Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[C:6]([C:10]1[CH:15]=[C:14](I)[C:13]([O:17][CH3:18])=[CH:12][C:11]=1[F:19])([CH3:9])([CH3:8])[CH3:7].[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.Cl>C1COCC1>[C:6]([C:10]1[C:11]([F:19])=[CH:12][C:13]([O:17][CH3:18])=[C:14]([B:20]([OH:25])[OH:21])[CH:15]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(F)c(C(C)(C)C)cc1I
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(F)c(C(C)(C)C)cc1B(O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium (1.6 M in hexanes, 406 μL, 0.649 mmol) was added to a stirred solution of 1-tert-butyl-2-fluoro-5-iodo-4-methoxybenzene (200 mg, 0.649 mmol) in dry THF (2 mL) at −78° C. under N2. The reaction was stirred at −78° C. for 1 h then triisopropyl borate (214 mg, 262 μL, 1.14 mmol) was added dropwise. The reaction was stirred at −78° C. for 1 h and 0° C. for 1 h. 1N HCl was added and the reaction was extracted with EtOAc (3×). The combined extracts were dried (Na2SO4) and concentrated in vacuo to afford (5-tert-butyl-4-fluoro-2-methoxyphenyl)boronic acid. 1H NMR (600 MHz, CDCl3): δ 6.86 (d, J=8.0 Hz, 1H); 6.57 (d, J=13.0 Hz, 1H); 3-85 (s, 3H); 1.33 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]([NH:12][NH2:13])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:16]S(O)(=O)=O.C(OCC)(OCC)OCC.O1CCCC1>O>[N+:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH2:9][C:10]2[O:11][CH:16]=[N:13][N:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)O
Reactant: NNC(=O)COc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(OCC)OCC
Product: O=[N+]([O-])c1ccc(OCc2nnco2)cc1
Yield: 343.3 %

