Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][O:12][C:13](=[O:21])[C@H:14]([CH2:16][C:17]([O:19]C)=[O:18])[CH2:15][C:4]=2[CH:3]=1.[OH2:22].O.[OH-].[Li+]>O1CCCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:15][C@@H:14]([CH2:16][C:17]([OH:19])=[O:18])[C:13]([OH:12])=[O:21])[C:5]([CH2:11][OH:22])=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: COC(=O)C[C@@H]1Cc2cc(Br)c3[nH]ncc3c2COC1=O
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C[C@H](Cc1cc(Br)c2[nH]ncc2c1CO)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
(S)-Methyl 2-(4-bromo-8-oxo-6,7,8,10-tetrahydro-3H-oxepino[3,4-e]indazol-7-yl)acetate (135 mg, 0.368 mmol) was dissolved in a mixture of tetrahydrofuran (4.0 mL) and methanol (4.0 mL). Water (4.0 mL) was added to the mixture followed by lithium hydroxide hydrate (31.5 mg, 0.751 mmol). Reaction stirred at room temperature for 5 hours. Another 30 mg of lithium hydroxide hydrate was added to the mixture. Reaction stirred at room temperature for 18 hours. Reaction was quenched with 1.6 mL 1N hydrochloric acid. Organic solvents were removed from the mixture by roto-vap. Material was extracted from the remaining aqueous twice with ethyl acetate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 73% yield. MS (M−H)−=355.2, 357.1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@H:28]([CH3:33])[C:29]([O:31]C)=O)[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[NH3:34]>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@H:28]([CH3:33])[C:29]([NH2:34])=[O:31])[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12
Reactant: N
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12)C(N)=O
Yield: 88 %

Procedure:
Using the same procedure as in Example 5, methyl (2R)-2-[(4-{[1-(1,3-thiazol-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.54 mmol) was reacted with ammonia to give the title compound as a white solid (212 mg, 88%); NMR Spectrum 1.67 (d, 3H), 5.14 (q, 1H), 6.04 (s, 2H), 7.02 (d, 1H), 7.36 (d, 1H), 7.56 (br s, 1H), 7.66 (d, 1H), 7.83-7.72 (m, 4H), 7.90 (br s, 1H), 8.19 (s, 1H), 8.53 (s, 2H), 10.82 (br s, 1H); Mass spectrum 446.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCCc1ccccc1
Yield: 100.6 %

Procedure:
5-Phenyl-pentanol (40 g, 244 mmoles) in methylene chloride (80 ml) at 0° C. was added with triethylamine (39 ml, 28.34 g, 280 mmoles) and a solution of methyl-sulfonyl chloride (20.7 ml, 30.69 g, 268 mmoles) in methylene chloride (40 ml). The temperature was left to rise to the room value, then the mixture was poured into water and the organic phase was isolated, washed with water, anhydrified and concentrated to give 59.49 g of the title product (yield: 99%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10]([C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(NC4CC4)nc(Cl)nc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(NC4CC4)nc(Cl)nc32)cc1
Temperature: 100 °C
Yield: 89.8 %

Procedure:
To a mixture of 2-chloro-N-cyclopropyl-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.3 g, 0.61 mmol), Pd(PPh3)2Cl2 (0.086 g, 0.122 mmol) and pyridine-4-ylboronic acid (0.165 g, 1.342 mmol) in dioxane (3 mL) was added a solution of Na2CO3 (0.2 g, 1.83 mmol) in water (1.5 mL). After degassing, the mixture was heated at 100° C. for 1.5 h. The mixture was purified by flash column chromatography (Hexane/EtOAc=1:1) to give 2-chloro-N-cyclopropyl-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.241 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-])=[O:25])=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].[O:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>>[O:28]1[CH2:29][CH2:30][N:31]([C:34]2[CH:35]=[CH:36][C:37]([NH:38][C:24]([C:21]3[O:22][C:23]4[C:15]([N:12]5[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=6)[CH2:14][CH2:13]5)=[CH:16][CH:17]=[CH:18][C:19]=4[CH:20]=3)=[O:25])=[CH:39][CH:40]=2)[CH2:32][CH2:33]1
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: [Li+]
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (60 mg, 0.16 mmol) and 4-morpholinoaniline (37 mg, 0.20 mmol). Yield: 38 mg (44%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:20][CH2:19][C@:18]3([CH2:24][CH2:23][NH:22][C:21]3=[O:25])[N:17]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:12][CH:11]=1.[H-].[Na+].I[CH3:36].O>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C@H:16]2[CH2:20][CH2:19][C@:18]3([CH2:24][CH2:23][N:22]([CH3:36])[C:21]3=[O:25])[N:17]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2ccc(OCc3ccccc3F)cc2)CC[C@]12CCNC2=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC[C@]2(CC[C@H](c3ccc(OCc4ccccc4F)cc3)N2C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.2 %

