 7.5, CH[CH3]2), 3.48-3.44 (1 H, m, NHCHHCOH[CF3]2, 3.86-3.81 (1 H, m, NHCHHCOH[CF3]2, 4.62-4.555 (1 H, m, CHMe2), 4.78-4.74 (2 H, m, NHCH2ArH), 5.35 (1H, s, br, OH), 6.36 (1 H, s, br, NH), 7.27-7.22 (2 H, m, ArH), 7.7-7.67 (1 H, m, ArH), 8.5 (1 H, d, J 5, ArH), 8.66 (1 H, s, ArH); δC (CDCl3, 500 MHz) 159.99 (C), 154.63 (C), 149.53 (C), 149.05 (C), 148.6 (CH), 137.79 (C), 135.41 (C), 135.38 (CH), 135 (CH), 123.44 (CH), 75.03 (C), 47.62 (CH2), 46.84 (CH), 42.05 (CH2), 22.1 (2×CH3); m/z 464.2 (M+H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[F:17][C:18]1[CH:23]=[C:22]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH2:31][NH2:32])=[CH:26][N:25]=2)[CH:21]=[CH:20][N:19]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[F:17][C:18]1[CH:23]=[C:22]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH2:31][NH:32][C:14](=[O:16])[C:11]3[CH:10]=[CH:9][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[CH:13][N:12]=3)=[CH:26][N:25]=2)[CH:21]=[CH:20][N:19]=1
Reactant: Cc1cc(CN)cnc1-c1ccnc(F)c1
Reactant: O=C(O)c1ccc(-c2cccc(F)c2)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(CNC(=O)c2ccc(-c3cccc(F)c3)cn2)cnc1-c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-(3-fluorophenyl)picolinic acid 6-7 (32 mg, 0.15 mmol), (2′-fluoro-3-methyl-2,4′-bipyridin-5-yl)methanamine 30-5 (28 mg, 0.13 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (60 mg, 0.16 mmol) in DMF (1.0 mL) was added DIEA (0.068 mL, 0.39 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted into DMSO and purified by HPLC to give N-((2′-fluoro-3-methyl-2,4′-bipyridin-5-yl)methyl)-5-(3-fluorophenyl)picolinamide 30 as a white solid. MS m/z 417.2 (M+1). 1H NMR 400 MHz (DMSO-d6) δ 9.54 (t, 1H), 8.95 (dd, 1H), 8.47 (d, 1H), 8.29 (m, 2H), 8.07 (dd, 1H), 7.69 (m, 2H), 7.63 (m, 1H), 7.55 (m, 1H), 7.48 (m, 1H), 7.29 (m, 2H), 4.52 (d, 2H), 2.28 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][CH2:5][C:6](Cl)=O.[NH2:10][NH:11][C:12]([NH2:14])=[S:13].CS(O)(=O)=O>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:9])[CH2:4][CH2:5][C:6]1[S:13][C:12]([NH2:14])=[N:11][N:10]=1
Reactant: COC(=O)CCC(=O)Cl
Reactant: NNC(N)=S
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)CCc1nnc(N)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Chlorocarbonyl-propionic acid methyl ester (4.4 g, 21 mmol) is added dropwise to a stirred suspension of thiosemicarbazide (4.0 g, 44 mmol) in THF (25 ml) at 0° C. After stirring at room temperature for 18 h the product which precipitates is removed by filtration and washed with diethyl ether. This product (7.1 g, 34 mmol) is suspended in toluene (30 ml) at 0° C. and methane sulfonic acid (3.37 ml, 52 mmol) is added dropwise to the stirred reaction. The reaction is heated at 70° C. for 3 hours then concentrated at reduced pressure. Methanol (30 ml) is added followed by slow addition of aqueous ammonia, with stirring, until the solution is basic. The titled compound which precipitates is removed by filtration and purified by chromatography on silica, eluting with chloroform-methanol (10:1).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[CH:8]=[CH:9][CH:10]=1)=[O:4].[H][H]>[Pd].C(O)C.CN(C=O)C>[CH3:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: CNC(=O)c1cccc(/C=C/C(=O)OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(CCC(=O)OC)c1
Yield: 80.1 %

