Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[F:29]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:25]4[CH:26]=[CH:27][C:28]([F:29])=[C:23]([Cl:22])[CH:24]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Product: COc1ccc(-c2nc3cc(-c4ccc(F)c(Cl)c4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 3-chloro-4-fluorophenylboronic acid (150 mg, 0.85 mmol) the subtitle compound was obtained (163 mg, 72%). 1H NMR (CDCl3) δ 8.74(d, 1H), 8.45(dd, 1H), 7.87(d, 1H), 7.64(m, 2H), 7.52(dd, 1H), 7.49–7.44(m, 1H), 7.28–7.21(m, 2H), 4.08(s, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[N:7]=[CH:6][N:5]=1)[CH3:2].[C:19](OC(=O)C)(=[O:21])[CH3:20].[ClH:26]>C(OCC)(=O)C>[ClH:26].[CH2:17]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:19](=[O:21])[CH3:20])[CH:11]=2)[N:7]=[CH:6][N:5]=1)[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CCN(CC)c1cc(-c2cccc(N)c2)ncn1
Agent: Cl
Solvent: CCOC(C)=O
Product: CCN(CC)c1cc(-c2cccc(NC(C)=O)c2)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5.6 g. (0.022 mole) of 4-diethylamino-6-(m-aminophenyl)pyrimidine is slowly added, with cooling, 25 ml. of acetic anhydride. The resulting solution is stirred overnight at room temperature and is then diluted with 500 ml. of ethyl acetate amd treated with sufficient gaseous hydrogen chloride to complete the precipitation of the desired product. The solvent and excess acetic anhydride are removed under reduced pressure and the residue washed from the flask with 20 ml. of 1:1 hexane/ethyl acetate 6.6 g., m.p. 235°-237° C. It proves to be identical to that prepared by the Acid Chloride Method.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH:5]([N:24]=C(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH3:2].C(O)C.[ClH:42]>C1COCC1>[ClH:42].[NH2:24][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]([O:3][CH2:1][CH3:2])=[O:38]
Reactant: CCCCCCCCCCCCCCCCCCC(N=C(c1ccccc1)c1ccccc1)C(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCC(N)C(=O)OCC
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a stirred solution of ethyl-N-(diphenylmethylene)-2-aminoeicosanoate prepared as in Example 28A (104 g, 0.200 mol) in a 1:1 mixture (300 ml) of absolute ethanol and THF was added 0.5N hydrochloric acid (1.0 l) at room temperature over 10 min. The resulting solution was stirred for 30 min. Ethanol and THF were removed in vacuo and the aqueous slurry was extracted with CH2Cl2 (4×1 l). The extracts were combined and dried (MgSO4). The solvent was removed in vacuo and the crude product was recrystallized from hexane to give 74.3 g (95% yield) of colorless needles: mp 91°-4° C.; 1H NMR (CDCl3) δ 0.88 (t, J=6.6 Hz, 3 H), 1.26 (m, 33 H), 1.43 (m, 1 H), 1.56 (m, 1 H), 2.03 (quart, J=7.4 Hz, 2 H), 4.03 (m, 1 H), 4.27 (m, 2 H), 8.84 (br s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:17][C@@H:18]2[C:24](=[O:25])[NH:23][C:22]3[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:21]=3[O:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:16])[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Br[CH2:39][CH:40]1[CH2:42][CH2:41]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH:40]1([CH2:39][N:23]2[C:22]3[CH:26]=[C:27]([O:30][CH3:31])[CH:28]=[CH:29][C:21]=3[O:20][C@H:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:18]([NH:17][C:15](=[O:16])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]3[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=3)[C:24]2=[O:25])[CH2:42][CH2:41]1
Reactant: BrCC1CC1