Procedure:
To a solution of 1,1-dimethylethyl (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (D26) (70 mg, 0.159 mmol) in dry DMF (1 ml) at 0° C. was added NaH 60% wt dispersion in mineral oil (10 mg, 0.238 mmol); after 15 minutes of stirring at room temperature, iodomethane (30 μl, 0.477 mmol) was added and the resulting mixture was stirred at room temperature for 2.5 hours. The mixture was cooled to 0° C., and water (4 ml) and ethyl acetate (10 ml) were added, the organic layer was washed with ice cold brine (3×10 ml), dried over Na2SO4 and evaporated. The crude material was purified by chromatography on silica gel using cyclohexanes/ethyl acetate (7:3) to afford the title compound as a white solid (63 mg, 88%); Rt (HPLC): 5.99 min; Rf (cyclohexane:ethyl acetate=1:1): 0.28; MS: (ES/+) m/z: 477 [M+Na+]; C26H31FN2O4 requires 454. 1H NMR (400 MHz, CDCl3) δ(ppm): 7.66 (d, 2H); 7.56-7.49 (m, 1H); 7.35-7.25 (m, 1H); 7.20-7.13 (m, 1H); 7.12-7.04 (m, 1H); 6.97 (dd, 2H); 5.14 and 5.12 (s, s, 2H); 5.02 and 4.88 (d, d, 1H); 3.52-3.45 and 3.41-3.22 (m, m, 2H); 2.96 and 2.92 (s, s, 3H); 2.67-2.56 and 2.53-2.42 (m, m, 1H); 2.40-2.22 (m, 2H); 2.08-1.79 (m, 2H); 1.77-1.68 (m, 1H), 1.40 and 1.16 (s, s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[C@@H:15]1(N)[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1N.CC(C)([O-])C.[Na+]>O1CCOCC1.[Cu](I)I>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: Brc1ccc(Nc2ncccn2)cc1
Agent: I[Cu]I
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Brc1ccc(N(c2ccccc2)c2ncccn2)cc1
Temperature: 110 °C
Reaction time: 22 h

Procedure:
Under an argon atmosphere, a suspension of N-(4-bromophenyl)pyrimidin-2-amine (250 mg), copper iodide (1.9 mg), trans-1,2-cyclohexanediamine (0.015 ml) and sodium-tert-butoxide (144 mg) in dioxane (1 ml) was stirred at 110° C. for 22 hours in a pressure-resistant test tube. The reaction solution was filtered and the filtrate was concentrated. The residue was purified by thin layer chromatography (silica gel, mobile phase: chloroform/ethyl acetate=5/1) to obtain N-(4-bromophenyl)-N-phenylpyrimidin-2-amine (56 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(N(C(C)C)CC)(C)C.ClC(Cl)(O[C:37](=[O:43])OC(Cl)(Cl)Cl)Cl.[NH2:45][C:46]1[S:47][C:48]([C:51]([F:54])([F:53])[F:52])=[N:49][N:50]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:37]([NH:45][C:46]2[S:47][C:48]([C:51]([F:54])([F:53])[F:52])=[N:49][N:50]=2)=[O:43])=[CH:18][C:17]=1[F:23]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1nnc(C(F)(F)F)s1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4nnc(C(F)(F)F)s4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.4 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (100 mg) was dissolved in chloroform (5 ml) and diisopropylethylamine (0.5 ml) to prepare a solution. A solution of triphosgene (100 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 15 min. Next, 2-amino-5-trifluoromethyl-1,3,4-thiadiazole (70 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Distilled water was added to the reaction solution, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine and was dried over sodium sulfate. The organic layer was concentrated under the reduced pressure, and the residue was purified by HPLC using chloroform/acetone for development to give 72 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([OH:8])[CH:7]=1.O.O.[Sn](Cl)Cl.C[CH2:19][OH:20].C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1>[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[NH:9][C:19](=[O:20])[O:8][C:6]=2[CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1O
Reactant: CCO
Agent: Cl[Sn]Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2cc(F)c(Br)cc2o1
Temperature: 70 °C
Yield: 71.6 %

