Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:38])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[CH:32]=[CH:31][N:30]=[C:29]([O:33]C(C)(C)C)[N:28]=3)[CH2:16][CH2:15]1)(=[O:13])=[O:12])=[CH:5]2.Cl>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([S:11]([N:14]1[CH2:15][CH2:16][N:17]([C:20](=[O:38])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[CH:32]=[CH:31][N:30]=[C:29]([OH:33])[N:28]=3)[CH2:18][CH2:19]1)(=[O:13])=[O:12])=[CH:5]2
Reactant: CC(C)(C)Oc1nccc(-c2ccccc2C(=O)N2CCN(S(=O)(=O)c3cc4cc(Cl)ccc4[nH]3)CC2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(c1ccccc1-c1ccnc(O)n1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(5-chloroindol-2-ylsulphonyl)-4-[(2-tert-butyloxypyrimidin-4-yl)benzoyl]piperazine (200 mg, 0.361 mmol) in dichloromethane and methanol (10 ml of a 4:1 mixture) was added a solution of hydrogen chloride in methanol (0.40 ml of ˜4.5 M, 1.8 mmol), and the reaction stirred at ambient temperature for 1 hr. The solvent was removed in vacuo and the residue crystallised from ethanol to give 1-(5-chloroindol-2-ylsulphonyl)-4-[(2-hydroxypyrimidin-4-yl)benzoyl]piperazine as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:33])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][CH2:25][C:26]([O:28]CC)=[O:27])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:31][CH3:32])=[CH:13][CH:12]=1)=[O:10].[OH-].[K+]>O.CO>[Cl:33][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][CH2:25][C:26]([OH:28])=[O:27])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:31][CH3:32])=[CH:13][CH:12]=1)=[O:10]
Reactant: CCOC(=O)CNc1ccc2oc3c(OC)ccc(C(=O)Nc4c(Cl)cncc4Cl)c3c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccc(NCC(=O)O)cc12
Yield: 53.3 %

Procedure:
N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-(2-ethoxy-2-oxo-ethylamino)-dibenzo[b,d]furan-1-carboxamide (Example 52) (100 mg, 0.204 mmol) was hydrolysed using potassium hydroxide (5 eq.) in 3 ml water and 3 ml methanol for 12 h at room temperature. The solid precitated was filted and washed with ethanol to obtain the product as pale yellow solid (50 mg). mp: >260° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=O)[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[OH:15][CH:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH2:26][OH:27])[CH:20]=1)[CH2:17][NH2:18]>C(O)C.[Pd].C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([NH:18][CH2:17][CH:16]([OH:15])[C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([CH2:26][OH:27])[CH:20]=2)[CH3:13])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: NCC(O)c1ccc(O)c(CO)c1
Reactant: COC(=O)c1ccc(CC(C)=O)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CC(C)NCC(O)c2ccc(O)c(CO)c2)cc1
Reaction time: 18 h
Yield: 43 %

Procedure:
A solution of 1-(4-carbomethoxyphenyl)propan-2-one (70 g) and 2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethanamine (66.7 g) in ethanol (1750 cm3) was stirred under reflux for 4 hours. The solution was cooled and added to a suspension of 10% palladium on charcoal, (Johnson Matthey type 87 L), (20 g) in ethanol (50 cm3) and the resulting mixture hydrogenated at 90 psi and 50°-55° for 18 hours. The mixture was filtered through a Claraid bed, the residue washed with ethanol (about 500 cm3) and the filtrate evaporated under reduced pressure to yield a viscous gum. The gum was dissolved in hot ethyl acetate (100 cm3) and decanted from a small amount of residual brown oil. On standing a white solid crystallised which was filtered off, washed with diethyl ether (about 100 cm3) and dried to give the title compound 56.3 g (43%), mp 139°-141°. (13C NMR indicated this to be a 7:3 