Procedure:
A mixture of 2-(4-nitrophenoxy)acetohydrazide (1.10 g), methanesulfonic acid (0.10 g), triethyl orthoformate (2.31 g) and tetrahydrofuran (50 mL) was heated under reflux for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-[(4-nitrophenoxy)methyl]-1,3,4-oxadiazole as colorless crystals (0.79 g, yield 69%) from a fraction eluted with hexane-ethyl acetate (1:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 125-126° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]([OH:17])=[CH:10][CH:9]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[N:20]=1.Cl>CS(C)=O.O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([F:18])[N:20]=2)=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14]
Reactant: Fc1cccc(F)n1
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cc(Br)ccc1Oc1cccc(F)n1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of cesium carbonate (3.20 mL, 40.0 mmol), 5-bromosalicylic acid (4.34 g, 20.00 mmol) and 2,6-difluoropyridine (5.52 g, 48.0 mmol) in 8 mL of DMSO was stirred at 110° C. for 3 h. After cooling to rt, the reaction mixture was dissolved in water and the pH was adjusted to ˜3 with 1 N HCl. The reaction mixture was extracted with EtOAC (3×25 mL), washed with brine and evaporated to dryness to give crude 5-bromo-2-(6-fluoropyridin-2-yloxy)benzoic acid which was used directly in the next step.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[NH2:16])[N:7]=1)=[O:5])[CH3:2].[F:19][C:20]1[CH:21]=[CH:22][C:23]([O:38][CH3:39])=[C:24]([C:26]([CH3:37])([CH3:36])[CH2:27][C:28]([OH:35])([C:31]([F:34])([F:33])[F:32])[CH:29]=O)[CH:25]=1>O1CCCC1.[Ti]>[CH2:17]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N:16]=[CH:29][C:28]([OH:35])([C:31]([F:32])([F:34])[F:33])[CH2:27][C:26]([C:24]2[CH:25]=[C:20]([F:19])[CH:21]=[CH:22][C:23]=2[O:38][CH3:39])([CH3:36])[CH3:37])[N:7]=1)=[O:5])[CH3:18]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: CCN(CC)C(=O)c1ccc2c(N)cccc2n1
Agent: [Ti]
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc2c(N=CC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution that consists of 210 mg (0.86 mmol) of 5-aminoquinoline-2-carboxylic acid diethylamide, 266 mg (0.86 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 0.36 ml (1.73 mmol) of titanium tetraethylate in 15 ml of tetrahydrofuran is stirred for one hour at room temperature and then for 3 hours at 80° C. After removal of the solvent and purification on silica gel with hexane-ethyl acetate (0–70%), 230 mg (52% of theory) of the product is obtained.
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:26]([O:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][NH:36]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:26]([O:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][N:36]1[C:14](=[O:16])[CH2:13][CH2:12][C:11](=[O:17])[C@@H:10]([NH:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: O=C(O)CCC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of the free acid compound 4 (100 mg, 0.3055 mmol, 1.0 eq.) and L-proline benzyl ester hydrochloride (74 mg, 0.3055 mmol, 1.0 eq.) in dry CH2Cl2 (10 mL) was cooled at 0° C. 1-Hydroxybenzotriazole hydrate (HOBt) (42 mg, 0.3055 mmol, 1.0 eq.), N-ethyl-N′-(dimethylaminopropyl)-carbodiimide hydrochloride (EDC.HCl) (59 mg, 0.3055 mmol, 1.0 eq.) and iPr2NEt (0.10 mL, 0.6110 mmol, 2.0 eq.) were added and the resulting mixture stirred at 0° C. for 2 h. The cooling bath was removed and the reaction mixture then stirred for a further 48 h at room temperature. The reaction mixture was diluted with H2O (30 mL) and the extracted with EtOAc (3×30 mL). The combined organic extract were washed sequentially with saturated aqueous NaHCO3 (30 mL), brine (30 mL), and dried over anhydrous MgSO4. Evaporation of the solvent gave a crude residue, which was subjected to column chromatography on silica gel elution with 50% EtOAc-hexane afforded the desired compound (5S)-5-[(N-benzoyl)amino]-4-oxo-6-phenyl-hexanoyl-L-proline benzyl ester as a pale yellow viscous oil which foams (0.138 g, 88%); Rf 0.23 (50% EtOAc-hexane); IR (liquid film) ν 1726 (CO), 3200 (NH) cm−1; 1H NMR (300 MHz, CDCl3) δH 1.98 (2H, m, —CH2), 2.21 (2H, m, —CH2), 2.65 (2H, m, —CH2CO), 3.00 (1H, m, —CHαPh), 3.12 (1H, m, —CHβPh), 3.35 (2H, m, —CH2CO), 3.60 (2H, m, —CH2N), 4.52 (1H, m, —CHN), 5.03 (1H, m, —CH—), 5.14 (2H, dd, J=1.8 and 8.4 Hz, —OCH2Ph), 6.93 (1H, d, J=6.9 Hz, —NH—) and 7.15-7.77 (15H, m, Ar—H); 13C NMR (75 MHz, CDCl3) δC 22.8, 24.7, 28.3, 28.9, 29.2, 34.1, 34.6, 36.8, 46.5, 46.9, 58.9, 59.6, 66.7, 66.8, 126.8, 126.9, 127.0, 127.9, 128.3, 128.5, 128.7 (2C), 129.4, 131.6, 133.9, 135.7, 136.7, 166.9, 170.3, 171.9 and 207.4; HRMS m/z calcd for C31H32N2O5 (M+) 512.23436, found 512.23112.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:34])[C:11]([C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)[C:15](=[O:27])[C:14]=12)C1C=CC=CC=1>FC(F)(F)C(O)=O>[ClH:26].[Cl:26][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][N:16]1[CH2:17][CH2:18][N:13]2[CH:12]=[C:11]([C:28](=[O:33])[C:29]([CH3:31])([CH3:32])[CH3:30])[C:10](=[O:34])[C:9]([OH:8])=[C:14]2[C:15]1=[O:27]
Reactant: CC(C)(C)C(=O)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N(Cc1cccc(Cl)c1)CC2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)c1cn2c(c(O)c1=O)C(=O)N(Cc1cccc(Cl)c1)CC2
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 134.1 %

Procedure:
9-Benzyloxy-2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (43 mg) was dissolved in trifluoroacetic acid (2 ml) and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated and toluene was added, and the mixture was concentrated again. Subsequently, a suitable amount of hydrochloric acid/ethyl acetate solution was added, and the mixture was concentrated again. Ethyl acetate (0.6 ml)-diisopropyl ether (1 ml) was added to the obtained residue and the obtained solid was collected by filtration to give 2-(3-chlorobenzyl)-7-(2,2-dimethylpropionyl)-9-hydroxy-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione hydrochloride (25.6 mg).
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:20]2O[C@H]3[C@@H:22]([O:23][Si:24]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[O:25][Si:26]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[O:27]C3)[C@@H:21]2[O:43][CH3:44])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[CH3:46][OH:47].[O:48]1CCOC[CH2:49]1>>[C@@H:1]1([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:20]2[O:47][C@H:46]([CH2:49][OH:48])[C@@H:22]([O:23][Si:24]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[O:25][Si:26]([CH:31]([CH3:33])[CH3:32])([CH:34]([CH3:35])[CH3:36])[OH:27])[C@@H:21]2[O:43][CH3:44])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C1COCCO1
Reactant: CO
Reactant: CO[C@H]1[C@@H]2O[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)OC[C@H]2O[C@H]1n1cnc2c(N[C@H]3CCc4ccccc43)ncnc21
Agent: Cl
Product: CO[C@H]1[C@H](O[Si](O[Si](O)(C(C)C)C(C)C)(C(C)C)C(C)C)[C@@H](CO)O[C@H]1n1cnc2c(N[C@H]3CCc4ccccc43)ncnc21
Reaction time: 2 h
Yield: 13 %