Procedure:
To a 100 mL of round bottom flask was added 5-bromo-4-fluoro-2-nitrophenol (0.98 g, 4.15 mmol), tin(II) chloride dihydrate (4.73 g, 20.76 mmol) and 5 mL of EtOH. The reaction mixture was heated to 70° C. for 30 minutes. The reaction mixture was concentrated and washed with saturated NaHCO3 solution, and extracted with DCM (100 mL×3), and concentrated providing the crude product. 1,1′-Carbonyldiimidazole (808 mg, 4983 μmol) was added to the crude product in 20 mL of THF. The reaction mixture was heated at reflux overnight. The reaction mixture was concentrated and purified with silica gel column chromatography, eluting with 0-30% EtOAc/hexane to give 6-bromo-5-fluorobenzo[d]oxazol-2(3H)-one (690 mg, 71.6% yield). MS m/z: 232 (M+1).
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[NH:14][C:13]1[C:8]3=[CH:9][CH:10]=[C:11]2[CH:21]=[CH:20][CH:19]=[CH:18][C:12]2=1.[Br:22]Br.O>ClCCl>[Br:22][C:10]1[CH:9]=[C:8]2[C:13]([NH:14][C:15]3[C:7]2=[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=[CH:17][CH:16]=3)=[C:12]2[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=12
Reactant: BrBr
Reactant: c1ccc2c(c1)ccc1c2[nH]c2ccc3ccccc3c21
Solvent: ClCCl
Solvent: O
Product: Brc1cc2c([nH]c3ccc4ccccc4c32)c2ccccc12
Yield: 160.8 %

Procedure:
10.3 g of 7H-dibenzo[a,g]carbazole was dissolved in dichloromethane (150 mL) at 0° C. with stirring. To this was dropped a dichloromethane solution of bromine (3.1 g in dichloromethane). After being stirred at room temperature for 2 h, the solution was poured into 200 mL of water, filtered, and washed with 500 mL water. The white residue was recrystallized in ethanol and yielded 12-bromo-7H-dibenzo[a,g]carbazole as colorless crystals (10.8 g).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:12]=1>>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[C:11]([O:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[N:12][C:13]([NH:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1)=[CH:14]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: OCCN1CCCCC1
Product: COc1ccc2c(OCCN3CCCCC3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from 2-piperidin-1-yl-ethanol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [6-methoxy-1-(2-piperidin-1-yl-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 382(MH+).
Reaction SMILES: [NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]#[N:18])[CH2:11][C@H:10]2[O:19][CH3:20])=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1.N.[H][H]>[Ni].CO>[NH2:1][C:2]1[C:22]([Cl:23])=[CH:21][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][C@H:10]2[O:19][CH3:20])=[O:7])=[C:4]([O:24][CH3:25])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCC#N)C[C@H]1OC
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCN)C[C@H]1OC
Yield: 13 %

Procedure:
A mixture of 3 parts of cis-4-amino-5-chloro-N[1-(2-cyanoethyl)-3-methoxy-4-piperidinyl]-2-methoxybenzamide and 200 parts of methanol, saturated with ammonia was hydrogenated at normal pressure and at 20° C. with 2 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in trichloromethane. The solution was washed with water, dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried in vacuo at 60° C., yielding 0.4 parts (13%) of cis-4-amino-N-[1-(3-aminopropyl)-3-methoxy-4piperidinyl]-5-chloro-2-methoxybenzamide; mp. 174.8 (interm. 3).
Reaction SMILES: C(O[C:4]([CH:6]1[C:14](=[O:15])[C:13]2[CH:12]=[N:11][CH:10]=[CH:9][C:8]=2[C:7]1=[O:16])=[O:5])C.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:17][C:4]([CH:6]2[C:14](=[O:15])[C:13]3[CH:12]=[N:11][CH:10]=[CH:9][C:8]=3[C:7]2=[O:16])=[O:5])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)C1C(=O)c2ccncc2C1=O
Product: O=C(Nc1ccccc1)C1C(=O)c2ccncc2C1=O

