Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[C:34](B(O)O)=[CH:33][CH:32]=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[F:28][C:29]1[C:34]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:19])([F:20])[F:18])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)=[CH:33][CH:32]=[CH:31][N:30]=1
Reactant: OB(O)c1cccnc1F
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cccnc2F)c1

Procedure:
A mixture of (R)-5-chloro-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 38.1, 50 mg, 0.124 mmol), (2-fluoropyridin-3-yl)boronic acid (26 mg, 0.187 mmol), 2 M Na2CO3 (0.124 mL, 0.249 mmol) and DME (2.5 mL) was flushed with argon. PdCl2(dppf)(CH2Cl2) (10 mg, 0.012 mmol) was added and the mixture was subjected to MW irradiation 140° C. for 30 min, filtered through a PL-Thiol MP SPE cartridge (StratoSpheres™, 6 mL), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative LC-MS to afford the title compound. LC-MS (Condition 6) tR=1.71 min, m/z=463.0 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:9])[C:6]([NH2:8])=[O:7].Cl.N[C@H]1[CH2:16][O:15][CH2:14][C@@H]1O>C(N(CC)CC)C>[OH:1][C@H:2]1[CH2:16][O:15][CH2:14][C@@H:3]1[NH:4][C:5](=[O:9])[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)C(=O)NCCO
Reactant: N[C@H]1COC[C@@H]1O
Agent: Cl
Solvent: CCN(CC)CC
Product: NC(=O)C(=O)N[C@H]1COC[C@@H]1O
Yield: 65 %

Procedure:
Prepared as in Intermediate 3, using (3R,4S)-4-aminotetrahydrofuran-3-ol hydrochloride [Schaus et al, J. Org. Chem., 62, 4197 (1997)] and triethylamine, to give the title compound as a pale brown powder (1.13 g, 65% ); NMR [(CD3)2SO] 3.45–3.56 (2H, m), 3.84–3.94 (2H, m), 3.98–4.01 (1H, m), 4.19–4.24 (1H, m), 5.24 (1H, t), 7.79 (1H, br s), 8.06 (1H, br s), and 8.66 (1H, d).
Reaction SMILES: ClC1C=CC(C=C)=CC=1.Br[C:11]1[CH2:15][CH2:14][O:13][N:12]=1.[OH:16][C:17]1[CH:18]=[N:19][CH:20]=[N:21][CH:22]=1>>[N:19]1[CH:18]=[C:17]([O:16][C:11]2[CH2:15][CH2:14][O:13][N:12]=2)[CH:22]=[N:21][CH:20]=1
Reactant: BrC1=NOCC1
Reactant: Oc1cncnc1
Agent: C=Cc1ccc(Cl)cc1
Product: c1ncc(OC2=NOCC2)cn1

Procedure:
3-(pyrimidin-5-yloxy)-4,5-dihydroisoxazole I-153a and I-153b were prepared in 2 steps 1-chloro-4-vinylbenzene using Method 1. The resulting bromo-4,5-dihydroisoxazole was reacted with 5-hydroxypyrimidine using Method 5. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=277.3 m/z. Activity: B
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:16][C@H:15]3[N:12]([C:13](=[O:20])[C@@H:14]3[C@H:17]([OH:19])[CH3:18])[C:11]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])=[CH:6][CH:5]=1)[CH3:2].C(=O)([O-])O.[Na+:38].O.[H][H]>C1COCC1.[C].[Pd]>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:16][C@H:15]3[N:12]([C:13](=[O:20])[C@@H:14]3[C@H:17]([OH:19])[CH3:18])[C:11]=2[C:21]([O-:23])=[O:22])=[CH:6][CH:5]=1)[CH3:2].[Na+:38]
Reactant: [H][H]
Reactant: CCOc1ccc(C2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Reaction time: 3 h
Yield: 42 %