Reactant: COc1ccc2c(c1)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)[C@@H](c1ccccc1)O2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)N(CC1CC1)C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)[C@@H](c1ccccc1)O2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of N2-[(3,5-difluorophenyl)acetyl]-N1-[(2,3-cis)-7-methoxy-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-L-alaninamide (68) (95 mg, 0.186 mmol) in DMF (1 mL) under nitrogen was added (bromomethyl)cyclopropane (70 mg, 0.518 mmol) and powdered cesium carbonate (170 mg, 0.521 mmol). The mixture was stirred overnight at ambient temperature then diluted with water and extracted with ethyl acetate. The residue obtained from the organic extract was purified by flash chromatography on silica gel eluting with diethyl ether to afford the title compound in a 1:1 mixture with the 2S,3R diastereomer (65 mg, 62%) as a white solid. TLC Rf=0.26 (diethyl ether). 1H NMR (300 MHz, CDCl3) δ0.23 (m, 1H), 0.37-0.65 (m, 3H), 1.07 (d 1.5H, J=7.0 Hz), 1.21 (d, 1.5H, J=7.0 Hz), 3.43 (s, 1H), 3.47 (s, 1H), 3.83 (s, 3H), 4.09 (m, 1H), 4.25 (m, 1H), 5.05 (m, 1H), 5.61 (m, 1H), 5.89 (br d, 1H), 5.99 (br d, 1H), 6.20 (br t, 1H), 6.66-6.85 (m, 5H) 7.19 (d, 1H, 8.3 Hz), 7.30-7.42 (m, 6H). MS APCI, m/z=564 (M+1). LC/MS: 2.77 min.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[F:26][CH:27]([F:33])[CH2:28][NH:29][CH2:30][CH2:31][NH2:32]>>[F:26][CH:27]([F:33])[CH2:28][NH:29][CH2:30][CH2:31][NH:32][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1
Reactant: NCCNCC(F)F
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCNCC(F)F)c2c1

Procedure:
The title compound was prepared in analogy to Example 5-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and N-(2,2-difluoroethyl)ethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 461, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (dd, J=7.83, 1.26 Hz, 1 H), 7.83 (d, J=6.82 Hz, 1 H), 7.60 (td, J=7.45, 1.26 Hz, 2 H), 7.46-7.38 (m, 2 H), 7.28 (dd, J=8.59, 1.77 Hz, 1 H), 6.04 (s, 1 H), 5.13 (s, 2 H), 3.58 (t, J=4.80 Hz, 2 H), 3.46 (t, J=6.19 Hz, 2 H), 3.37 (s, 3 H), 3.10-2.97 (m, 4 H), 2.41 (s, 3 H).
Reaction SMILES: [N:1]1(C(=O)C)[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[N:2]1>C(O)C.[OH-].[Na+]>[NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[N:2]1
Reactant: CC(=O)n1ncc2cnccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1cc2[nH]ncc2cn1
Reaction time: 0.5 h
Yield: 81.5 %

Procedure:
To a solution of 6.44 g of 1-pyrazolo[4,3-c]pyridin-1-yl-ethanone in 120 mL of ethanol, 10 mL of 5N sodium hydroxide aqueous solution was added at room temperature and stirred at this temperature for 30 minutes. After neutralization with 5N hydrochloric acid, the solvent was evaporated, the residue was washed with ethyl acetate, and the solvent of filtrate was evaporated, to afford 3.88 g of the title compound as pale yellow crystals.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]2[C:18]([CH2:21][CH2:22][OH:23])=[CH:19][N:20]=[C:15]2[C@H:14]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:13][CH2:12]1.I[CH3:33]>O1CCCC1>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@H:11]1[CH2:17][N:16]2[C:18]([CH2:21][CH2:22][O:23][CH3:33])=[CH:19][N:20]=[C:15]2[C@H:14]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[CH2:13][CH2:12]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CCO)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCc1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
Sodium hydride (60% dispersion in mineral oil; 4.0 mg, 0.112 mmol) was added to a solution of tert-butyl (6S,9R)-6-(2,3-difluorophenyl)-3-(2-hydroxyethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (19 mg, 0.047 mmol) and iodomethane (3.0 μL, 0.051 mmol) in tetrahydrofuran (0.5 mL) at 0° C., and the mixture was allowed to warm to ambient temperature. After 18 h, additional sodium hydride (2.0 mg, 0.056 mmol) and iodomethane (3.0 μL, 0.051 mmol) were added. After 1 h, the reaction was quenched with water. Saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (2×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (100% dichloromethane→94% dichloromethane/methanol) gave the title compound (6 mg). MS 422.1 (M+1).