Procedure:
In a similar manner to Example 1a, 5,7-dioxo-6,7-dihydro-5H-[2]pyrindine-6-carboxylic acid phenylamide was obtained starting from 5,7-dioxo-6,7-dihydro-5H-[2]pyrindine-6-carboxylic acid ethyl ester and aniline. The desired product was obtained as a brownish orange powder. ESI−MS: m/z 267 (MH+); 1H-NMR (DMSO-d6): δ6.93 (1H, t, J=7.3 Hz), 7.26 (2H, t-like, 7.3 Hz), 7.33 (1H, dd, J=1.4 Hz, 4.6 Hz), 7.59 (2H, d, J=7.3 Hz), 8.51 (1H, d, J=1.4 Hz), 8.72 (1H, d, J=4.6 Hz), 10.78 (1H, brs).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([OH:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1.O[C:15]1[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]([CH3:28])[CH:16]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH:8]([O:13][C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]([CH3:28])[CH:16]=2)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(O)c1cccc(Br)n1
Reactant: CCOC(=O)COc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)n1
Temperature: 25 °C
Yield: 64.6 %

Procedure:
To a stirred solution of 1-(6-bromo-2-pyridinyl)-1-pentanol (2.00 g, 8.19 mmol) and ethyl (4-hydroxy-2-methylphenoxy)acetate (1.89 g, 8.99 mmol) in dry THF (160 mL) at 0° C. (ice/water bath) under nitrogen was added ADDP (4.13 g, 16.37 mmol) portion-wise over 5 min followed by nBu3P (1.07 mL, 4.30 mmol) drop-wise over 1-2 min. The mixture was stirred with slow warming to rt over 21 h and then concentrated under vacuum, diluted with EtOAc (300 mL) and washed with water (200 mL). The aqueous layer was then re-extracted with EtOAc (300 mL) and the combined organic layer washed with brine (350 mL), dried (MgSO4), filtered and reduced to give a orange solid residue. Purification by SPE (silica, 20 g Cartridge) eluting with cyclohexane:EtOAc (gradient 1:0 to 1:1) afforded the title compound (2.31 g).
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].C([N:27](CC)CC)C.Cl[C:33]1[N:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][N:34]=1>C(Cl)Cl>[NH2:27][C:33]1[N:38]=[CH:37][C:36]([S:39]([N:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH:13]=[CH:12][C:11]([C:5]([OH:10])([C:6]([F:9])([F:8])[F:7])[C:4]([F:3])([F:23])[F:24])=[CH:16][CH:15]=3)[CH2:18][CH2:19]2)(=[O:41])=[O:40])=[CH:35][N:34]=1
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)c1cnc(Cl)nc1
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Product: Nc1ncc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.1 %

Procedure:
A 100-mL round-bottomed flask was charged with 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (0.45 g, 1.13 mmol, Example 91), 10 mL of CH2Cl2, triethylamine (0.63 mL, 4.51 mmol), and 2-chloro-5-pyrimidinesulfonyl chloride (0.24 g, 1.13 mmol, Matrix Scientific, Columbia, S.C.). After stirring for 15 min at room temperature, the mixture was concentrated then diluted with 10 mL of EtOH and 10 mL of NH4OH. The mixture was stirred at room temperature for an additional 1 h and then diluted with EtOAc. The organics were separated, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography on silica gel (0 to 65% EtOAc in hexanes) to give 2-(4-(4-((2-amino-5-pyrimidinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.22 g). 1H NMR (400 MHz, CD3OD) δ=8.58 (s, 2H), 7.57 (d, J=8.8 Hz, 2H), 7.03 (d, J=9.2 Hz, 2H), 3.38-3.34 (m, 4H), 3.22-3.17 (m, 4H). m/z (ESI, +ve ion) 485.6 (M+H)+. GK-GKRP IC50 (Binding)=0.258 μM; GK-GKRP EC50 (LC MS/MS-2)=0.518 μM.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[NH:19][C:18](=O)[N:17]2[N:21]=[C:22]([CH:24]3[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]3)[N:23]=[C:16]2[CH:15]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[ClH:3].[Cl:3][C:18]1[N:17]2[N:21]=[C:22]([CH:24]3[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]3)[N:23]=[C:16]2[CH:15]=[C:14]([C:8]2[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=2[Cl:6])[N:19]=1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)[nH]c(=O)n3n2)CC1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)nc(Cl)n3n2)CC1
Product: Cl
Temperature: 120 °C
Reaction time: 16 h