mixture of diastereoisomers). On standing two further crops of the title compound crystallised from the filtrate giving a total yield of 84.7 g (64.7%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].COC1C=CC(C[N:15]2[C:19]3[N:20]=[CH:21][C:22]4[CH2:23][N:24]([C:28](=[O:37])[C@H:29]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[NH3+:30])[CH2:25][CH2:26][C:27]=4[C:18]=3[CH:17]=[N:16]2)=CC=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH:17]1[C:18]2[C:27]3[CH2:26][CH2:25][N:24]([C:28](=[O:37])[C@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[NH3+:30])[CH2:23][C:22]=3[CH:21]=[N:20][C:19]=2[NH:15][N:16]=1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)[C@@H]([NH3+])c2ccccc2)CC4)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: [NH3+][C@H](C(=O)N1CCc2c(cnc3[nH]ncc23)C1)c1ccccc1
Temperature: 65 °C
Yield: 108.1 %

Procedure:
To (S)-2-(3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-oxo-1-phenylethanaminium 2,2,2-trifluoroacetate (0.109 g, 0.18 mmol) was added trifluoroacetic acid (2 mL). The reaction mixture was heated at 65° C. for 16 hours. On completion of the reaction, toluene (5 mL) was added followed by removal of the solvent under reduced pressure. The mixture was evaporated to dryness in the Genevac and a dark brown solid was obtained. The crude product was purified using reverse phase HPLC to give the pure desired product, (S)-2-(8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridin-7(6H)-yl)-2-oxo-1-phenylethanaminium 2,2,2-trifluoroacetate as a pale yellow solid (0.082 g, 84%). M.p.>100° C.; 1H NMR (400 MHz, DMSO-d6) δ12.75 (brs, 1H), 8.62 (brs, 2H), 8.39/8.13 (s, 1H, rotamers), 8.08/8.06 (s, 1H, rotamers), 7.56-7.35 (m, 5H), 5.74 (m, 1H), 4.91 (m, 2H), 3.73 (m, 2H), 3.08 (m, 2H); LCMS [M+H]: 308.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:18]=[CH:17]3)=[CH:10][C:9]=1[CH3:29].Cl[CH2:31][C:32]1[C:33]([C:40]2[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:47])=[N:34][O:35][C:36]=1[CH:37]([CH3:39])[CH3:38].O>CN(C)C=O>[Cl:46][C:45]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:47])[C:40]=1[C:33]1[C:32]([CH2:31][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:18]=[CH:17]4)=[CH:10][C:9]=2[CH3:29])=[C:36]([CH:37]([CH3:39])[CH3:38])[O:35][N:34]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Reactant: CCOC(=O)c1ccc2cc(-c3ccc(O)c(C)c3)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)c(C)c3)ccc2n1
Yield: 21.7 %

Procedure:
Cesium carbonate (54.9 mg, 168.6 μmol) was added to ethyl 6-(4-hydroxy-3-methylphenyl)-2-quinolinecarboxylate (47.1 mg, 153.3 μmol) and 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (51.3 mg, 168.6 μmol) in N,N-dimethylformamide (3.1 mL) at room temperature. The resulting suspension was stirred for twenty hours, then water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 3:7 ethyl acetate:hexanes to give 19.1 mg (22%) of ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-3-methylphenyl]-2-quinolinecarboxylate as an oil. 1H NMR (400 MHz, d6-DMSO): δ 8.56 (d, J=9 Hz, 1H), 8.28 (s, 1H), 8.19-8.09 (m, 3H), 7.66-7.59 (m, 4H), 7.55 (dd, J=9, 7 Hz, 1H), 7.09 (d, J=9 Hz, 1H), 4.91 (s, 2H), 4.42 (q, J=7 Hz, 2H), 3.52 (septet, J=7 Hz, 1H), 1.97 (s, 3H), 1.38 (t, J=7 Hz, 3H), 1.36 (d, J=7 Hz, 6H). ESI-LCMS m/z 575 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:12](=[O:13])[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:4]=1[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)#[N:2].[H-].[Na+].C(O)C[OH:29]>>[C:1]([C:3]1[C:12](=[O:13])[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[C:5]([C:14]([O:16][CH2:17][CH2:18][OH:29])=[O:15])[C:4]=1[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)#[N:2]
