Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][C:15](=[O:24])[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][C:15](=[O:24])[CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CC(=O)CCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CC(=O)CCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-2-one and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=O)=[CH:4][CH:3]=1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][N:31]2[CH2:32][CH2:33][CH:28]([C:24]3[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=3)[CH2:29][CH2:30]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Oc2ccc(Cl)cc2)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc(Oc4ccc(Cl)cc4)c3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3-(4-chlorophenoxy)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 463.2 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][NH2:32])[CH3:28]>CC#N>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:15]2[N:14]=[C:13]([C:9]3[S:8][C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][NH:32][CH2:31][CH2:30][N:29]([CH2:33][CH3:34])[CH2:27][CH3:28])=[N:11][C:10]=3[CH3:12])[CH:18]=[CH:17][N:16]=2)=[CH:21][CH:22]=1
Reactant: Cc1nc(NC(=O)CCBr)sc1-c1ccnc(Nc2ccc(Cl)cc2)n1
Reactant: CCN(CC)CCN
Solvent: CC#N
Product: CCN(CC)CCNCCC(=O)Nc1nc(C)c(-c2ccnc(Nc3ccc(Cl)cc3)n2)s1

Procedure:
By treatment of 3-bromo-N-{5-[2-(4-chloro-phenylamino)-pyrimidin-4-yl]-4-methyl-thiazol-2-yl}-propionamide with N′,N′-diethyl-ethane-1,2-diamine. Anal. RP-HPLC: tR=11.8 min (10-70% MeCN, purity>97%). 1H-NMR (DMSO-D6) δ: 1.20 (t, 6H, J=7.0 Hz, CH3), 1.53 (d, 2H, J=6.5 Hz, CH2), 2.52 (s, 6H, CH3), 3.18 (m, 4H, CH2), 3.28 (m, 4H, CH2), 7.13 (d, 1H, J=5.0 Hz, pyrimidinyl-H), 7.30 (m, 2H, Ph-H), 7.81 (m, 2H, Ph-H), 8.51 (d, 1H, J=5.0 Hz, pyrimidinyl-H), 9.82 (brs, 1H, NH).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]2[C:8](=[O:15])[O:9][C:10]([O:12][CH2:13][CH3:14])=[N:11][C:6]=2[CH:5]=1)([O-])=O.C1CCCCC=1>C1C=CC=CC=1.[Pd]>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]2[C:8](=[O:15])[O:9][C:10]([O:12][CH2:13][CH3:14])=[N:11][C:6]=2[CH:5]=1
Reactant: CCOc1nc2cc([N+](=O)[O-])ccc2c(=O)o1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: c1ccccc1
Product: CCOc1nc2cc(N)ccc2c(=O)o1
Yield: 47 %