Procedure:
4.5 ml of phosphoryl chloride were added to 1.25 g (3.2 mmol) of 7-(2-chloro-4-fluorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (Example 50A), 1.46 g (6.41 mmol) of benzyltriethylammonium chloride were added and the reaction mixture was stirred at 120° C. for 16 h. The reaction mixture was concentrated and carefully, with vigorous stirring, added to ice. The mixture was stirred for another 10 min. Three times, the aqueous phase was extracted with dichloromethane. The combined organic phases were freed from the solvent and the residue was dried under high vacuum. This gave 715 mg (55% of theory) of the product.
Reaction SMILES: O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:22][C:23]([Si](C)(C)C)([F:25])[F:24].[Br:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([CH3:52])[C:38]([C:40]2[CH:51]=[CH:50][C:43]3[N:44]([CH3:49])[C:45](=[O:48])[N:46]([CH3:47])[C:42]=3[CH:41]=2)=[O:39])=[C:33]([Cl:53])[CH:32]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O.CO>[Br:30][C:31]1[CH:36]=[CH:35][C:34]([CH:37]([CH3:52])[C:38]([C:40]2[CH:51]=[CH:50][C:43]3[N:44]([CH3:49])[C:45](=[O:48])[N:46]([CH3:47])[C:42]=3[CH:41]=2)([OH:39])[C:23]([F:25])([F:24])[F:22])=[C:33]([Cl:53])[CH:32]=1
Reactant: CC(C(=O)c1ccc2c(c1)n(C)c(=O)n2C)c1ccc(Br)cc1Cl
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)n(C)c(=O)n2C)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tetrabutylammonium fluoride trihydrate (31 mg) was added to a solution of (trifluoromethyl)trimethylsilane (1 ml of a 2M solution in THF) and 5-[2-(4-bromo-2-chloro-phenyl)-propionyl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (410 mg) in THF (20 ml) at room temperature. The mixture was stirred for 30 min at room temperature. MeOH (1 ml) and 1M tetrabutylammonium fluoride in THF (1 ml) were added and the mixture was stirred 1 h at room temperature. Water (50 ml) was added and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated to an oil. The residue was purified by flash chromatography (SiO2, 0 to 100% EtOAc/heptane) to give the title compound (400 mg) as a colorless oil. MS (m/e)=479.0 [M+H+].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:15]=[N:14][C:13]2[C:8]1=[N:9][CH:10]=[N:11][C:12]=2[O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]2([C:37](O)=[O:38])[CH2:36][CH2:35]2)=[O:33])=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[F:24][C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:32]([C:34]2([C:37]([NH:23][C:20]3[CH:21]=[CH:22][C:17]([O:16][C:12]4[N:11]=[CH:10][N:9]=[C:8]5[C:13]=4[N:14]=[CH:15][N:7]5[CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)=[CH:18][CH:19]=3)=[O:38])[CH2:36][CH2:35]2)=[O:33])=[CH:29][CH:30]=1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: Nc1ccc(Oc2ncnc3c2ncn3C2CCCCO2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(F)cc1)C1(C(=O)Nc2ccc(Oc3ncnc4c3ncn4C3CCCCO3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a mixture of 4-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-yloxy]-phenylamine (0.311 g, 1 mmol) and 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (0.334 g, 1.5 mmol) in DMF (5 mL) was added TEA (216 μL, 2 mmol) followed by HATU (0.76 g, 2 mmol). The resulting solution was stirred overnight at room temperature. The reaction mixture was dumped into water (25 mL) and extracted with EtOAc (2×). The combined organic extracts were washed with 10% LiCl(aq.) (4×), satd. NaHCO3(aq) (2×), water, (1×) and brine (1×), followed by drying over MgSO4 and concentration in vacuo. The crude solids were purified by flash chromatography (silica gel, 1:1 EtOAc:Hexanes containing 2% 7N NH3 in MeOH), affording N-(4-fluorophenyl)-N′-(4-{[9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide (0.430 g, 83% yield) as a solid. 1H NMR (400 MHz, CDCl3): δ 9.50 (s, 1H), 8.95 (s, 1H), 8.45 (s, 1H), 7.60 (m, 2H), 7.45 (m, 2H), 7.20 (m, 2H), 7.0 (m, 2H), 5.8 (m, 1H), 4.20 (m, 1H), 3.8 (m, 1H), 2.20 (m, 3H), 1.80 (m, 2H), 1.7 (m, 5H). MS (ESI) for C27H25FN6O4: 517 (MH+).