Reaction SMILES: [OH-].[Na+:2].C[O:4][C:5](=[O:21])[CH2:6][C:7]1[NH:8][C:9](=[O:20])[C:10]([F:19])=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:12]=1>C1COCC1>[F:19][C:10]1[C:9](=[O:20])[NH:8][C:7]([CH2:6][C:5]([O-:21])=[O:4])=[N:12][C:11]=1[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1.[Na+:2]
Reactant: COC(=O)Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C([O-])Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.43 ml of 2N sodium hydroxide is added to a solution of 116 mg of (5-fluoro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetic acid methyl ester in 1.2 ml of THF. The reaction medium is stirred at ambient temperature for 24 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is oven-dried under vacuum in the presence of P2O5 so as to give 110 mg of sodium (5-fluoro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate, the characteristics of which are the following:
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:17]2[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)=[O:23])[CH2:18]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: COc1ccc(C2(O)CCC(=O)CC2)cc1
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-hydroxy-4-(4-methoxy-phenyl)-cyclohexanone (as prepared in Example 7, Step B) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][NH2:14])=[CH:9][CH:8]=2)[N:6]=1.[C:17]([NH:20][C:21]1[N:26]=[CH:25][C:24]([CH:27]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:28]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:23][CH:22]=1)(=[O:19])[CH3:18].C(N(C(C)C)CC)(C)C>CS(C)=O>[C:44]([Si:41]([CH3:43])([CH3:42])[O:40][C@H:27]([C:24]1[CH:23]=[CH:22][C:21]([NH:20][C:17](=[O:19])[CH3:18])=[N:26][CH:25]=1)[CH2:28][NH:14][CH2:13][CH2:12][O:11][C:10]1[CH:15]=[CH:16][C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][CH:4]=2)=[CH:8][CH:9]=1)([CH3:47])([CH3:46])[CH3:45]
Reactant: Cc1nc(-c2ccc(OCCN)cc2)cs1
Reactant: CC(=O)Nc1ccc(C(COS(=O)(=O)c2ccc(C)cc2)O[Si](C)(C)C(C)(C)C)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc([C@H](CNCCOc2ccc(-c3csc(C)n3)cc2)O[Si](C)(C)C(C)(C)C)cn1
Temperature: 80 °C
Yield: 44.6 %

Procedure:
In a round-bottomed flask, 2-[4-(2-methyl-thiazol-4-yl)-phenoxy]-ethylamine (175 mg, 0.747 mmol) and toluene-4-sulfonic acid 2-(6-acetylamino-pyridin-3-yl)-2-(tert-butyl-dimethyl-silanyloxy)-ethyl ester (231 mg, 0.498 mmol) were dissolved in dimethylsulfoxide (0.50 mL), and diisopropyl ethyl amine (0.105 mL, 0.600 mmol) was added in one portion. The resulting mixture was heated to about 80° C. for about sixteen hours, and was then partitioned between diethyl ether and water. The aqueous phase was extracted with diethyl ether four times, and the combined organic extracts were then washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting white solid was purified by column chromatography (methylene chloride to 10% methanol/methylene chloride) to afford 117 mg (45%) of the desired product. LRMS ([M+1]+): 527.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=1>O>[N:1]1([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(Cl)ccn1
Reactant: C1CCNCC1
Solvent: O
Product: Cc1cc(N2CCCCC2)ccn1

Procedure:
Piperidine (31.7 ml) and 4 -chloro-2 -picoline (13.65 g) were heated together in a bomb at 170 ° for 4.5 hours. After cooling, the mixture was taken up in water and extracted with ether. After drying (K2CO3) and stripping, the residue was distilled to give 4 -piperidino-2 -picoline, 15.45 g, b.p. 105°-10 ° (0.1 mm).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10](Cl)[C:11]([CH3:13])=[CH2:12])(=[O:3])[CH3:2].C([N+]([O-:23])(CC)CC)C.O1CCOCC1>[Cu]Cl.O>[C:1]([O:4][CH2:5][CH:6]=[C:7]([CH3:15])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:13])[CH:12]=[O:23])(=[O:3])[CH3:2]
Reactant: CC[N+]([O-])(CC)CC
Reactant: C=C(C)C(Cl)CCC(C)=CCOC(C)=O
Agent: Cl[Cu]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)OCC=C(C)CCC=C(C)C=O
Reaction time: 10 h
Yield: 61.2 %

Procedure:
2.36 g (9.41 mmols) of 6-chloro-3,7-dimethyl-2,7-octadienyl acetate (purity: 92%), 92 mg (0.93 mmols) of copper(I) chloride and 3.65 g (29.6 mmols) of triethylamine N-oxide (purity: 95%) were placed in a flask, to which 5 ml of dioxane was added, followed by agitation of the mixture at 50° C. for 10 hours. 40 ml of water was added to the reaction mixture, after which it was extracted twice each with 70 ml of diethyl ether. The resultant extract was successively washed with each 20 ml of 3% sulfuric acid, a saturated sodium hydrogen carbonate aqueous solution and a saturated ammonium chloride aqueous solution, and dried with magnesium sulfate. The solvent was distilled off from the solution and the resultant residue was purified by column chromatography using silica gel [eluent: ethyl acetate/hexane (ratio by volume)=1/9-1/3], thereby obtaining 1.21 g of 8-acetoxy-2,6-dimethyl-2,6-octadienal. Yield: 61%. The results of the instrumental analysis were found to be substantially coincident with those obtained in Example 9(b).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:28][CH3:29])=[C:10]([CH2:19][NH:20][C:21](=[O:27])[CH2:22][CH2:23][C:24]([OH:26])=O)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([CH2:38][NH2:39])[CH:34]=[CH:35][C:36]=1[Cl:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>ClCCl>[Br:30][C:31]1[CH:32]=[C:33]([CH2:38][NH:39][C:24](=[O:26])[CH2:23][CH2:22][C:21]([NH:20][CH2:19][C:10]2[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]3=[N:8][C:9]=2[CH2:28][CH3:29])=[O:27])[CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: NCc1ccc(Cl)c(Br)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CCC(=O)NCc1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
In a 100 mL round-bottomed flask was added 4-({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-4-oxobutanoic acid (1.0 g, 2.478 mmol), 1-(3-bromo-4-chlorophenyl)methanamine (0.595 g, 2.7 mmol), HATU (1.065 g, 2.8 mmol) and triethylamine (0.641 ml, 4.6 mmol) in dichloromethane (35 mL) to give a yellow suspension. The mixture was stirred overnight at room temperature. The reaction was quenched with saturated NaHCO3 and diluted with DCM. The organic layer were separated, then washed with water followed by saturated NaCl. The organic layer was dried over Na2SO4 and evaporated to a small volume, about 15 mL, from which a crystalline solid appeared which was collected, washed very sparingly with DCM and dried to give N-[(3-bromo-4-chlorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}butanediamide (1 g, 66.6%) as a solid. LC-MS m/z 605.5 (M+H)+, 0.75 min (ret time).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:16]([OH:17])=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH:4]=[N:3]1.[O:18](S(C(F)(F)F)(=O)=O)[S:19]([C:22]([F:25])([F:24])[F:23])(=O)=[O:20]>N1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:16]([O:17][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:20])=[O:18])=[CH:15][CH:14]=[C:13]3[C:8]=2[CH:9]=[CH:10][CH:11]=[N:12]3)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2c(O)ccc3ncccc23)cn1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: Cn1cc(-c2c(OS(=O)(=O)C(F)(F)F)ccc3ncccc23)cn1
