Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:39])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](O)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].Cl.[CH3:41][O:42][NH:43][CH3:44].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:39])[N:18]([C@H:28]3[CH2:29][CH2:30][C@H:31]([O:34][CH2:35][C:36]([N:43]([O:42][CH3:41])[CH3:44])=[O:37])[CH2:32][CH2:33]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2]
Reactant: CNOC
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)O)CC2)c2ncnn12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of [(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetic acid (0.9 g), N-methoxymethanamine hydrochloride (0.25 g), 1-hydroxybenzotriazole (0.39 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.49 g), triethylamine (0.36 mL) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.75 g, 77%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C)C=O>[N:18]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(c1cc(F)ccc1CBr)N1CCOCC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc(F)cc1C(=O)N1CCOCC1
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of intermediate 42, (2-(bromomethyl)-5-fluorophenyl)(morpholino)methanone, (1.0 g, 3.32 mmol) in dimethylformamide (10 mL) was added sodium azide (230 mg, 3.5 mmol) and the mixture stirred under a nitrogen atmosphere for 1 h. The solvent was evaporated in vacuo, and the residue dissolved in CH2Cl2, then washed with water. The organic phase was dried (Na2SO4), filtered, concentrated, and the residue purified by column chromatography (SiO2, CH2Cl2) to provide 770 mg (Yield 88%) of the title compound as an oil: 1H NMR (300 MHz, CDCl3) δ ppm: 3.27 (2H, s) 3.51–3.65 (2H, m) 3.66–3.97 (4H, m) 4.38 (2H, brs) 6.92 (1H, dd, J=8.2, 2.7 Hz) 7.07 (1H, dt, J=8.5, 3 Hz) 7.34 (1H, dd, J=8.4, 5.5 Hz); LC/MS m/z 265 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=O.C1C=CC2N(O)N=[N:28]C=2C=1.CN1CCOCC1.C(Cl)CCl.[OH-].[NH4+]>C1COCC1>[C:18]([O:17][C:15](=[O:16])[NH:14][CH2:13][C:5]1([C:3](=[O:2])[NH2:28])[C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: On1nnc2ccccc21
Reactant: COC(=O)C1(CNC(=O)OC(C)(C)C)CC12CCCCC2
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NCC1(C(N)=O)CC12CCCCC2
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino-methyl)-spiro[2.5]octane-1-carboxylic acid methyl ester (17.9 g, 63.2 mmol) in THF (700 mL) was added HOBT (9.00 g, 66.4 mmol), 4-methylmorpholine (7.3 mL, 66.4 mmol) followed by EDC (13.9 g, 72.7 mmol). The solution was stirred for 2 hours and then concentrated ammonium hydroxide (8.5 mL, 126 mmol) was added. The mixture was stirred for 18 hours and then the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and half saturated potassium hydrogen sulfate. An emulsion occurred but the layers were separable. The organic layer was washed with half saturated potassium hydrogen sulfate (2 times) and brine. The organic layer was filtered to remove the emulsified solid. The organic layer was dried over sodium sulfate and filtered. Hexane was added to the filtrate to induce crystallization. The precipitate was isolated by vacuum filtration, washed with hexane and dried in a vacuum oven to give 16.2 g (91%) of (1-carbamoyl-spiro[2.5]oct-1-ylmethyl)-carbamic acid tert-butyl ester as a white solid: 1H NMR (300 MHz, CDCl3) δ 0.65 (d, J=5.0 Hz, 1H), 1.17 (d, J=5.0 Hz, 1H), 1.43(s, 9H), 1.4-1.5 (m, 4H), 1.7-1.7 (m, 6H), 3.37 (dd, J=6.0, 14.0 Hz, 1H), 3.60 (dd, J=6.0, 14.0 Hz, 1H), 5.0 (s, 1H), 5.38 (s, 1H), 6.1 (s, 1H); MS (APCI) m/z 283 [M+H]+.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH2:10][C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=2)[N:9]=1.[Cl-:22].[NH4+:23]>>[ClH:22].[C:16]1([C:13]2[CH:12]=[C:11]([CH2:10][CH:8]3[NH:9][C:3](=[NH:23])[CH2:4][CH2:5][CH2:6][CH2:7]3)[O:15][N:14]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: COC1=NC(Cc2cc(-c3ccccc3)no2)CCCC1