Procedure:
4-Nitrobenzyl (5R,6S)-3-(4-ethoxyphenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.39 g) prepared in accordance to the method described in Tetrahedron Letters, 34, 3211-3214 (1993)] was dissolved in THF (28 mL), and thereto were added under ice cooling sodium hydrogencarbonate in ion-exchange water (28 mL), and 10% palladium-carbon [50% water] (0.14 g). Then the atmosphere was changed with a hydrogen gas, and the mixture was stirred at the same temperature for 3 hours. After filtration of the insoluble materials with Celite, to the filtrate was added chloroform (80 mL). The organic layer was separated, and extracted with ion-exchange water (20 mL). The organic solvent in the aqueous solution separated and extracted was removed over one hour period in vacuo, purified with C18 reverse column chromatography (Wakosil C18 reverse column, mobile phase; ion-exchange water/THF) and lyophilized to give sodium (5R,6S)-3-(4-ethoxyphenyl)-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.44 g, yield 42%).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[C:21]([OH:23])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[CH3:58][NH:59][O:60][CH3:61].C(N(C(C)C)CC)(C)C>O.CN(C=O)C>[CH3:61][O:60][N:59]([CH3:58])[C:21]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])=[O:23]
Reactant: CNOC
Reactant: O=C(O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
4-Phenyl-8-(trifluoromethyl)quinoline-3-carboxylic acid (6.19 g, 19.51 mmol) was taken into DMF (75 mL) and cooled to 0° C. Then PyBOP (10.66 g, 20.49 mmol) was added followed by N,O-dimethylhydroxylamine hydrochloride (2.09 g, 21.46 mmol) and diisopropylethylamine (8.50 mL, 48.78 mmol). The reaction was stirred for 3 hours allowing to warm to room temperature during that time. The reaction was poured into water and extracted with ethyl acetate. The combined organics was washed with water, half-saturated brine and then dried over magnesium sulfate. Purification was carried out via column chromatography using 30% ethyl acetate in hexane as the eluent to yield the desired compound as a white solid (6.37 g, 90.6%). MS (ESI) m/z 361 ([M+H]+); Anal. Calcd for C19H15F3N2O2.0.15H2O: C, 62.86; H, 4.25; N, 7.72. Found: C, 62.89; H, 4.14; N, 7.55.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:4]([O:9][NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14])=[N:5][CH:6]=[CH:7][CH:8]=1.[CH2:18]([N:21]=[C:22]=[O:23])[CH2:19][CH3:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:17][C:2]([F:1])([F:16])[C:3]1[C:4]([O:9][N:10]([C:11]([O:12][CH2:13][CH3:14])=[O:15])[C:22](=[O:23])[NH:21][CH2:18][CH2:19][CH3:20])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)NOc1ncccc1C(F)(F)F
Reactant: CCCN=C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCNC(=O)N(Oc1ncccc1C(F)(F)F)C(=O)OCC
Temperature: 45 °C
Reaction time: 40 h
Yield: 84.7 %

Procedure:
Ethyl N-(3-trifluoromethyl-2-pyridyloxy)-carbamate (2.30 g; 9.19 mmoles) was dissolved in 50 ml of toluene, and 2.34 g (27.6 mmoles) of n-propyl isocyanate and 0.2 g (2.0 mmoles) of triethylamine were added, and the mixture was stirred at 45° C. for 40 hours. The toluene and the excess of n-propyl isocyanate in the reaction mixture were evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate/hexane) to give 2.61 g (yield 85 %) of the desired compound as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[N+:35]([C:38]1[CH:39]=[C:40]([CH:45]=[CH:46][C:47]=1[O:48][CH2:49][C@@H:50]([NH2:52])[CH3:51])[C:41]([O:43][CH3:44])=[O:42])([O-:37])=[O:36].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[N+:35]([C:38]1[CH:39]=[C:40]([CH:45]=[CH:46][C:47]=1[O:48][CH2:49][C@@H:50]([NH:52][C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:51])[C:41]([O:43][CH3:44])=[O:42])([O-:37])=[O:36]
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)c1ccc(OC[C@H](C)N)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC[C@H](C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.8 %