Temperature: 0 °C
Reaction time: 5 h
Yield: 84.7 %

Procedure:
5-(1-Methyl-1H-pyrazol-4-yl)-quinolin-6-ol (2.9 g, 12.89 mmol) was dissolved in pyridine (30 mL) and the mixture was cooled to 0° C. in an ice bath under a flow of nitrogen. Tf2O (2.6 mL, 15.47 mmol) was added slowly. Then the reaction mixture was stirred at room temperature for 5 hours. The mixture was partitioned between dichloromethane (50 mL) and saturated aqueous NaHCO3 (50 mL). The organic phase was separated and washed with brine (5×30 mL). The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 3.9 g of Trifluoromethanesulfonic acid 5-(1-methyl-1H-pyrazol-4-yl)-quinolin-6-yl ester (84% yield): 1H NMR (300 MHz, CDCl3) δ: 4.05 (s, 3H), 7.48˜7.44 (m, 1H), 7.69˜7.61 (m, 3H), 8.18 (d, 1H), 8.32 (m, 1H), 8.98 (m, 1H); MS (m/z) 358 [M+H]+.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:16]C(=O)C)=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=2)[CH2:6][CH2:5]1)(=O)C.Cl>>[NH2:16][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][C:10]=1[N+:13]([O-:15])=[O:14])[NH:4][CH2:5][CH2:6]2
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])N(C(C)=O)CC2
Agent: Cl
Product: Nc1cc2c(cc1[N+](=O)[O-])NCC2

Procedure:
Product B is deacetylated by refluxing with 85 ml. conc. hydrochloric acid for 1 hr. 30 min. The whole is evaporated extracted with 400 ml. hot methanol, neutralized with excess ammonium hydroxide and filtered. The product is dissolved in 500 ml. ethyl acetate, treated with activated charcoal and saturated with HCl gas. The product is further purified by mixing with water and activated charcoal, and filtered. The filtrate containing the salt of the product is placed under nitrogen, neutralized with ammonium hydroxide solution, filtered, washed with water and dried to give a red solid 5-amino-6-nitroindoline, m. 190°-1.5° C. (D).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:18][CH2:19][CH3:20])[C:4](=[O:17])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)=[N:8][C:9]=2[N:10]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>C(O)CCC>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:2]2[N:3]([CH2:18][CH2:19][CH3:20])[C:4](=[O:17])[C:5]3[NH:6][C:7]([C:11]4[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=4)=[N:8][C:9]=3[N:10]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(N)cc1
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(C)c3)[nH]c2c1=O
Solvent: CCCCO
Product: CCCn1c(Nc2ccc(OC)cc2)nc2nc(-c3cnn(C)c3)[nH]c2c1=O
Temperature: 22.5 °C
Yield: 48.4 %

Procedure:
A mixture of 2-Chloro-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one (0.1 g, 0.34 mmol), p-anisidine (0.049 g, 0.4 mmol) and 1-butanol (5 ml), were heated at reflux temperature for 20 hours. The reaction mixture was cooled to 20-25° C. and evaporated to dryness, then added water (20 ml) to the residue and extracted with ethyl acetate (4×20 ml). The organic layers were mixed and washed with brine (30 ml), dried over Na2SO4 and evaporated to dryness and the crude product was washed with diethyl ether and dried to obtain 2-(4-Methoxy-phenylamino)-8-(1-methyl-1H-pyrazol-4-yl)-1-propyl-1,7-dihydro-purin-6-one (0.0625 g, 48%) as an off white solid.