Reactant: CCOC(=O)c1c(N2CCCCC2)c(C#N)c(=O)n2ccccc12
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)c(C(=O)OCCO)c2ccccn2c1=O
Temperature: 100 °C
Reaction time: 14 h

Procedure:
To a solution of 1.10 g of 3-cyano-1-ethoxycarbonyl-2-piperidino-4H-quinolizin-4-one (Example 6, S-35) in 30 ml of ethylene glycol was added 150 mg of 60% sodium hydride, and the reaction mixture was stirred at 100° C. for 14 hours. After cooling, the precipitated crystals were collected by filtration and then the crude crystals were chromatographed on a silica gel column using a mixed solvent of dichloromethane and diethyl ether (1:1) as an eluent to obtain 180 mg of 3-cyano-1-(2-hydroxyethoxycarbonyl)-2-piperidino-4H-quinolizin-4-one.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.CN1CCNCC1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:1]([N:10]1[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: CN1CCNCC1
Reactant: C=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CC(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of acryloyl choride (102.0 g, 1.13 moles) in methylene chloride (100 ml) was added dropwise into a solution of N-methyl piperazine (86.0 g, 0.86 moles) in methylene chloride (450 ml) over a period of one hour. During the addition, the temperature of the N-methyl piperazine/methylene chloride was kept below 25° C. After the addition was complete, the reaction mixture was stirred at room temperature for two hours. The reraction mixture was neutralized with 260 g of 17% sodium carbonate solution. The organic layer containing the crude product was separated from the aqueous layer via a separatory funnel. The aqueous layer was washed well with methylene chloride. Combination of the organic phases and rotoevaporation of the solvent yielded 100.0 grams of crude product. Distillation of the crude product yield a fraction (74°-78° C./5 mm Hg) that was>98% by G.C. analysis. 13C nmr and IR analysis gave spectra consistent with the title compound.
Reaction SMILES: [CH2:1]([S:4]([N:7]1[CH2:12][CH2:11][C:10]([C@@H:19]([NH2:21])[CH3:20])([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)(=[O:6])=[O:5])[CH2:2][CH3:3].CCN(C(C)C)C(C)C.[Cl:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:33]=1[C:34](Cl)=[O:35]>CN(C=O)C>[Cl:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:33]=1[C:34]([NH:21][C@H:19]([C:10]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8][N:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:5])=[O:6])[CH2:12][CH2:11]1)[CH3:20])=[O:35]
Reactant: CCCS(=O)(=O)N1CCC(c2ccccn2)([C@H](C)N)CC1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)N1CCC(c2ccccn2)([C@H](C)NC(=O)c2c(Cl)cccc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of {(1S)-1-[1-(propylsulfonyl)-4-pyridin-2-ylpiperidin-4-yl]ethyl}amine (80 mg, 0.26 mmol) in DMF (0.7 mL) was treated with i-Pr2NEt (0.2 mL, 1.15 mmol) and 2,6-dichloro-benzoyl chloride (0.15 mL, 0.8 mmol) and stirred at room temperature for 30 min. The reaction mixture was purified directly by reverse phase HPLC to afford the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([CH:24]=[O:25])=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.CO.[BH4-].[Na+]>C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([CH2:24][OH:25])=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C=O)s2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(CO)s2)c1
Yield: 86.5 %

Procedure:
To 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole-2-carbaldehyde (Example 88, Step 1, 0.15 g, 0.41 mmol) was added methanol (4 mL) and sodium borohydride (0.016 g, 0.41 mmol). Once complete, the reaction was diluted with ethyl acetate, washed carefully with aqueous saturated ammonium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to yield [5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methanol (0.13 g, 85%). MS ESI: [M+H]+ m/z 366.7. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.83 (d, J=4.8, 1H), 7.98 (s, 2H), 7.45 (s, 1H), 7.28 (d, J=4.9, 1H), 7.17 (s, 1H), 6.10 (t, J=5.8, 1H), 4.71 (d, J=5.8, 2H), 2.31 (s, 3H). rhSYK activity=+++
Reaction SMILES: [Cl:1][C:2]1[C:47]([Cl:48])=[CH:46][C:5]2[N:6]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C@@H:15]3[C@H:19]4[O:20][C:21]([CH3:24])([CH3:23])[O:22][C@H:18]4[C@H:17]([N:25]4[C:29]5[N:30]=[CH:31][N:32]=[C:33]([NH:34][CH:35]6[CH2:37][CH2:36]6)[C:28]=5[CH:27]=[CH:26]4)[CH2:16]3)=[N:8][C:4]=2[CH:3]=1.CO.C=O.[BH3-][C:54]#N.[Na+]>C1COCC1>[Cl:1][C:2]1[C:47]([Cl:48])=[CH:46][C:5]2[N:6]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:44])[CH3:45])[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:14][C@@H:15]3[C@H:19]4[O:20][C:21]([CH3:24])([CH3:23])[O:22][C@H:18]4[C@H:17]([N:25]4[C:29]5[N:30]=[CH:31][N:32]=[C:33]([NH:34][CH:35]6[CH2:36][CH2:37]6)[C:28]=5[CH:27]=[CH:26]4)[CH2:16]3)[CH3:54])=[N:8][C:4]=2[CH:3]=1
Reactant: [BH3-]C#N
Reactant: CC1(C)O[C@@H]2[C@@H](CNCCCCc3nc4cc(Cl)c(Cl)cc4n3COCC[Si](C)(C)C)C[C@@H](n3ccc4c(NC5CC5)ncnc43)[C@@H]2O1
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN(CCCCc1nc2cc(Cl)c(Cl)cc2n1COCC[Si](C)(C)C)C[C@H]1C[C@@H](n2ccc3c(NC4CC4)ncnc32)[C@@H]2OC(C)(C)O[C@H]12
Reaction time: 2 h

Procedure:
7-[(3aS,4R,6R,6aR)-6-({[4-(5,6-Dichloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl)butyl]amino}methyl)-2,2-dimethyl-hexahydrocyclopenta[d][1,3]dioxol-4-yl]-N-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.222 g, 0.311 mmol) was dissolved in THF (5 ml) and MeOH (5 ml) and formaldehyde (0.05 ml, 0.621 mmol) was added at r.t. under N2. NaBH3CN (0.023 g, 0.373 mmol) was added at r.t. and the reaction left for 2 hrs. After this time LCMS analysis showed the reaction was complete so the reaction was quenched by addition of sat. NaHCO3 solution (10 ml), water (10 ml) and DCM (10 ml). The organic layer was separated and the aqueous layer was extracted with DCM (2×10 ml). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give the crude product. The crude product was purified by silica flash column chromatography using between 100% DCM and 15% MeOH:95% DCM as eluent to give the product as a colorless oil
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)=[CH:4][CH:3]=1.[N:19](OC(C)(C)C)=[O:20].Cl>C(O)C.C(O)CC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])/[C:9](=[N:19]\[OH:20])/[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)=[CH:4][CH:3]=1
Reactant: CSc1nccc(CC(=O)c2ccc(F)cc2)n1
Reactant: CC(C)(C)ON=O
Agent: Cl
Solvent: CCO
Solvent: CCCO
Product: CSc1nccc(/C(=N/O)C(=O)c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-(4-fluorophenyl)-2-(2-(methylthio)pyrimidin-4-yl)ethanone, 73 (1.0 g) in ethanol (20 mL) at −10° C., under an atmosphere of nitrogen, is added dropwise t-butyl nitrite (0.5 mL) followed by hydrogen chloride in n-propanol (2.5 to 3 N, 0.6 mL) while maintaining the temperature below −5° C. Once the addition is complete, the solution is allowed to warm to room temperature with stirring and after 2 h the solvent is evaporated and the residue partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The layers are separated; the aqueous phase is extracted with ethyl acetate and the combined organic phases dried over sodium sulfate. Filtration and evaporation of the solvent affords the title compound, 74 (1.0 g).