Procedure:
A mixture of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (591 mg, 1.23 mmol), methyl (S)-3-nitro-4-(2-amino-1-propoxy)benzoate (313 mg, 1.23 mmol), and Et3N (257 mL, 1.84 mmol) in DMF (5 mL) was stirred at room temp for 2 days. The mixture was diluted with EtOAc, washed with 0.5 N HCl, brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica-gel with 5% MeOH in CHCl3 as eluent to give 310 mg (46%) methyl (S)-3-nitro-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetylamino]-1-propoxy]benzoate as a gum. 1H-NMR (CDCl3) δ1.28 (d, 3H, J=6.8 Hz), 2.31 (s, 3 H), 3.49 (s, 2 H, 3.71 (s, 3 H), 3.92 (s, 3 H), 4.14-4.16 (m, 2 H), 4.38-4.41 (m, 1 H), 5.88-5.90 (m, 1 H), 6.49 (s, 1 H), 6.70-6.71 (m, 1 H), 6.77-6.79 (m, 1 H), 7.05-7.30 (m, 4 H), 7.55-7.57 (m, 1 H), 8.02-8.06 (m, 2 H), 8.16-8.19 (m, 1 H), 8.51-8.52 (m, 1 H); MS (FAB) m/z 551 (M++1).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:8]=[CH:7][C:3]=1[CH:4]1[O:6][CH2:5]1.[CH:27]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[ClH:1].[Cl:1][C:2]1[C:10]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:8]=[CH:7][C:3]=1[CH:4]([OH:6])[CH2:5][NH:32][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NC1CCCC1
Reactant: Clc1c(C2CO2)ccc(OCc2ccccc2)c1OCc1ccccc1
Product: Cl
Product: OC(CNC1CCCC1)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1Cl

Procedure:
Following the procedures outlined in Example 1, the 2-chloro-3,4-dibenzyloxystyrene oxide is reacted with cyclopentylamine to give 2-chloro-α-(cyclopentylaminomethyl)-3,4-dibenzyloxybenzyl alcohol hydrochloride, m.p. 181°-182°C. Similar hydrogenation over palladium-on-carbon gives 2-chloro-α-(cyclopentylaminomethyl)-3,4-dihydroxybenzyl alcohol as an amorphous solid.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].OCC1N=CN(C)N=1.N1C=CC=CC=1CO[C:27]1[C:36]2[C:31](=[C:32](OCC3C=CC=CN=3)[CH:33]=[CH:34][CH:35]=2)[C:30]2=NN=C(C3C=C(C)ON=3)[N:29]2[N:28]=1.O>CN(C)C=O>[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[N:29][N:28]=1
Reactant: Cc1cc(-c2nnc3c4c(OCc5ccccn5)cccc4c(OCc4ccccn4)nn23)no1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cn1cnc(CO)n1
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2cnncc2c1
Reaction time: 0.25 h
Yield: 79.7 %

Procedure:
Lithium hexamethyldisilazide (1.0 M solution in hexane) (0.22 ml, 1.10 mmol) was added to stirred solution of 3-hydroxymethyl-1-methyl-1,2,4-triazole (90 mg, 0.79 mmol) (prepared using the conditions of Itoh and Okongi, EP-A-421210) in N,N-dimethylformamide (10 ml) at −10° C. under nitrogen, and the mixture stirred for 0.25 h. After this time, Intermediate 6 (100 mg, 0.53 mmol) was added and the mixture stirred at −10° C. for 0.5 h and then room temperature overnight. Water was added to the reaction mixture and the resulting precipitate filtered off and recrystallised from dichloromethane/ethyl acetate to give the title-phthalazine (55 mg, 27%), mp 221-223° C.; 1H NMR (360 MHz, CDCl3) δ 1.54 (3H, t, J=10.2 Hz, CH3), 3.96 (3H, s, CH3), 4.47 (2H, q, J=10.2 Hz, CH2), 5.71 (2H, s, CH2), 6.26 (1H, s, Ar—H), 7.79 (1H, m, Ar—H), 7.94 (1H, m, Ar—H), 8.08 (1H, s, Ar—H), 8.25 (1H, d, J=11.0 Hz, Ar—H), 8.70 (1H, d, J=8.1 Hz, Ar—H); MS (ES30) m/e 393 [MH]+; Anal. Found. C, 54.87; H, 3.91; N, 28.27; C18H16N8O3 requires C, 55.09; H, 4.11; N, 28.55%.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].O[C:7]1[C:8]2[N:9]([CH:18]=[CH:19][CH:20]=2)[N:10]=[CH:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)CC)C>ClCCl.C(O)C>[Cl:3][C:7]1[C:8]2[N:9]([CH:18]=[CH:19][CH:20]=2)[N:10]=[CH:11][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnn2cccc2c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cnn2cccc2c1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 86454.6 %