Reaction SMILES: [F:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[N:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[N:32]=5)[C:27](=[O:38])[N:26]([CH3:39])[CH:25]=4)[C:17]=3[CH:18]=[O:19])[C:14](=[O:15])[C:3]=12.[BH4-].[Na+]>CO>[F:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[C:17]([CH2:18][OH:19])=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[N:32]=5)[C:27](=[O:38])[N:26]([CH3:39])[CH:25]=4)[CH:21]=[CH:22][N:23]=3)[C:14](=[O:15])[C:3]=12
Reactant: Cc1nccc(Nc2cc(-c3ccnc(N4CCn5c6c(c(F)c5C4=O)CCCC6)c3C=O)cn(C)c2=O)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nccc(Nc2cc(-c3ccnc(N4CCn5c6c(c(F)c5C4=O)CCCC6)c3CO)cn(C)c2=O)n1
Reaction time: 0.33 h
Yield: 50.9 %

Procedure:
To a solution of 213c (120 mg, 0.23 mmol) at 0° C. in methanol (10 mL) was added sodium borohydride (26 mg, 0.69 mmol). The reaction mixture was stirred for 20 minutes and quenched with water (10 mL). It was then extracted with dichloromethane (3×20 mL) and the combined organic layer was concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 213 (62 mg, 44%) as a white solid. MS-ESI: [M+H]+ 530.3. 1H NMR (500 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.93 (d, J=2.5 Hz, 1H), 8.50 (d, J=5.0 Hz, 1H), 8.21 (d, J=6.0 Hz, 1H), 7.69 (d, J=2.5 Hz, 1H), 7.37 (d, J=5.0 Hz, 1H), 7.13 (d, J=5.5 Hz, 1H), 4.96 (t, J=5.5 Hz, 1H), 4.57-4.45 (m, 2H), 4.23-4.18 (m, 2H), 4.08-4.05 (m, 1H), 3.90-3.87 (m, 1H), 3.62 (s, 3H), 2.64-2.56 (m, 2H), 2.45 (s, 3H), 2.43-2.42 (m, 2H), 1.78-1.76 (m, 2H), 1.72-1.66 (m, 2H).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:9][CH2:8][CH2:7]1)(=[O:5])[CH3:4]>C(O)C.CCCCCC>[CH2:13]([NH:12][C:10]([C:6]1([C:3](=[O:5])[CH2:4][Br:1])[CH2:9][CH2:8][CH2:7]1)=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)C1(C(=O)NCc2ccccc2)CCC1
Reactant: BrBr
Solvent: CCO
Solvent: CCCCCC
Product: O=C(CBr)C1(C(=O)NCc2ccccc2)CCC1
Reaction time: 0.25 h
Yield: 78.2 %

Procedure:
Bromine (0.593 mL, 11.51 mmol) was added dropwise to a 0° C. stirred solution of 1-acetyl-N-benzylcyclobutanecarboxamide (2.22 g, 9.60 mmol) in ethanol (35.5 mL). After 15 minutes, the ice bath was removed. The flask was sealed, and stirring was continued for 6.5 hrs. HPLC and LC/MS after 5 hrs indicated a complete or nearly complete reaction. The reaction was quenched by the addition of 25 mL of sat. aq NaHSO3 soluition. EtOAc was added (50 mL), the layers were separated, the aq layer was extracted with EtOAc (20 mL), the combined EtOAc layers were washed with water, brine, dried over Na2SO4, and concentrated under vacuum to give the crude product (2.80 g) as an oily yellow solid. The crude product was sonicated briefly in hexane. The ppt was collected by filtration, rinsed with hexane, and dried under vacuum to yield 2.33 g of the title compound as a pale yellow solid. LC/MS: m/e 312.08 (one of 2 Br-pattern peaks, M+H).