Procedure:
To a solution of N-[(1S)-2,3-dihydro-1H-inden-1-yl]-9-[(6aR,8R,9S,9aR)-2,2,4,4-tetraisopropyl-9-methoxytetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-9H-purin-6-amine (238 mg, 0.37 mmol) in methanol/dioxane (1:4, 8 mL) was added 3.2 mL 0.2N HCl. After stirring for two hours the solvent was removed in vacuo and the residue purified by silica gel chromatography (10 to 50% EtOAc/hexanes) to afford 32 mg (13%) of the title compound.
Reaction SMILES: B(O)(O)O.[NH2:5][C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][C:9](=[O:11])[NH2:10].[CH2:15](N)[CH3:16]>>[NH2:5][C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][C:9]([NH:10][CH2:15][CH3:16])=[O:11]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: CCN
Agent: OB(O)O
Product: CCNC(=O)CC[C@H](N)C(=O)O
Reaction time: 22 h

Procedure:
Glutaminase in an amount of 0.3 U per 1 ml of the buffer was added to boric acid buffer (disodium borate-sodium hydroxide, pH 11) containing 0.3 M glutamine and 1.5 M ethylamine, and the mixture was incubated at 30° C. for 22 hours to react the components. Two-hundred and twenty-five millimoles of theanine was isolated from 1 L of the reaction mixture. Incidentally, a by-product, glutamic acid, was 20 mmol. Theanine was isolated and purified from the reaction mixture by applying the reaction mixture to a Dowex 50×8, Dowex 1×2 column chromatography and eluting with ethanol.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]1[N:17]=[N:18][N:19]([CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])[N:20]=1)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([C:5]1[N:14]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:32][CH:33]=2)[C:13](=[O:15])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:16]3[N:17]=[N:18][N:19]([CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])[N:20]=3)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=CCCCn1nnc(-c2ccc3[nH]c(CCCC)nc(=O)c3c2)n1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCCCn1nnc(-c2ccc3nc(CCCC)n(Cc4ccc(-c5ccccc5C#N)cc4)c(=O)c3c2)n1
Yield: 94.9 %

Procedure:
A mixture of 1.01 g of 2-butyl-6-[2-(4-pentenyl)-2H-tetrazol-5-yl]-4(1H)-quinazolinone, 1.09 g of 4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile and 2.0 g of potassium carbonate in 100 ml of acetone is refluxed for 24 hours. The reaction mixture is filtered and the filtrate evaporated in vacuo to a residue which is purified by chromatography on silica gel by elution with 30% ethyl acetate-hexanes to give 1.5 g of the desired product as a yellow foam.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([O:14][CH3:15])[N:11]=[C:10]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[ClH:27].N([O-])=O.[Na+].[S:32](=[O:34])=[O:33]>CN(C)C=O.O.C(O)(=O)C.[Cu](Cl)Cl>[CH3:15][O:14][C:12]1[N:13]=[C:8]([C:4]2[CH:3]=[C:2]([S:32]([Cl:27])(=[O:34])=[O:33])[CH:7]=[CH:6][CH:5]=2)[CH:9]=[C:10]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:11]=1
Reactant: O=S=O
Reactant: Cl
Reactant: COc1ccc(CCNc2cc(-c3cccc(N)c3)nc(OC)n2)cc1
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CCNc2cc(-c3cccc(S(=O)(=O)Cl)c3)nc(OC)n2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
[6-(3-Amino-phenyl)-2-methoxy-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]amine [1.46 g, Example 2] in dimethylformamide (4 mL) is added to concentrated hydrochloric acid and crushed ice (8 mL). The mixture is cooled to 0° C., treated with dropwise sodium nitrite (0.32 g) in water (3 mL). After stirring at 0° C. for 15 minutes this mixture is treated with a solution of copper chloride (0.36 g) in a saturated solution of sulfur dioxide in acetic acid (15 mL) previously cooled to 0° C. The reaction mixture is allowed to reach room temperature over 30 minutes and poured into water. The resulting precipitate is filtered and air dried affording 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzenesulfonylchloride [0.4 g, Intermediate (10)]. 1H NMR [(CD3)2SO]: δ 8 (1H, s); 7.7-7.8 (1H, m); 7.5 (1H, m); 7.2 (1H, s); 7.1 (2H, d, J=7.0); 6.8 (2H, d, J=7.0); 6.6 (1H, s); 4 (3H, s); 3.85 (3H, s); 3.7-3.8 (2H, m); 2.8 (2H, t).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:13][C:14](Cl)(Cl)Cl)=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([CH3:12])=[CH:5]2.C[O-:19].[Na+].OS(O)(=O)=O.[C:26]([O-])(O)=[O:27].[Na+]>CO>[CH3:26][O:27][C:14](=[O:19])[CH2:13][C:3]1[C:2]([Cl:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([CH3:12])[N:7]=[CH:8]2
Reactant: Cc1cc2c(CC(Cl)(Cl)Cl)c(Cl)ccc2cn1
Reactant: C[O-]
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1c(Cl)ccc2cnc(C)cc12
Temperature: 70 °C
Yield: 70 %