Procedure:
7-Nitro-2-ethoxy-4H-3,1-benzoxazin-4-one (1 gm, 4.2 m mol.), 10% Pd-C (1 gm), and cyclohexene (2.5 ml) were refluxed in dry benzene (50 ml) under anhydrous conditions for 3 hours. The hot reaction mixture was filtered immediately through celite and the catalyst on celite was washed with hot benzene (25 ml). The combined filtrate was evaporated to dryness under reduced pressure. The residue was stirred in anhydrous ether (30 ml) to give 410 mg (47%) of the title compound, 7-amino-2-ethoxy-4H-3,1-benzoxazin-4-one, as a pale yellow powder, after filtration. The product can be further purified by chromatography on silica gel column, if necessary (silica gel 60; EtOAc:pet. ether=1:2); m.p. 185°-187° C.; IR (KBr): νmax 3425, 3330 cm-1 (NH2), 1740 cm-1 (C=O), 1640 cm-1 (C=N); N'NMR (CDCl3): δ 1.43 ppm (t, J=7.1 Hz, 3H, OCH2CH3), 4.30 ppm (b, 2H, NH2), 4.75 ppm (q, J=7.1 Hz, 2H, OCH2CH3), 6.5-7.98 ppm (m, 3H, aromatic protons).
Reaction SMILES: [OH:1][C:2]1([C:13]([F:16])([F:15])[F:14])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.[Cl:17][C:18]1[CH:23]=[N:22][CH:21]=[C:20](Cl)[N:19]=1.[H-].[Na+]>CN(C=O)C>[Cl:17][C:18]1[N:19]=[C:20]([O:1][C:2]2([C:13]([F:16])([F:14])[F:15])[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])[CH2:5]2)[CH:21]=[N:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC(O)(C(F)(F)F)C1
Reactant: Clc1cncc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(Oc2cncc(Cl)n2)(C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of tert-butyl 3-hydroxy-3-(trifluoromethyl)azetidine-1-carboxylate (0.37 g, 1.5 mmol) and 2,6-dichloropyrazine (0.23 g, 1.5 mmol) in DMF (5 mL) at 0° C. was added sodium hydride (60% mineral oil dispersion; 0.073 g, 1.8 mmol). The reaction mixture was allowed to warm to room temperature. After 15 minutes, the reaction mixture was partitioned between EtOAc (50 mL) and brine (50 mL). The organic layer was washed with additional brine (50 mL). The first aqueous layer was back-extracted with EtOAc (50 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (EtOAc/Hexanes gradient) to afford tert-butyl 3-[(6-chloropyrazine-2-yl)oxy]-3-(trifluoromethyl)azetidine-1-carboxylate. LRMS calculated for C13H15ClF3N3O3[M+H]+, 354.1; found 298.0 [M-tButyl+H]+. 1H NMR (600 MHz, DMSO-D6) 8.50 (s, 1H); 8.46 (s, 1H); 4.53 (br s, 2H); 4.20 (br d, 2H); 1.37 (s, 9H).
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH:19]=[O:20])[CH:17]=[CH:18][C:4]1=2)[CH3:2].CC(=CC)C.P([O-])(O)(O)=[O:27].[Na+].Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([C:19]([OH:27])=[O:20])[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C=O)ccc21
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a t-butanol (20 ml) and H2O (5 ml) solution of 1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbaldehyde (2.25 g) and 2-methyl-2-butene(3.25 ml) were added sodium dihydrogenphosphate (0.92 g) and sodium chlorite (2.081 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The organic layer was dried with sodium sulfate, and was condensed under reduced pressure to give the title compound (0.98 g) as a white powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.Cl[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1N1CCCCC1
Reaction time: 18.5 h
Yield: 96.4 %

Procedure:
Piperidine (660 μl, 6.66 mmol, commercially available product) was added at room temperature to an N,N-dimethylformamide (DMF; 1 ml) solution of 1,4-dichloro-2-nitrobenzene (390 mg, 2.03 mmol, commercially available product). The resulting mixture was stirred for 18.5 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 g, hexane/ethyl acetate=10/1). Thus, 1-(4-chloro-2-nitrophenyl)piperidine (471 mg, 96.4%) was yielded as an orange-colored oily material.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][N:4]=1)#[N:2].[CH3:13][N:14]([CH:16]=O)[CH3:15]>>[C:1]([C:3]1[CH:8]=[C:7]([CH:9]=[CH:13][N:14]([CH3:16])[CH3:15])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][N:4]=1)#[N:2]
Reactant: CN(C)C=O
Reactant: Cc1cc(C#N)ncc1[N+](=O)[O-]
Product: CN(C)C=Cc1cc(C#N)ncc1[N+](=O)[O-]

Procedure:
A stirred solution of 2-cyano-4-methyl-5-nitropyridine (2.48 g, 15.2 mmol) in DMF (10 mL) and DMF-dimethylacetal (2.7 mL, 20 mmol) was heated to 90° C. for two h. The solution was cooled and evaporated in vacuo to give the title compound as a deep red solid:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[NH2:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:26](Cl)(Cl)=[O:27]>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:26](=[O:27])[NH:11][C:10]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: NC(=NNc1ccc(Br)cc1)c1c(F)cccc1Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(Br)cc1
Temperature: 2.5 °C
Reaction time: 2.5 h