Product: Cl
Product: N=C1CCCCC(Cc2cc(-c3ccccc3)no2)N1

Procedure:
The product of Example 130 is reacted with ammonium chloride by the method of example 5 to generate the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[CH3:37][O:38][C:39](=[O:42])[CH2:40][NH2:41]>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([NH:41][CH2:40][C:39]([O:38][CH3:37])=[O:42])=[O:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)CNC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 80 °C
Yield: 34.7 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (1.18 g, 3.00 mmol) and triethylamine (1.51 g, 15.00 mmol) in ethanol (30 ml) was treated with glycine methyl ester hydrochloride (1.88 g, 15.00 mmol) and the resulting mixture was heated at 80° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled and the solvent removed under reduced pressure. The residue was partitioned between water and ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of hexane:ethyl acetate (90:10) gradually changing to hexane:ethyl acetate (50:50) to afford the title compound (456 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[CH:12][N:13]=[C:7]2[CH:6]=1)=O.[BH4-].[Na+]>CO>[NH3:8].[N:13]1[CH:12]=[CH:11][N:8]2[CH:9]=[CH:10][C:5]([CH2:3][OH:2])=[CH:6][C:7]=12
Reactant: COC(=O)c1ccn2ccnc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N
Product: OCc1ccn2ccnc2c1
Temperature: 25 °C
Yield: 193.6 %

Procedure:
To a cooled (0° C.) solution of imidazo[1,2-α]pyridine-7-carboxylic acid methyl ester (2.15 g, 12.2 mmol) in methanol (50 ml) was added sodium borohydride (4.64 g, 12.2 mmol) in portions over 15 min. The mixture was heated under reflux for 3 h, cooled to ambient temperature and evaporated to dryness. The residue was dissolved in dichloromethane:methanol (300 ml of a 1:1 mixture) and pre-adsorbed onto silica. Purification by silica gel chromatography eluting with dichloromethane/methanol/conc. ammonia (95:5:0.5) gave imidazo[1,2-α]pyridin-7-ylmethanol (1.75 g, 77%) as a colourless oil. 1H NMR (400 MHz, CDCl3) δH 4.71 (2H, s), 6.79 (1H, dd, J 7 and 1), 7.37 (1H, s), 7.52 (1H, s), 7.56 (1H, d, J 1), 8.05 (1H, d, J 7).
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl-].[C:15]([CH2:18][CH2:19][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:17])=[O:16].CC(C)([O-])C.[K+]>O1CCCC1>[N:1]1([C:6]2[CH:13]=[CH:12][C:9](/[CH:10]=[CH:19]/[CH2:18][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)C/C=C/c1ccc(-n2ccnc2)cc1
Temperature: -50 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
5.45 g of 4-(1H-imidazol-1-yl)benzaldehyde and 12.93 g of β-carboxyethyltriphenylphosphonium chloride were suspended in 70 ml of tetrahydrofuran. The obtained suspension was cooled to -50° C. and vigorously stirred. 30 ml of a solution of 7.83 g of potassium t-butoxide in tetrahydrofuran was gradually added dropwise to the resulting suspension. The temperature of the obtained mixture was gradually raised to 0° C. After one hour, ice-water was added to the mixture. The obtained mixture was washed with ether. The pH of the aqueous layer was adjusted with concentrated hydrochloric acid to about 4 to precipitate a solid. This solid was recovered by filtration and washed with water and methanol to obtain 5.44 g of the title compound as a pale yellow powder (yield: 75%).