Procedure:
To a solution of 6-chloro-3-methyl-5-(2,2,2-trichloro-ethyl)isoquinoline (3.3 g, 10.7 mmol) in anhydrous methanol (64 mL) was added a 30% solution of NaOMe in methanol (9.6 mL) under an argon atmosphere. The resulting brown solution was heated for 3 h at 70° C. After cooling to 0° C., concentrated H2SO4 (5.7 mL) was carefully added and the resulting reaction mixture was heated for 1 h at 70° C. After cooling the reaction mixture was rendered basic (pH=9) with a saturated aqueous NaHCO3 solution and extracted three times with diethyl ether. The combined organic layers were dried over Na2SO4, filtered and concentrated at reduced pressure to afford a brown solid. Purification by flash column chromatography (silica gel, cyclohexane/ethyl actetate 70:30) afforded the title compound as a brown powder (1.91 g, 7.63 mmol, 70%). MS (ES+): 250 (M(C13H1235ClNO2)+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:10](=[O:28])[N:11]([C@H:21]2[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]2)[C:12]2[N:13]([N:18]=[CH:19][N:20]=2)[C:14]=1[CH2:15][CH2:16][CH3:17].[N+](=[C:39]([CH2:45][CH:46]=[CH2:47])[C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N-]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:35]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:10](=[O:28])[N:11]([C@H:21]3[CH2:26][CH2:25][C@H:24]([O:27][CH:39]([CH2:45][CH:46]=[CH2:47])[C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:23][CH2:22]3)[C:12]3[N:13]([N:18]=[CH:19][N:20]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])=[C:2]([F:1])[CH:3]=1)#[N:36]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Reactant: C=CCC(=[N+]=[N-])C(=O)OCC
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: C=CCC(O[C@H]1CC[C@H](n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3F)c(CCC)n3ncnc32)CC1)C(=O)OCC
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3′-fluoro-4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (2.0 g), rhodium(II) acetate (dimer) (0.018 g) and toluene (20 mL) was heated to 80° C. under an argon atmosphere, a solution of ethyl 2-diazopent-4-enoate (3.8 g) in toluene (20 mL) was added dropwise, and the mixture was stirred at 80° C. for 10 min. A solution of ethyl 2-diazopent-4-enoate (3.8 g) in toluene (10 mL) was further added, and the mixture was stirred at 80° C. for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.81 g, 32%).
Reaction SMILES: Cl.[F:2][C:3]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4]1.Br[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(N(CC)C(C)C)(C)C>C(#N)C>[F:2][C:3]1([F:8])[CH2:7][CH2:6][N:5]([CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:4]1
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: FC1(F)CCNC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCN1CCC(F)(F)C1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
900 mg of 3,3-difluoropyrrolidine hydrochloride (6.27 mmol, 1 equivalent) were initially charged in 62 ml of acetonitrile, 1475 mg of tert-butyl (2-bromoethyl)carbamate (6.58 mmol, 1.05 equivalent) and then 3.28 ml of N,N-diisopropylethylamine (2.43 g, 18.81 mmol, 3 equivalents) were added and the mixture was stirred at 80° C. overnight. 0.5 equivalent of 3,3-difluoropyrrolidine hydrochloride (450 mg, 3.14 mmol) was then added, and stirring of the reaction solution was continued at 80° C. overnight. The reaction solution was concentrated and purified on a silica gel column (mobile phase: cyclohexane/ethyl acetate gradient: from 5/1 to pure ethyl acetate). This gave 431 mg (28% of theory) of the title compound.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)([O-:4])=[O:3].[OH-].[Na+].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>O.C(OCC)C>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][O:9][C:8]2[CH:15]=[CH:16][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCCCOc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCCCCOc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 8.8 g of 4-(4-nitrophenoxy)-butaneamine hydrochloride (Example 34) in 200 ml of water is treated successively with 9 ml of 10N NaOH, and a solution of 7.5 g of 4-methylbenzenesulfonyl chloride in 200 ml of diethylether. The reaction is stirred at room temperature for 3 hours, the precipitate collected, washed with water and diethylether, and air dried. Recrystallization from 50% aqueous ethanol gives the desired product as a solid, m.p. 87°-88° C.; yield, 1.2 g.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]1[O:13][C:14]([CH3:17])=[N:15][N:16]=1.[C:18]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)([OH:20])=[O:19].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[C:18]([C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:3]3[C:8](=[C:7]([C:12]4[O:13][C:14]([CH3:17])=[N:15][N:16]=4)[CH:6]=[CH:5][CH:4]=3)[CH:9]=[CH:10][CH:11]=2)=[CH:23][CH:22]=1)([OH:20])=[O:19]
Reactant: Cc1nnc(-c2cccc3c(Br)cccc23)o1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1nnc(-c2cccc3c(-c4ccc(C(=O)O)cc4)cccc23)o1