Procedure:
To POCl3 (225 mL, 2.42 mmol) at 0° C. was added ethyl 4-hydroxypyrrolo[1,2-b]pyridazine-3-carboxylate (50 g, 0.242 mmol) and the mixture was stirred until complete dissolution. At this time, triethylamine (36.8 mL, 0.266 mmol) was added dropwise and the resulting mixture was heated to 110° C. and allowed to stir for ˜16 h. The resulting mixture was allowed to cool and the POCl3 was removed in vacuo to afford a dark brown residue. This material was dissolved in dichloromethane and was cooled to 0° C. and diluted with 375 mL of ethanol. The resulting mixture was stirred at 0° C. for 30 min and then at rt for 1 h. The ethanol was removed under vacuum and the resulting semi-solid was dissolved in dichloromethane and stirred with 10% aqueous NaHCO3 for 1 h. The mixture was filtered through celite and the phases were separated. The aqueous portion was extracted with additional dichloromethane and the combined organic layers were washed with brine, dried over Na2SO4, decanted and the solvent was removed under vacuum to give the crude product. The crude material was purified by flash silica gel column chromatography to yield 47 g (86%) of a solid as the title compound. 1H NMR (400 MHz, CDCl3) δ ppm: 1.43 (t, J=7.2, 6.8 Hz, 3 H), 4.43 (q, J=7.2, 6.8 Hz, 2 H), 6.940-6.99 (m, 2H), 7.84 (q, J=0.8, 1.6 Hz, 1 H), 8.51 (s, 1H)). 13C-NMR (400 MHz, DMS-d6) ppm: 163.30, 141.89, 138.16, 124.86, 120.69, 114.99, 109.90, 105.22, 61.55, 14.21. LCMS (conditions A): m/z 225. HPLC (condition B): Retention time=3.47 min.
Reaction SMILES: [Br-].[F:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH2:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]=[O:12].[Cl-].[NH4+:18].CCO[CH2:22][CH3:23]>>[F:2][C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[CH2:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[CH:11]([OH:12])[CH2:10][CH2:9][CH2:8][N:18]1[CH2:4][CH2:5][N:6]([C:23]2[CH:22]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:11]1
Reactant: [NH4+]
Reactant: CCOCC
Reactant: O=Cc1cccn1Cc1ccccc1F
Agent: [Br-]
Agent: [Cl-]
Product: OC(CCCN1CCN(c2ccccc2)CC1)c1cccn1Cc1ccccc1F
Temperature: 45 °C
Reaction time: 20 h

Procedure:
The Grignard reagent of 4-phenylpiperaznopropylmagnesium bromide is added to benzane and the mixture is refluxed at 45°C for 1 hour. The mixture is permitted to cool and a solution of 1-(2-fluorobenzyl)pyrrole-2-carboxaldehyde in ether is added and then the mixture is stirred at 45°C for 20 hours. The reaction is permitted to cool, poured into ammonium chloride solution and the ammonium chloride solution is stirred for 30 minutes and extracted with chloroform. The combined chloroform extracts are washed well with water, dried and filtered and the solvent removed leaving 1-[1-(2-fluorobenyl)-2-pyrryl]-4-(4-phenylpiperazino)butanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.[CH:13]([NH:16][NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:15])[CH3:14].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([N:16]([CH:13]([CH3:15])[CH3:14])[NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1cccc(Br)c1
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1cccc(Br)c1
Yield: 67.2 %