Reaction SMILES: CN(CCN(C)C)C.[Li+].CC([N-]C(C)C)C.[Br:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.CN([CH:27]=[O:28])C>CCOCC>[Br:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH:27]=[O:28]
Reactant: Brc1cccnc1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li+]
Solvent: CCOCC
Product: O=Cc1ccncc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
To a solution of TMEDA (1.91 mL, 12.7 mmol) and LDA (12.7 mmol) in ether (50 mL) at −78° C. was added 3-bromo-pyridine (1.22 mL, 12.7 mmol). After 60 minutes at −78° C., DMF (1.08 mL, 13.9 mmol) was added, and the mixture allowed to warm to room temperature. After 1 hour at room temperature the reaction was quenched with saturated aqueous NaHCO3 (100 mL), extracted with CH2Cl2 (4×15 mL), dried (MgSO4), filtered and concentrated in vacuo to give the crude oil. Purification by column chromatography on silica gel (Hexanes: EtOAc 4:1) afforded the title compound as a crystalline solid (1.2 g, 51%). 1H NMR (CDCl3) 7.70 (d, 1H, J=4.8 Hz), 8.71 (d, 1H, J=4.8 Hz), 8.91 (s, 1H), 10.36 (s, 1H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:26]([F:27])=[CH:25][C:24]([CH2:28][OH:29])=[C:23](Cl)[N:22]=3)[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:31]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:26]([F:27])=[CH:25][C:24]([CH2:28][OH:29])=[C:23]([CH3:31])[N:22]=3)[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3nc(Cl)c(CO)cc3F)CC2)CC1
Reactant: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1nc(N2CCC(=NOC3CCN(C(=O)OC(C)C)CC3)CC2)c(F)cc1CO
Temperature: 100 °C

Procedure:
55b (30 mg, 0.068 mmol), trimethylboroxine (25 mg, 0.2 mmol) and potassium carbonate (50 mg, 0.36 mmol) were combined in 0.5 mL of dioxane and heated at 100° C. for 20 h. The mixture was cooled, concentrated under a stream of nitrogen, diluted with water (2 mL) and extracted with ethyl acetate (2×2 mL). The combined extracts were dried under a stream of nitrogen and the residue was purified by preparative HPLC to afford 55-1 as a colorless oil: LC-MS 423.1 (MH+), tR=5.95 (Method 2). EC50: 206 nM.