Procedure:
To a cold solution of N′-(4-bromophenyl)-2-chloro-6-fluorobenzenecarbo hydrazonamide (0.050 g, 0.146 mmol) in CHCl3 was added pyridine (0.5 mL) and phosgene (1.0 mL) at 0-5° C. The reaction mass was stirred at 0-5° C. for 2-3 h. The reaction mass was quenched in water, neutralized with dilute acetic acid and extracted with DCM. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained crude product was purified with column chromatography on silica gel eluting with 1.0% MeOH:DCM to afford 0.020 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.50 (t, J=8.7 Hz, 1H), 7.56-7.71 (m, 4H), 7.89 (d, J=9.3 Hz, 2H), 12.69 (s, 1H). MS (m/z): 368.15 (M)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([C:15]1[C:16]([CH2:47][OH:48])=[C:17]([C:21]3[CH:22]=[C:23]([NH:29][C:30]4[N:35]=[CH:34][C:33]([CH:36]5[CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37]5)=[CH:32][CH:31]=4)[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=3)[CH:18]=[CH:19][CH:20]=1)[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[NH:38]1[CH2:37][CH:36]([C:33]2[CH:32]=[CH:31][C:30]([NH:29][C:23]3[C:24](=[O:28])[N:25]([CH3:27])[CH:26]=[C:21]([C:17]4[C:16]([CH2:47][OH:48])=[C:15]([N:9]5[CH2:8][C:7]6[C:11](=[CH:12][CH:13]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH:6]=6)[C:10]5=[O:14])[CH:20]=[CH:19][CH:18]=4)[CH:22]=3)=[N:35][CH:34]=2)[CH2:39]1
Reactant: Cn1cc(-c2cccc(N3Cc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2ccc(C3CN(C(=O)OC(C)(C)C)C3)cn2)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2cccc(N3Cc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2ccc(C3CNC3)cn2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.9 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with 117e (495 mg, 0.761 mmol), methylene chloride (3 mL) and trifluoroacetic acid (3 mL), and the mixture was stirred at room temperature for 3 h. After this time, the reaction mixture was concentrated, and the resulting residue was partitioned between 10% aqueous potassium carbonate (10 mL) and methylene chloride (20 mL). The layers were separated, and the aqueous phase was extracted with methylene chloride (20 mL). The organic extracts were combined, dried over sodium sulfate and filtered, and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography to afford a 25% yield (104 mg) of 117 as a white solid: mp 185-186° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.54 (s, 1H), 8.10 (s, 1H), 7.71 (d, 2H, J=8.5 Hz), 7.66 (d, 1H, J=8.5 Hz), 7.61 (d, 1H, J=8.0 Hz), 7.49 (t, 1H, J=8.0 Hz), 7.44 (d, 1H, J=6.5 Hz), 7.37 (m, 2H), 7.28 (d, 1H, J=8.5 Hz), 4.94 (s, 2H), 4.88 (t, 1H, J=4.5 Hz), 4.34 (d, 2H, J=4.5 Hz), 3.71 (m, 3H), 3.59 (s, 3H), 3.54 (m, 2H), 1.33 (s, 9H); MS (ESI+) m/z 550.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](S(C)(=O)=O)[N:18]=3)=[C:15]3[N:10]([CH2:11][O:12][CH2:13][CH2:14]3)[N:9]=2)=[CH:4][CH:3]=1.[CH:27]([NH2:30])([CH3:29])[CH3:28]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:30][CH:27]([CH3:29])[CH3:28])[N:18]=3)=[C:15]3[N:10]([CH2:11][O:12][CH2:13][CH2:14]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: CS(=O)(=O)c1nccc(-c2c(-c3ccc(F)cc3)nn3c2CCOC3)n1
Solvent: ClC(Cl)Cl
Product: CC(C)Nc1nccc(-c2c(-c3ccc(F)cc3)nn3c2CCOC3)n1