Procedure:
A solution of (3-(3-bromophenyl)propionic acid (257 mg, 1.12 mmoles) and benzoic acid N′-isopropyl-hydrazide (200 mg, 1.12 mmoles) in DMF (6 mL) was treated with triethylamine (0.47 mL, 3.36 mmoles), HOBT (182 mg, 1.34 mmoles) and EDCI (2.58 mg, 1.34 mmoles) at room temperature for 18 h. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate/hexanes gradient to afford the product as a solid (293 mg, 67%).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[C:23]4[CH:24]=[CH:25][C:26]([C:28]5[NH:29][C:30]([C:33]#[N:34])=[CH:31][CH:32]=5)=[CH:27][C:22]=4[C:21]([CH3:36])([CH3:35])[O:20][CH:19]3[CH3:37])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:38](=O)([O-])[O-].[K+].[K+].IC.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[C:33]([C:30]1[N:29]([CH3:38])[C:28]([C:26]2[CH:25]=[CH:24][C:23]3[N:18]([C:16]([O:15][CH2:14][CH:12]4[C:13]5[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=5[C:6]5[C:11]4=[CH:10][CH:9]=[CH:8][CH:7]=5)=[O:17])[CH:19]([CH3:37])[O:20][C:21]([CH3:36])([CH3:35])[C:22]=3[CH:27]=2)=[CH:32][CH:31]=1)#[N:34]
Reactant: O=C([O-])[O-]
Reactant: CC1OC(C)(C)c2cc(-c3ccc(C#N)[nH]3)ccc2N1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1OC(C)(C)c2cc(-c3ccc(C#N)n3C)ccc2N1C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
A mixture of 9H-fluoren-9-ylmethyl-6-[5-cyano-1H-pyrrol-2-yl]-2,4,4-trimethyl-2H-3,1-benzoxazine-1(4H)-carboxylate (0.4 g, 0.8 mmol) and potassium carbonate (1.5 g) in anhydrous DMF was treated at ambient temperature under a blanket of nitrogen with iodomethane (1.5 mL, excess). The mixture was stirred for 30 minutes. A saturated ammonium sulfate solution (50 mL) and ethyl acetate (50 mL) was added. The organic layer was separated and aqueous layer was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried (MgSO4), evaporated to yield the title compound as a white solid (0.35 g, 87%): mp 63-64° C.; 1H-NMR (DMSO-d6) δ 7.90 (m, 2H), 7.62 (d, 1H, J=7.7 Hz), 7.58 (d, 1H, J=7.7 Hz), 7.40 (m, 2H), 7.29-7.32 (m, 3H), 7.14 (dd, 1H, J=8.1, 1.9 Hz), 7.01-7.04 (m, 2H), 6.33 (d, 1H,J=4.3 Hz), 5.31 (q, 1H, J=5.8 Hz), 4.88 (dd, 1H, J=10.8, 5.0 Hz), 4.65 (dd, 1H, J=10.8, 4.6 Hz), 4.34 (t, 1H, J=4.6 Hz), 3.71 (s, 3H), 1.52 (s, 3H), 1.21 (s, 3H), 1.06 (d, 3H, J=5.4 Hz); MS (ESI) m/z 504 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH:9](O)[CH3:10])[CH:6]=[CH:5][CH:4]=1.[OH:12][C:13]1[CH:33]=[CH:32][C:16]2[CH2:17][C@@H:18]([CH2:28][C:29]([O-:31])=[O:30])[C:19](=[O:27])[N:20]([CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:21][C:15]=2[CH:14]=1.O[C:35]1C=CC2C[C@H](CC([O-])=O)C(=O)N(CC(F)(F)F)CC=2C=1>>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][O:12][C:13]2[CH:33]=[CH:32][C:16]3[CH2:17][C@@H:18]([CH2:28][C:29]([O:31][CH3:35])=[O:30])[C:19](=[O:27])[N:20]([CH2:22][C:23]([F:26])([F:24])[F:25])[CH2:21][C:15]=3[CH:14]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CNc1cccc(C(C)O)n1
Reactant: O=C([O-])C[C@H]1Cc2ccc(O)cc2CN(CC(F)(F)F)C1=O
Reactant: O=C([O-])C[C@@H]1Cc2ccc(O)cc2CN(CC(F)(F)F)C1=O
Product: CNc1cccc(CCOc2ccc3c(c2)CN(CC(F)(F)F)C(=O)[C@H](CC(=O)OC)C3)n1