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:3].[C:11](Cl)([Cl:13])=[O:12]>ClCCl.C1(C)C=CC=CC=1>[Cl:13][C:11]([O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N:2]([CH3:3])[CH3:1])[CH:5]=1)=[O:12]
Reactant: CN(C)c1cccc(O)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN(C)c1cccc(OC(=O)Cl)c1

Procedure:
A solution of 3-(N,N-dimethylamino)phenol (1.0 g)in dichloromethane (20 ml) was added, dropwise, to a solution of phosgene in toluene (1.93M, 30 ml) previously cooled to -5°. The resulting mixture was stirred at a temperature between -5 to 0° to 30', then decanted and concentrated in vacuo to a brown oil (0.63 g). IR: 1784 (C=O), 1616 and 1572 (C=C) cm-1; 1H-NMR: 7.23 (m); 6.65 (dd); 6.53 (dd); 6.50 (m); 2.96 (s).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([NH:20]/[C:21](/[NH2:24])=[N:22]/[OH:23])[CH:16]=[CH:17][C:18]=2[CH3:19])[C:3]1=[O:25].[S:26]1[CH:30]=[CH:29][N:28]=[C:27]1[C:31](Cl)=O.C(O)C>C1COCC1>[S:26]1[CH:30]=[CH:29][N:28]=[C:27]1[C:31]1[O:23][N:22]=[C:21]([NH:20][C:15]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([C:4]3[C:3](=[O:25])[N:2]([CH3:1])[C:11]4[C:6]([CH:5]=3)=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=4)[CH:14]=2)[N:24]=1
Reactant: O=C(Cl)c1nccs1
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(-c4nccs4)n3)ccc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 17 (0.1 mmol) in THF (1 mL) was added thiazole-2-carbonyl chloride (0.1 mmol). The reaction mixture was stirred at rt for 30 min. Then ethanol (1 mL) was added and heated at reflux for 3 h. After filtration, the mixture was purified by preparative LC/MS to give 3-(5-(5-(thiazol-2-yl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A9) MS m/z 431.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][OH:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([CH:24]([OH:25])[C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([NH2:20])[CH:22]=1)=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: Nc1cccc(CO)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)C(O)c1cccc(N)c1

Procedure:
N-t-butyloxycarbonylphenylalanine (1.00 g, 3.8 mmole) is dissolved in 4 ml of dichloromethane, in which is then suspended m-aminobenzyl alcohol. The cooled mixture is treated with 0.78 g (3.8 mmole) of dicyclohexylcarbodiimide for 12 to 24 hours. Dicyclohexylurea is removed by filtration, using an ethyl acetate wash. The filtrate is extracted three times with saturated aqueous potassium bisulfate, three times with aqueous potassium bicarbonate, and once with brine. The organic layer is dried over magnesium sulfate, filtered, and blown dry under flowing nitrogen. Column chromatography using silica gel and chloroform eluent produces, after removal of solvent, 1.19 g (3.2 mmole) of pure product. Structure assignment is supported by elemental analysis (C,H,N).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:15]2[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]2)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: OCC1CCNCC1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: ClCCl
Product: O=C(O)c1cc(S(=O)(=O)N2CCC(CO)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-5-chlorosulfonylbenzoic acid (5.0 g.) is added to a solution of 4-piperidyl carbinol (6.9 g.) in 40 ml. of methylene chloride. The solution is refluxed for 2 hours, cooled to room temperature and stirred overnight. The solution is evaporated to dryness, the gummy residue dissolved in 1N sodium hydroxide, and the alkaline solution extracted twice with ether. The aqueous solution is acidified with concentrated hydrochloric acid, and the precipitate recovered by filtration. Recrystallization from ethyl acetate yields crystals, m.p. 184°-187° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[O:11].Cl.O.N([O-])=O.[N-:26]=[N+:27]=[N-].[Na+]>>[OH:1][C:2]1[CH:7]=[C:6]([N:8]=[N+:26]=[N-:27])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])=[O:11]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccccc1NC(=O)Nc1ccc(N)cc1O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccccc1NC(=O)Nc1ccc(N=[N+]=[N-])cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
The N-(2-hydroxy-4-aminophenyl)-N'-(2-methoxyphenyl)urea (300 mg. 1.17 mmol) was added to HCl/H2O (1.17 mL/2.34 mL), cooled to 0° C. Solution nitrite (80.7 mg, 1.17 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0° C. for 30 minutes. The sodium azide (76 mg, 1.17 mmol) was added to reaction mixture and it was warmed to room temperature. The reaction mixture was stirred at room temperature for 18 hours. The it was extracted with three times by ethyl acetate. The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure and chromatography of the resulting solid on silica gel (hexane:ethyl acetate; 5:1) gave product (125 mg, 38%). EI-MS m/z 300 (M+H)+