Procedure:
2-(5-Bromo-1-naphthyl)-5-methyl-1,3,4-oxadiazole (D3) (1.50 g, 5.2 mmol) and 4-carboxyphenylboronic acid (0.86 g, 5.2 mmol) were stirred in dimethoxyethane (DME) (40 ml), and sodium carbonate (2.5 g, 23 mmol) in water (40 ml) was added. The mixture was purged by a stream of Ar for 15 min, when tetrakis (triphenylphosphine)palladium (0) (0.1 g, 0.008 mmol) was added. The mixture was stirred at reflux under Ar for 20 h, and then evaporated to remove DME. The grey suspension was acidified (5M HCl), and the solid was filtered off and dried in vacuo at 60° C. This material was heated at reflux in ethanol (30 ml), and filtered hot. The white solid so collected was dried in vacuo at 60° C. giving 1.32 (77%) of the title compound.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]([F:33])([F:32])[O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([N:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O[N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:33][C:14]([F:13])([F:32])[O:15][C:16]1[CH:17]=[CH:18][C:19]([S:22]([N:25]2[CH2:26][CH2:27][CH:28]([O:31][N:35]3[C:39](=[O:40])[C:38]4[C:37](=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:36]3=[O:45])[CH2:29][CH2:30]2)(=[O:23])=[O:24])=[CH:20][CH:21]=1
Reactant: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1CCC(O)CC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.5 %

Procedure:
Diethyl azodicarboxylate (40% in toluene, 1.0 ml, 2.2 mmol) was added to the mixture of 1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-ol (651 mg, 2.0 mmol), N-hydroxyphthalimide (359 mg, 2.2 mmol) and triphenylphosphine (577 mg, 2.2 mmol) in THF (8 ml) at 0° C. and stirred at room temperature for 2 days. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica (EtOAc/Hexanes 10/90-50/50) to give 2-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yloxy)isoindoline-1,3-dione (390 mg, 40%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[C:16]([Cl:26])=[CH:15][N:14]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:26][C:16]1[C:17]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)=[N:18][C:13]([NH:11][C@H:9]([C:6]2[N:7]=[CH:8][C:3]([F:2])=[CH:4][N:5]=2)[CH3:10])=[N:14][CH:15]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2Cl)n[nH]1
Temperature: 180 °C
Yield: 57.3 %

Procedure:
A mixture of (5)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 80 mg), 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 9, 122 mg) and DIPEA (0.134 ml) in n-BuOH (2.5 ml) was charged into a microwave reaction vessel. The vessel was sealed and heated in microwave reactor at 180° C. for 6 hours. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 min) to give the titled compound as solid (90 mg). NMR 10.34 (s, 1H), 8.91 (s, 3H), 8.30 (s, 1H), 5.94 (s, 1H), 4.96-5.34 (m, 1H), 2.25 (s, 3H), 1.56 (d, 3H); m/z 350.