Procedure:
A solution of 2-(4-fluorophenyl)-4,5-dihydro-3-[2-(methylsulfonyl)-4-pyrimidinyl]-7H-pyrazolo[1,5-c][1,3]oxazine (i.e. the product of Step E) (0.15 g, 0.4 mmol) and isopropylamine (0.95 g, 16 mmol) in 2.5 mL of chloroform in a sealed tube was heated in a microwave reactor for 1 h at 120° C. The reaction mixture was then concentrated under reduced pressure and purified by medium pressure liquid chromatography using 0-100% ethyl acetate in hexanes as eluant to give 100 mg of the title product, a compound of the present invention, as a white solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[C:21]([CH2:33][CH3:34])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH2:33]([C:21]1[CH:20]=[C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]4)[C:17]=23)[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH3:34]
Reactant: CN1CCNCC1
Reactant: CCc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccn1
Product: CCc1cc(Nc2ncnc3[nH]nc(OCCN4CCN(C)CC4)c23)ccc1OCc1ccccn1
Yield: 44 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[3-ethyl-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate (prepared as described in Example 19) and N-methylpiperazine to give the title compound in 44% yield; NMR Spectrum: 1.20 (t, 3H), 2.10 (s, 3H), 2.20-2.35 (m, 4H), 2.40-2.55 (m, 4H), 2.65 (q, 2H), 2.77 (t, 2H), 4.40 (t, 2H), 5.20 (s, 2H), 7.01 (d, 1H), 7.34-7.40 (m, 2H), 7.48-7.54 (m, 2H), 7.85 (td, 1H), 8.23 (s, 1H), 8.26 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 489 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.Cl.[NH2:13][C@@H:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16].CCN(C(C)C)C(C)C>C(#N)C>[C:8]([C:6]1[N:7]=[C:2]([Cl:1])[N:3]=[C:4]([NH:13][C@@H:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16])[CH:5]=1)(=[O:9])[NH2:10]
Reactant: COC(=O)[C@H](C)N
Reactant: NC(=O)c1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](C)Nc1cc(C(N)=O)nc(Cl)n1
Temperature: 50 °C
Yield: 79.4 %

Procedure:
To a mixture of 2,6-dichloropyrimidine-4-carboxamide (4.800 g, 25.00 mmol) in acetonitrile (100 mL) was added (S)-methyl 2-aminopropanoate hydrochloride (3.565 g, 25.54 mmol) and iPr2NEt (9.60 mL, 55.11 mmol). The mixture was heated at 50° C. overnight then concentrated in vacuo. The residue was chromatographed over silica gel with 20-60% acetone in hexanes. Two isomers were obtained from the chromatography. The first isomer to elute was (S)-methyl 2-((6-carbamoyl-2-chloropyrimidin-4-yl)amino)propanoate (A) and the second to elute was (S)-methyl 2-((4-carbamoyl-6-chloropyrimidin-2-yl)amino)propanoate (B). Separately, the appropriate product fractions were evaporated in vacuo to give (S)-methyl 2-((6-carbamoyl-2-chloropyrimidin-4-yl)amino)propanoate (A) as a pale tan powder (5.133 g, 19.84 mmol, 79% yield). LC/MS: m/z=259.2 [M+H]+ and (S)-methyl 2-((4-carbamoyl-6-chloropyrimidin-2-yl)amino)propanoate (B) as a tan powder (0.652 g, 2.52 mmol, 10% yield). LC/MS: m/z=259.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[C:25](#N)C.O>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(COc2ccnn2-c2cc(C(=O)O)ccn2)cc1F
Reactant: CC#N
Solvent: O
Product: COC(=O)c1ccnc(-n2nccc2OCc2ccc(C)c(F)c2)c1