Procedure:
A solution of (E)-methyl 3-[3-(methylcarbamoyl)phenyl]prop-2-enoate (3.77 g, 17.20 mmol) and 10% palladium on carbon (0.458 g, 0.43 mmol) in a mixture of ethanol (100 mL) and DMF (10.00 mL) was stirred at room temperature for 18 h under a balloon of hydrogen. The reaction mixture was filtered through celite and evaporated to dryness to afford methyl 3-(3-(methylcarbamoyl)phenyl)propanoate (3.05 g, 80%) as a white solid. MS: m/z 222 (MH+).
Reaction SMILES: [CH2:1]([CH:6]1[CH2:11][CH2:10][CH:9]([S:12]([CH2:15][S:16]([CH:19]2[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:21][CH2:20]2)(=[O:18])=[O:17])(=[O:14])=[O:13])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].C1(C)C=CC(S([N:39]=[N+:40]=[N-])(=O)=O)=CC=1.C(O)C.[OH-].[Na+]>CN(C)C=O.O>[CH2:1]([CH:6]1[CH2:7][CH2:8][CH:9]([S:12]([C:15]([S:16]([CH:19]2[CH2:20][CH2:21][CH:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24]2)(=[O:18])=[O:17])=[N+:39]=[N-:40])(=[O:14])=[O:13])[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CCCCCC1CCC(S(=O)(=O)CS(=O)(=O)C2CCC(CCCCC)CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: CCCCCC1CCC(S(=O)(=O)C(=[N+]=[N-])S(=O)(=O)C2CCC(CCCCC)CC2)CC1
Reaction time: 6.5 h
Yield: 11 %

Procedure:
In 22.4 g of dimethylformamide were dissolved 22.5 g (0.050 mol) of the bis(4-n-pentylcyclohexylsulfonyl)methane prepared above and 14.8 g (0.075 mol) of p-toluenesulfonylazide. To this solution were added 90.1 g of ethanol and 22.2 g of water. The solution was cooled on an ice bath, to which 2.0 g (0.050 mol) of sodium hydroxide in 23 g of water was added dropwise at a temperature below 5° C. The solution was ripened at the temperature for 6.5 hours. Filtration of the crystals gave 2.6 g of the desired bis(4-n-pentylcyclohexylsulfonyl)diazomethane. The yield was 46%.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][OH:7].[N+:12]([O-:15])([OH:14])=O.[N+:16]([O-])([OH:18])=[O:17]>N([O-])=O.[Na+]>[OH:1][C:2]1[C:11]([N+:12]([O-:15])=[O:14])=[CH:10][C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][OH:7]
Reactant: OCCOc1ccccc1O
Reactant: O=[N+]([O-])O
Agent: O=N[O-]
Agent: [Na+]
Product: O=[N+]([O-])c1cc(OCCO)c(O)c([N+](=O)[O-])c1

Procedure:
An attempt to nitrate 2-(2-hydroxyphenoxy)ethanol with 3N nitric acid and sodium nitrite catalyst at 25°-30° C. was unsuccessful.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[CH3:6][O-:7].[Na+].Cl[CH2:10][C:11]#[N:12]>CO>[CH3:6][O:7][C:11](=[NH:12])[CH2:10][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: C[O-]
Reactant: N#CCCl
Reactant: c1nc[nH]n1
Agent: [Na+]
Solvent: CO
Product: COC(=N)Cn1cncn1
Temperature: 25 °C

Procedure:
1,2,4-Triazole (3.45 g) was added to a sodium methoxide in methanol [prepared from sodium (1.15 g) and methanol (40 ml)], and the mixture was refluxed for 1 hour, and cooled to 25° C; chloroacetonitrile (3.78 g) was then added and the mixture was refluxed for a further 6 hours. The solution was filtered and the solvent removed in vacuo. The resultant mixture was dissolved in petroleum ether (50 ml; b.p. 40°-60° C) and the solution filtered to remove unreacted 1,2,4-triazole. Removal of the solvent in vacuo gave a residue which on distillation gave the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[CH2:21]([NH2:23])[CH3:22].C(OCC)(=O)C.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:19][C:17]1[CH:16]=[C:13]([CH:12]=[C:11]([O:10][C:5]2[C:6]([Cl:9])=[CH:7][CH:8]=[C:3]([CH2:2][NH:23][CH2:21][CH3:22])[C:4]=2[F:20])[CH:18]=1)[C:14]#[N:15]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CBr)c2F)c1
Reactant: CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCNCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.4 %