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[O:18]([C:19]1[CH:20]=[CH:21][C:22]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: O=C(c1ccccc1)C(O)c1ccc(Oc2ccccc2)cc1

Procedure:
Phenyglyoxal monohydrate (200 mg, 1.31 mM) and diphenylether (0.4 ml, 2.62 mM) were dissolved in dichloroethane (3 ml), titanium tetrachloride (0.07 ml, 0.66 mM) was added, and reacted at room temperature for 1 hour. Using the same procedure as in Example 1, 4'-phenoxybenzoin was obtained as crystal (331.2 mg, 80.7% yield).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:36])=[C:5]([C:27]([O:34]C)=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:31][O:30][C:29]1[C:3](=[O:2])[C:4]([CH3:36])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:11]([CH:20]=2)[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[O:13])[C:27](=[O:34])[C:28]=1[O:32][CH3:33]
Reactant: COC(=O)COc1ccc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)cc1C(=O)N1CCOCC1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC(=O)COc1ccc(CC2=C(C)C(=O)C(OC)=C(OC)C2=O)cc1C(=O)N1CCOCC1
Yield: 79.7 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(methoxycarbonylmethyloxy)benzoyl]morpholine (0.240 g, 0.478 mmol) was dissolved in a mixed solution of acetonitrile (12 ml) and water (4 ml) and after adding thereto CAN (0.655 g, 1.20 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:3) to obtain the titled compound (0.180 g, 0.381 mmol, 80%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]=[C:11]([CH3:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=2)[CH:2]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36])(=[O:31])=[O:30]>CN(C=O)C>[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH:36][C:14]([C:10]1[C:11]([CH3:13])=[N:12][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:8][CH:9]=1)=[O:16])(=[O:30])=[O:31]
Reactant: Cc1nc(-c2cccnc2)ncc1C(=O)O
Reactant: CNS(=O)(=O)c1cccc(CN)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1cccc(CNC(=O)c2cnc(-c3cccnc3)nc2C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A mixture of 2-(3-pyridyl)-4-methylpyrimidine-5-carboxylic acid (215 mg, 1 mmol, prepared according to the general procedure described in Example 42, steps 1 and 2) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (380 mg, 1 mmol) in dry DMF (12 mL) is treated with of diisopropylethylamine (0.18 mL) and stirred at room temperature for 30 min. 3-Methylsulfamoylbenzylamine hydrochloride (355 mg, 1.5 mmol) is added and the mixture is stirred at room temperature for 24 hours. The solvent is removed and the residue partitioned between EtOAc and saturated NaHCO3. The organic phase is separated, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by column chromatography eluting with 2% MeOH in EtOAc to afford 2-(3-pyridyl)-4-methyl-pyrimidine-5-carboxylic-acid-3-methylsulfamoyl-benzylamide (180 mg, 45%) as a solid. MS: 398 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.43 (s, 3H), 2.65 (s, 3H), 4.60 (d, 2H), 7.57-7.71 (m, 4H), 7.79 (s, 1H), 8.68-8.72 (d, 1H), 8.72-8.78 (d, 1H), 8.93 (s, 1H), 9.34 (t, 1H), 9.53 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][C:4]([OH:24])=[O:3])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccccn3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccccn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.6 %

Procedure:
To a solution of [1-hydroxy-4-methyl-6-(pyridin-2-yloxy)-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (75 mg, 0.23 mmol) in THF (4 mL) was added LiOH (20 mg, 0.48 mmol) in water (2 mL). The mixture was stirred at room temperature for 5 h and acidified by 1N HCl to pH 3. The mixture was concentrated and purified by HPLC affording the title compound (52 mg, 75%) as a white solid. 1H NMR (DMSO) δ 9.26 (m, 1H), 8.19 (s, 1H), 7.89 (m, 1H), 7.24 (s, 1H), 7.17 (m, 1H), 7.08 (m, 1H), 7.05 (m, 1H), 5.55 (d, 1H), 3.13 (d, 1H), 2.31 (s, 3H), 2.13 (m, 1H). MS found: (M+H)+=300.10.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:16]N1C(=O)CCC1=O>CC#N.CCOC(C)=O>[CH2:9]([O:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([Br:16])[CH:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1ncccc1OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1ncc(Br)cc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