Procedure:
The title compound was prepared from 2-[5-[(3-fluoro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid (EXAMPLE 93) according to the procedure for the preparation of Example 62. 1H NMR (400 MHz, CDCl3): δ 2.28 (3H, s), 3.97 (3H, s), 5.21 (2H, s), 5.75 (1H, s), 7.09-7.21 (3H, m), 7.60 (1H, s), 7.79 (1H, d, J=4.8 Hz), 8.35 (1H, s), 8.73 (1H, s). LCMS (mobile phase: 20%-95% Acetonitrile-Water-0.1% NH4OH): purity is >95%, Rt=3.936 min. [M+H] Calc'd for C18H16FN3O3, 342. Found, 342.
Reaction SMILES: CC(C)C([O:5][C@@H:6]1[C@@H:10]([CH2:11][O:12]C(=O)C(C)C)[O:9][C@@H:8]([N:18]2[C:22]3[N:23]=[C:24]([NH:29]C=O)[N:25]=[C:26]([O:27]C)[C:21]=3[C:20]([Cl:32])=[C:19]2[Cl:33])[CH2:7]1)=O.CC(O)=O>[OH-].[Na+]>[NH2:29][C:24]1[NH:25][C:26](=[O:27])[C:21]2[C:20]([Cl:32])=[C:19]([Cl:33])[N:18]([C@@H:8]3[O:9][C@H:10]([CH2:11][OH:12])[C@@H:6]([OH:5])[CH2:7]3)[C:22]=2[N:23]=1
Reactant: COc1nc(NC=O)nc2c1c(Cl)c(Cl)n2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1nc2c(c(Cl)c(Cl)n2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Yield: 95.5 %

Procedure:
A suspension of compound (49) (200 mg, 0.4 mmol) in 2N aq. NaOH (8 ml) is boiled under reflux for 3 h. After the solution has been neutralized with conc. AcOH, the reaction product is filtered, washed with water and dried. Colorless crystals (128 mg, 96%) are obtained after crystallizing from CH3CN. 1H-NMR ([D6 ] DMSO): δ=2.22 (m, Hα --C(2')), 2.92 (m, Hβ --C(2')), 3.52 (m, H--C(5')), 3.72 (m, H--C(4')), 4.33 (m, H--C(3')), 4.81 (t, 5'-OH), 5.22 (d, 3'-OH), 6.35 (dd, H--C(1')), 6.46 (br., NH2), 10.75 (s,NH).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:20]=1[CH2:21]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][CH2:21][C:20]1[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:19]=1[Cl:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1=NC(=O)CN1C(=O)OCc1ccccc1
Reactant: Fc1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CN(C(=O)OCc2ccccc2)C(NCc2ccc(F)cc2Cl)=N1
Temperature: 25 °C
Yield: 48.6 %

Procedure:
A suspension of 2-amino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (93.2 mg, 0.40 mmol), 2-chloro-4-fluoro-benzylbromide (89.2 mg, 0.40 mmol) and K2CO3 (83.01 mg, 0.60 mmol) in acetonitrile (10 mL) was heated to reflux under argon for 1 hr. Cooled to r.t. and the reaction mixture was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated to give a residue which was triturated with EtOAc and filtered to give 2-(2-chloro-4-fluoro-benzylamino)-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester as a white solid (73.0 mg, 48.7%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C:13]#[N:14])([O:9][CH2:10][CH2:11][OH:12])[CH2:7][Cl:8])(=[O:3])[CH3:2].[NH2:15][OH:16]>C(O)C>[C:1]([O:4][CH2:5][C:6]([CH2:7][Cl:8])([O:9][CH2:10][CH2:11][OH:12])[C:13]([NH:15][OH:16])=[NH:14])(=[O:3])[CH3:2]
Reactant: NO
Reactant: CC(=O)OCC(C#N)(CCl)OCCO
Solvent: CCO
Product: CC(=O)OCC(CCl)(OCCO)C(=N)NO
Temperature: 65 °C