Procedure:
A solution of 3-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.50 g, 1.33 mmol) in THF (10 mL) was added dropwise to a 2M solution of EtNH2 (6.67 mL, 13.33 mmol) in THF. The flask was sealed and stirred at RT overnight. Ethyl acetate (100 ml) and saturated NaHCO3 solution (100 ml) were added. The organic layer was washed with brine (150 mL), dried over MgSO4, filtered and concentrated to give the title compound (0.48 g, quant.) as a tan solid. 1H NMR shows title compound plus a little residual EtNH2. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.04 (br. s., 1H), 7.83 (s, 1H), 7.62 (s, 2H), 7.45-7.55 (m, 2H), 4.14 (s, 2H), 2.95 (q, 2H), 1.18 (t, 3H). LCMS m/z 340.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[N:6][C:5]=1[Cl:12].S(Cl)(C)(=O)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:19]=[N+:20]=[N-:21])=[N:6][C:5]=1[Cl:12]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1ccc(CO)nc1Cl
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN=[N+]=[N-])nc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.7 %

Procedure:
To a cold (0° C.) solution of 2-chloro-6-hydroxymethyl-nicotinic acid methyl ester (4.98 g, 24.8 mmol) in dichloromethane (161 mL) was added mesyl chloride (2.5 mL, 29.8 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate, water and brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was taken up in dimethylformamide (62 mL) and sodium azide (4.03 g, 62 mmol) added. After stirring at room temperature for 16 hours, the reaction mixture was cooled to 0° C., quenched with water (ca. 50 mL), and extracted three times with ethyl acetate. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was subjected to flash chromatography (Si-PPC, gradient 0% to 50%, ethyl acetate in hexane) to afford the title compound as a pale yellow oil (4.76 g, 85%). LCMS (method B): RT=3.22 min, [M+H]+=227.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[C:4](=[O:17])[C:3]=1[NH:18][C:19](=[O:39])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][S:28]([C:31]2[C:32]([CH3:38])=[N:33][N:34]([CH3:37])[C:35]=2[Cl:36])(=[O:30])=[O:29])=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:47][CH:48]1[CH2:51][CH2:50][CH2:49]1>CN(C=O)C>[NH2:1][C:2]1[N:7]([CH2:47][CH:48]2[CH2:51][CH2:50][CH2:49]2)[C:6](=[O:8])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[C:4](=[O:17])[C:3]=1[NH:18][C:19](=[O:39])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][S:28]([C:31]2[C:32]([CH3:38])=[N:33][N:34]([CH3:37])[C:35]=2[Cl:36])(=[O:30])=[O:29])=[CH:23][N:22]=1
Reactant: BrCC1CCC1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(CC(=O)Nc2c(N)[nH]c(=O)n(Cc3ccccc3F)c2=O)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(CC(=O)Nc2c(N)n(CC3CCC3)c(=O)n(Cc3ccccc3F)c2=O)nc1
Temperature: 40 °C
Yield: 15 %

Procedure:
A solution of N-[6-amino-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-2-[5-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-pyridin-2-yl]-acetamide in N,N,-dimethylformamide was treated with potassium carbonate (4.0 eq.) and (bromomethyl)cyclobutane (2.0 eq.). The reaction mixture was heated to 40° C. for 16 h. At this time, the N,N,-dimethylformamide was removed in vacuo. The residue was triturated with chloroform and then methanol to remove impurities. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 10/90 methanol/chloroform) afforded N-[6-amino-1-cyclobutylmethyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-2-[5-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonylamino)-pyridin-2-yl]-acetamide (15%) as a light brown solid; LRMS for C29H31ClFN7O5S (M+H)+ at m/z=645.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]([NH:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[O:12])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=O)[N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Cl)=[CH:37][CH:36]=1>CC(N(C)C)=O.C(OCC)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]([C:11]([NH:13][CH2:14][CH:15]2[CH2:16][CH2:17]2)=[O:12])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]([CH2:39][C:38]1[CH:41]=[CH:42][C:35]([O:34][CH3:33])=[CH:36][CH:37]=1)[N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Nc1nc(C(=O)NCC2CC2)nc2c1[nH]c(=O)n2Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COc1ccc(CC2Nc3c(N)nc(C(=O)NCC4CC4)nc3N2Cc2ccccc2)cc1
Temperature: 55 °C
Yield: 28.5 %