To a stirred solution of 2-amino-3-benzyloxypyridine (42.0 g, 0.21 mol) in CH3CN (600 mL) at 0° C. was added N-bromosuccinimide (37.1 g, 0.21 mol) over 30 minutes. The mixture was stirred for 0.5 hr, after which the reaction was then diluted with EtOAc (900 mL) and partitioned with H2O (900 mL). The organic layer was washed with brine and dried (Na2SO4), filtered and concentrated to dryness under vacuum to yield 3-benzyloxy-5-bromo-pyridin-2-ylamine (31.0 g, 0.11 mol, 53%). 1H NMR (CDCl3, 300 MHz) δ 4.63-4.78 (brs, 2H), 5.04 (s, 2H), 7.07 (d, 1H, J, 1.8 Hz), 7.33-7.42 (m, 5H), 7.73 (d, 1H, J, 1.8 Hz).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:53]([O:60][C:61]([N:63]1[CH2:67][CH:66]([C:68]2[C:76]3[C:71](=[CH:72][C:73]([F:77])=[CH:74][CH:75]=3)[NH:70][CH:69]=2)[CH:65]2[NH:78][CH2:79][CH2:80][CH:64]12)=[O:62])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>CN1C(=O)CCC1.CCOC(C)=O>[CH2:53]([O:60][C:61]([N:63]1[CH2:67][CH:66]([C:68]2[C:76]3[C:71](=[CH:72][C:73]([F:77])=[CH:74][CH:75]=3)[NH:70][CH:69]=2)[CH:65]2[N:78]([C:10](=[O:12])[CH:2]([NH:1][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:3]([O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH3:9])[CH2:79][CH2:80][CH:64]12)=[O:62])[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: O=C(OCc1ccccc1)N1CC(c2c[nH]c3cc(F)ccc23)C2NCCC21
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(OC(C)(C)C)C(NC(=O)OC(C)(C)C)C(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution containing Boc-Thr(tBu)-OH (138 mg, 0.5 mmol) in anhydrous NMP (4 mL) was cooled to 0° C. HATU (190 mg, 0.5 mmol) and DIPEA (111 mg, 0.8 mmol) were added followed by the addition of crude 42 (195 mg, 0.5 mmol) in anhydrous NMP (5 mL). The reaction mixture was slowly warmed to ambient temperature. After 4 h, the reaction mixture was diluted with EtOAc and washed successively with 1M HCl, aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 336 mg of crude 43 as an amber-colored foam which was used without further purification. Mass spectrum, m/z [637.3] (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12](=O)[C:13]([O:15][CH3:16])=[O:14].Cl.[CH3:19][O:20][NH2:21]>CO>[CH3:19][O:20][N:21]=[C:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]=1[OH:1])[C:13]([O:15][CH3:16])=[O:14]
Reactant: CON
Reactant: COC(=O)C(=O)c1ccc2ccccc2c1O
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)OC)c1ccc2ccccc2c1O
Yield: 76.9 %

Procedure:
69 g (0.26 mol) of methyl 1-hydroxy-2-naphthylglyoxylate and 44 g (0.53 mol) of O-methylhydroxylamine hydrochloride in 800 ml of methanol are stirred under reflux for 6 h. The mixture is then concentrated; the residue is taken up in ethyl acetate, and the solution is washed with H2O, dried over sodium sulfate and concentrated again. 52 g (0.20 mol) of methyl 1-hydroxy-2-naphthylglyoxylate O-methyloxime (77% yield) are obtained.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3].Br[C:20]1[S:24][C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][N:32]3[CH:35]=[CH:36][N:37]=[C:31]3[CH:30]=2)=[O:26])=[CH:22][CH:21]=1.BrC1C=CC(N)=CC=1>>[N:37]1[CH:36]=[CH:35][N:32]2[CH:33]=[CH:34][C:29]([CH2:28][NH:27][C:25]([C:23]3[S:24][C:20]([C:9]4[N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[N:6]=[CH:7][CH:8]=4)=[CH:21][CH:22]=3)=[O:26])=[CH:30][C:31]=12
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(Br)s1
Agent: Nc1ccc(Br)cc1
Product: CC(C)Cn1nccc1-c1ccc(C(=O)NCc2ccn3ccnc3c2)s1