Procedure:
A solution of 3-chloro-2-cyano-2-(2-hydroxyethoxy)propyl acetate (9.40 g, 42.4 mmol) in ethanol (150 mL) was treated with 50% aqueous hydroxylamine solution (2.94 g, 44.5 mmol, Aldrich) and the reaction was heated (65° C.) for 1.5 hrs. The solution was cooled to room temperature and the product was used as-is in the subsequent reaction: LC/MS m/z 255.20 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[Cl:11][C:12]1[N:13]=[C:14](Cl)[C:15]2[C:20]([CH3:21])=[C:19]([CH3:22])[S:18][C:16]=2[N:17]=1>>[Cl:11][C:12]1[N:13]=[C:14]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:15]2[C:20]([CH3:21])=[C:19]([CH3:22])[S:18][C:16]=2[N:17]=1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1C
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Cc1sc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c2c1C

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 2,4-dichloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-5,6-dimethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine
Reaction SMILES: [Br:1][CH2:2][CH2:3][OH:4].[CH3:5][C:6]([Si:9](Cl)([CH3:11])[CH3:10])([CH3:8])[CH3:7]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:1][CH2:2][CH2:3][O:4][Si:9]([C:6]([CH3:8])([CH3:7])[CH3:5])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCBr
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCBr
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 2-bromo-ethanol (12.5 g, 0.1 mol) and TEA (11.2 g, 0.11 mol) in CH2Cl2 (40 mL), TBSCl (15.8 g, 0.105 mol) and DMAP (0.122 g, 1 mmol) were added. The reaction mixture was stirred at room temperature for 12 h, washed (10 mL 2M HCl, 10 mL H2O), dried (Na2SO4) and concentrated to give the desired product as colorless oil. 1H NMR (CDCl3): δ 3.88 (m, 2H), 3.39 (m, 2H), 0.89 (s, 9H), 0.08 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16](OC)=[O:17])[CH:15]=[C:10]3[CH:9]=[N:8]2)=[CH:4][CH:3]=1.[NH2:22][OH:23].[OH-].[Na+].Cl>CO.O>[F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([NH:22][OH:23])=[O:17])[CH:15]=[C:10]3[CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: COC(=O)c1cc2cnn(Cc3ccc(F)cc3)c2cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(NO)c1cc2cnn(Cc3ccc(F)cc3)c2cn1
Reaction time: 2 h
Yield: 52 %

Procedure:
To a stirring solution of methyl 1-(4-fluorobenzyl)-1H-pyrazolo[3,4-c]pyridine-5-carboxylate (96 mg, 0.33 mmol) in methanol (4 mL) was added a 50% v/v solution of hydroxylamine in water (2 mL) followed by 10% sodium hydroxide solution in water (1 mL). The mixture was stirred for 2 hours, then 10% hydrochloric acid solution in water (1 mL) was added until a neutral pH was obtained, and the mixture was concentrated under reduced pressure. Methanol was added and the mixture was purified by reverse phase preparative HPLC (Dionex, 0-40% acetonitrile:water v/v, 40 minutes) to provide a white solid (50 mg, 52% yield). 1H NMR (DMSO-d6): δ ppm 9.22 (s, 1H), 8.39 (s, 1H), 8.37 (s, 1H), 7.37 (m, 2H), 7.15 (m, 2H), 5.83 (s, 2H). Anal. HPLC: >95% (@ 254, 222 nM). HRMS calcd for C14H11FN4O2 (M+H) 287.0939, found 287.0936.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:23])[CH:15]=[CH:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:23])[CH:15]=[C:16]([C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1)[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[CH3:12]
Reactant: Brc1ccc2cc[nH]c2c1
Reactant: CCOC(=O)C=Cc1cccnc1
Product: CCOC(=O)C=C(c1cccnc1)c1ccc2cc[nH]c2c1

Procedure:
3-(1H-Indol-6-yl)-3-pyridin-3-yl-acrylic acid ethyl ester CLVII was prepared from 6-bromo-1H-indole and 3-pyridin-3-yl-acrylic acid ethyl ester using the procedure described above for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl esterLVIII (Example 14).