Procedure:
6-Amino-9-benzyl-N-(cyclopropylmethyl)-8-oxo-8,9-dihydro-7H-purine-2-carboxamide (Example 1, 50 mg, 0.15 mmol) was taken up in 3 ml DMA and firstly triethylamine (27 μl, 0.18 mmol) and then para-methoxybenzyl chloride (26 μl, 0.18 mmol) were added in one portion each and the whole stirred and heated to 55° C. for 16 h. The mixture was diluted with ethyl acetate (5 ml) and washed with water (2×3 ml). The combined organics were dried over MgSO4 and concentrated in vacuo to a yellow residue which was purified by column chromatography using a gradient of 100% DCM:→98:2 DCM:MeOH as the eluant. Combination and evaporation of the appropriate fractions provided the title compound as a white solid (19 mg).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH:22]([O:24][C:25](=[O:29])[CH2:26][CH2:27][CH3:28])[CH3:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:30]1(N=C=NC2CCCCC2)CCCC[CH2:31]1.C(O)(=O)CCCCC>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([CH:22]([O:24][C:25](=[O:29])[CH2:26][CH2:27][CH2:28][CH2:30][CH3:31])[CH3:23])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(C)OC(=O)CCC)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC(=O)O
Product: CCCCCCCCOc1ccc(-c2ccc(C(C)OC(=O)CCCCC)cc2)cc1
Reaction time: 6 h
Yield: 76.3 %

Procedure:
Seven grammes (21 mmol) of (-)-1-(4-octyloxybiphenyl-4'-yl)ethanol prepared in Example 2, 7.5 g (36 mmol) of N,N'-dicyclohexylcarbodiimide and 1.0 g of 4-dimethylaminopyridine were dissolved in 200 ml of dichloromethane. To the solution, 3.4 g (29 mmol) of caproic acid was added and the mixture was stirred for six hours at room temperatre. The deposit crystals were filtered, 200 ml of water was added to the filtrate, and the organic layer was separated. 6N hydrochloric acid was added to the organic solution, and then the solution was neutralized with the aqueous solution of 2N sodium hydroxide. The neutralized solution was washed with water until the washed water became neutral. The solvent and low-boiling fractions were distilled off from the obtained solution. The residue was recrystallized from ethanol and the desired (-)-4-octyloxy-4'-(1-hexanoyloxyethyl)biphenyl 6.8 g was obtained. m.p. 60.8° C., [α]D -78.4° (c 0.88, C2H5OH).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[Cl:13][C:14]1[C:19]([NH2:20])=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16][N:15]=1.CO[CH:27]1[CH2:31][CH2:30][CH:29](OC)O1.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[F:1][C:2]1[C:7]([N:8]2[CH:19]=[CH:18][CH:17]=[CH:16]2)=[CH:6][C:5]([C:9]([F:10])([F:11])[F:12])=[CH:4][N:3]=1.[Cl:13][C:14]1[C:19]([N:20]2[CH:27]=[CH:31][CH:30]=[CH:29]2)=[CH:18][C:17]([C:21]([F:22])([F:23])[F:24])=[CH:16][N:15]=1
Reactant: Nc1cc(C(F)(F)F)cnc1Cl
Reactant: COC1CCC(OC)O1
Reactant: Nc1cc(C(F)(F)F)cnc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: FC(F)(F)c1cnc(Cl)c(-n2cccc2)c1
Product: Fc1ncc(C(F)(F)F)cc1-n1cccc1
Yield: 93.4 %