Procedure:
The title compound was prepared as described in Example 51A, substituting 1-isobutyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5-bromo-N-(imidazo[1,2-a]pyridin-7-ylmethyl)thiophene-2-carboxamide for 4-bromoaniline. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.24 (t, J=5.9 Hz, 1H), 8.51 (dd, J=7.0, 0.7 Hz, 1H), 7.90 (d, J=0.8 Hz, 1H), 7.87 (d, J=3.9 Hz, 1H), 7.57-7.49 (m, 2H), 7.43 (s, 1H), 7.39 (d, J=3.9 Hz, 1H), 6.87 (dd, J=7.0, 1.6 Hz, 1H), 6.56 (d, J=1.9 Hz, 1H), 4.51 (d, J=5.9 Hz, 2H), 4.08 (d, J=7.4 Hz, 2H), 2.09 (dp, J=13.8, 6.9 Hz, 1H), 0.80 (d, J=6.7 Hz, 6H); MS (ESI(+)) m/e 380 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]([CH3:32])[CH:20]1[CH2:24][CH2:23][N:22]([C:25]2[N:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:31][C:28]1[CH:29]=[N:30][C:25]([N:22]2[CH2:23][CH2:24][CH:20]([N:19]([CH3:32])[CH3:18])[CH2:21]2)=[CH:26][CH:27]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CN(C)C1CCN(c2ccc(N)cn2)C1
Product: CN(C)C1CCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Yield: 71.2 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with 6-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-3-amine (309 mg, 1.5 mmol) to afford the desired product (342 mg, 71%) as a yellow solid: ESI MS m/z 480 [C24H26BrN5O+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:28])[O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17](CC2C=CC=CC=2)[CH2:16][CH2:15]3)=[CH:5][CH:4]=1>C(Cl)(Cl)Cl.CO>[CH3:1][N:2]([CH3:29])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:28])[O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH2:16][CH2:15]3)=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(NC(=O)Oc2ccc3c(c2)CCN3Cc2ccccc2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C)c1ccc(NC(=O)Oc2ccc3c(c2)CCN3)cc1

Procedure:
The title compound was synthesized from 1-benzylindolin-5-yl 4-dimethylaminophenylcarbamate (30 mg, 77 μmol) using the same procedure employed for Example 123 (silica gel column chromatography: chloroform/methanol=99/1 to 90/10). The product was obtained as a white solid (4.0 mg, 17%) having the following characteristics.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)=[O:15])=[CH:11][C:10]([C:30]([CH3:33])([CH3:32])[CH3:31])=[N:9]2)=[CH:4][CH:3]=1.[CH3:34][C:35]1([CH3:42])[CH2:40][C:39](=[O:41])[O:38][C:36]1=[O:37]>C1COCC1.CCOCC>[C:30]([C:10]1[CH:11]=[C:12]([NH:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)=[CH:19][CH:18]=2)=[O:15])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:39](=[O:41])[CH2:40][C:35]([CH3:42])([CH3:34])[C:36]([OH:38])=[O:37])=[CH:3][CH:4]=2)[N:9]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2ccc(N)cc2)n1
Reactant: CC1(C)CC(=O)OC1=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(CC(=O)Nc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1)C(=O)O
Temperature: 60 °C
Yield: 84.6 %

Procedure:
A solution of 1-[2-(4-amino-phenyl)-5-tert-butyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yloxy)-phenyl]-urea (208 mg, 0.47 mmol) and 2,2-dimethylsuccinic anhydride (66 mg, 0.52 mmol, 1.1 eq) in 2 mL THF was stirred at room temperature overnight. HPLC analysis indicated that starting material was remaining. The reaction was then heated at 60° C. for 2 days, at which time HPLC analysis indicated the reaction was complete. The reaction mixture was cooled to room temperature, and the resulting suspension was diluted with Et2O. The solid was isolated by filtration to afford the desired product (227 mg, 85%). 1H-NMR (DMSO-d6) δ 12.06 (s, 1H), 10.06 (s, 1H), 9.09 (s, 1H), 8.40 (d, J=6.0 Hz, 2H), 8.31 (s, 1H), 7.69 (d, J=9.0 Hz, 2H), 7.47 (d, J=9.0 Hz, 2H), 7.39 (d, J=9.0 Hz, 2H), 7.07 (d, J=9.0 Hz, 2H), 6.85 (dd, J=1.5 & 4.7 Hz, 2H), 6.33 (s, 1H), 2.59 (s, 2H), 1.26 (s, 9H), 1.21 (s, 6H); MS LC-MS [M+H]+=571.3, RT=2.49 min.