Procedure:
According to the method of Example 37(a), except substituting 6-(methylamino)-2-pyridylethanol for the 2-[(3-hydroxy-1H-propyl)amino]pyridine-N-oxide, and substituting (S)-8-hydroxy-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate for the (R)-8-hydroxy-3-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate, the title compound was prepared as a colorless oil: MS (ES) m/e 466.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[N:25][C:26]=1[N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[C:5]([CH3:19])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[N:7]2.Cl[C:37]1[CH:42]=[C:41]([CH3:43])[N:40]=[C:39]([NH2:44])[N:38]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>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.O>[NH2:44][C:39]1[N:38]=[C:37]([C:23]2[CH:22]=[C:21]([NH:20][C:4]3[C:3]4[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=4[F:1])[N:7]=[C:6]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=4)[C:5]=3[CH3:19])[C:26]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[N:25][CH:24]=2)[CH:42]=[C:41]([CH3:43])[N:40]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(B(O)O)cnc1N1CCOCC1
Reactant: Cc1cc(Cl)nc(N)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2cnc(N3CCOCC3)c(Nc3c(C)c(-c4ccccn4)nc4cc(F)cc(F)c34)c2)nc(N)n1
Temperature: 120 °C

Procedure:
A solution of 5-(5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ylamino)-6-morpholinopyridin-3-ylboronic acid (0.026 mmol, described herein), 4-chloro-6-methylpyrimidin-2-amine (3.7 mg, 0.026 mmol), sodium carbonate (8.18 mg, 0.077 mmol), dichlorobis(triphenylphosphine)palladium(ii) (1.8 mg, 2.57 μmol), 1,4-dioxane (560 μL) and water (140 μL) heated in a microwave at 120° C. for 60 min. The reaction was then cooled to rt and partitioned between EtOAc and water. The organic layer was dried (magnesium sulfate) and concentrated, and chromatography afforded N-(5-(2-amino-6-methyl-4-pyrimidinyl)-2-(4-morpholinyl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.72-8.81 (1H, m), 8.52-8.61 (1H, m), 7.85-7.96 (2H, m), 7.61-7.71 (1H, m), 7.52-7.61 (1H, m), 7.47-7.52 (1H, m), 7.41 (1H, m), 7.03 (1H, m), 6.84-6.93 (1H, m), 5.22 (2H, br. s.), 3.94 (4H, br. s.), 3.45-3.73 (2H, m), 3.00-3.40 (2H, br. s.), 2.33-2.52 (3H, m), 2.15-2.29 (3H, m). Mass Spectrum (ESI) m/e=541.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:25])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1SC(C)=NN=1)=[O:17])(=[O:10])=[O:9].[CH3:26][O:27][C:28]1[CH:34]=[CH:33][C:31](N)=[C:30](C)[CH:29]=1>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH3:25])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:18][C:19]1[CH:33]=[CH:34][C:28]([O:27][CH3:26])=[CH:29][C:30]=1[CH3:31])=[O:17])(=[O:9])=[O:10]
Reactant: COc1ccc(N)c(C)c1
Reactant: Cc1nnc(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)s1
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)c2sccc2S(=O)(=O)Nc2onc(C)c2Cl)c(C)c1

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxy-2-methylphenyl)aminoarbonyl]thiophene-3-sulfonamide was prepared by the method set forth for N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-methyl-1,3,4-thiadiazol-5-yl)aminocarbonyl]thiophene-3-sulfonamide (EXAMPLE 150), except that 4-methoxy-2-methylaniline was used instead of 2-amino-5-methyl-1,3,4-thiadiazole and that pyridine was not used. The title compound was obtained via HPLC purification as a dull yellow powder (66% yield, m.p. 58-62° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:23]([O:14][C:12]1[C:11]([C:15]#[N:16])=[CH:10][C:9]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:13]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N#Cc1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)[nH]c1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)nc1OCc1ccccc1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To a solution of 6-(4-chlorophenyl)-5-(phenyl)-2-oxo-1,2-dihydropyridine-3-nitrile (200 mg, 0.65 mmol) from Example 1, Step B in DMF (3 mL) was added benzyl bromide (0.10 mL, 0.85 mmol) and then cesium carbonate (276 mg, 0.85 mmol). The reaction was stirred at 55° C. for 3 h and was then diluted with water and extracted twice with methylene chloride. The organic layers were washed with a portion of brine and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The products were separated by preparative TLC (30% ethyl acetate in hexanes) to give the desired higher Rf O-alkylation title product.