Procedure:
A solution of the mixture (1.1 g) from Example 17 b., 2,5-dimethoxytetrahydrofuran (0.9 g, 0.007 m) and acetic acid (5 ml) was heated at reflux with stirring. After 11/2 hours, the solution was cooled and poured into saturated Na2CO3 solution. The aqueous layer was extracted with CHCl3 and the organic layer was dried over Na2SO4, filtered and concentrated to dryness. The residue was chromatographed on silica gel and the product eluted with 1:1 CH2Cl2 :hexane to yield 0.65 g of a mixture of 2-chloro and 2-fluoro-3-(1-pyrrolyl)-5-trifluoromethylpyridine.
Reaction SMILES: [Mg].C1(Br)CC1.[CH:6]1([N:9]2[CH2:14][CH2:13][CH:12]([C:15]3[N:19]=[C:18]([C:20]4[CH:27]=[CH:26][C:23](C#N)=[CH:22][CH:21]=4)[O:17][N:16]=3)[CH2:11][CH2:10]2)[CH2:8][CH2:7]1.[Cl-:28].[NH4+].[CH2:30]1[CH2:34][O:33][CH2:32][CH2:31]1>>[ClH:28].[CH:30]1([C:34]([C:23]2[CH:26]=[CH:27][C:20]([C:18]3[O:17][N:16]=[C:15]([CH:12]4[CH2:11][CH2:10][N:9]([CH:6]5[CH2:8][CH2:7]5)[CH2:14][CH2:13]4)[N:19]=3)=[CH:21][CH:22]=2)=[O:33])[CH2:31][CH2:32]1
Reactant: [Cl-]
Reactant: C1CCOC1
Reactant: N#Cc1ccc(-c2nc(C3CCN(C4CC4)CC3)no2)cc1
Agent: BrC1CC1
Agent: [Mg]
Agent: [NH4+]
Product: Cl
Product: O=C(c1ccc(-c2nc(C3CCN(C4CC4)CC3)no2)cc1)C1CC1

Procedure:
To a Grignard mixture (prepared from magnesium (50 mg, 2.1 mmol) and cyclopropylbromide (211 mg, 1.7 mmol) in dry THF (2 ml)) placed under an atmosphere of nitrogen was added dropwise a solution of 4-[3-(1-cyclopropylpiperidin-4-yl)[1,2,4]oxadiazol-5-yl]benzonitrile (250 mg, 0.85 mmol, prepared as described in Example 37) in dry THF (1.5 ml). When addition was complete the mixture was heated at reflux for 1 h. The mixture was allowed to cool and then saturated ammonium chloride (1 ml) was added. The mixture was extracted with ethyl acetate (15 ml) and the organic phase was dried (MgSO4) and the solvent was evaporated. The residue was dissolved in a mixture of ethanol (10 ml) and 1 N hydrochloric acid (1 ml) and the solvents were evaporated. The residue was re-evaporated with acetonitril and then stirred with ethyl acetate. This afforded 0.23 g containing the title compound. HPLC: Rt=12.45 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:21]3[CH2:30][CH2:29][C:24]4([O:28][CH2:27][CH2:26][O:25]4)[CH2:23][CH2:22]3)[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C1(C2[O:39]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.O>O1CCCC1.C([Li])CCC.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:21]3([OH:39])[CH2:30][CH2:29][C:24]4([O:28][CH2:27][CH2:26][O:25]4)[CH2:23][CH2:22]3)[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: COc1ccc(-c2nc(C3CCC4(CC3)OCCO4)sc2-c2ccc(C)cc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(C3(O)CCC4(CC3)OCCO4)sc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
To a solution of 8-(4-(4-methoxyphenyl)-5-(p-tolyl)thiazol-2-yl)-1,4-dioxaspiro[4.5]decane (Reference Example 95) (734 mg, 1.74 mmol) in tetrahydrofuran (8.7 mL), 1.63 M n-butyllithium/solution in n-hexane (1.17 mL) was added at −78° C., and the obtained solution was stirred at the same temperature for 1 hour. The reaction solution was added at −78° C. to a solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (546 mg, 2.09 mmol) in tetrahydrofuran (8.7 mL), and the obtained solution was allowed to warm gradually to room temperature with stirring. Distilled water was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (417 mg, 0.954 mmol, 55%) as a colorless amorphous product.