Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[CH:2]([CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)S([O-])(=O)=O.[NH3:18].CS([O-])(=O)=O>CO>[CH3:17][C:12]1[CH:11]=[C:10]([CH:15]=[C:14]([CH3:16])[CH:13]=1)[O:9][CH2:8][CH:7]([NH2:18])[CH3:2]
Reactant: N
Reactant: Cc1cc(C)cc(OCCC(C)S(=O)(=O)[O-])c1
Agent: CS(=O)(=O)[O-]
Solvent: CO
Product: Cc1cc(C)cc(OCC(C)N)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A 20 cc autoclave was charged with 5.42 g (21 mmol) of 1-methyl-2-(3,5-dimethylphenoxy)ethyl-methanesulfonate and 6 ml of methanol, and ammonia was added in an amount of 7.67 g which was 20 times, by mole, as much as the above methanesulfonate. The mixture was continuously stirred at 100° C. for 8 hours to finish the reaction. After the reaction mixture was allowed to cool, remaining ammonia was removed, and the reaction mixture was transferred into a 500 ml beaker with 50 ml of water and 20 ml of ethyl ether. A 20% hydrochloric acid aqueous solution was added until the reaction liquid was made acidic, and the reaction liquid was washed with 50 ml of diethyl ether three times. Then, while the water layer was cooled, a 20% sodium hydroxide aqueous solution was added to make it alkaline, and the reaction liquid was subjected to extraction with 50 ml of diethyl ether three times. The extract was dried over 10 g of anhydrous sodium sulfate, and the solvent was removed under reduced pressure to give 3.25 g of 1-(3,5-dimethylphenoxy)-2-aminopropane (boiling point 113° C./3 mmHg). This amount of 3.25 g corresponded to a yield of 86.6%, or was very high. The results of NMR and IR analyses were as follows.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([CH3:28])[CH:27]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:32]1[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]1)=[O:20])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(F)c(F)cc2nc1OC
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1nc2cc(F)c(F)cc2nc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 70 %

Procedure:
Ethyl N-(6,7-di fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethyl phenyl)piperazine were reacted by the same way with the example 169 to obtain the titled compound (yield, 70%). 1H NMR (300 MHz, CDCl3) δ 2.30 (s, 6H), 3.26-3.28 (m, 4H), 3.74-3.76 (m, 4H), 4.15 (s, 3H), 6.59 (s, 3H), 7.29 (s, 1H), 7.49-7.53 (m, 1H), 7.52-7.62 (m, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([S:17][C:18]2[N:22]4[CH:23]=[C:24]([C:27](=O)[CH3:28])[CH:25]=[CH:26][C:21]4=[N:20][N:19]=2)=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.Cl.[NH2:31][OH:32].Cl>CCO>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:8]=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([S:17][C:18]2[N:22]4[CH:23]=[C:24](/[C:27](=[N:31]/[OH:32])/[CH3:28])[CH:25]=[CH:26][C:21]4=[N:20][N:19]=2)=[CH:12][CH:11]=3)[CH2:5][CH2:6]1
Reactant: NO
Reactant: CC(=O)c1ccc2nnc(Sc3ccc4ncc(N5CCOCC5)cc4c3)n2c1
Agent: Cl
Solvent: CCO
Product: C/C(=N\O)c1ccc2nnc(Sc3ccc4ncc(N5CCOCC5)cc4c3)n2c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 64.7 %

Procedure:
To a solution of (77.3) (10 mg, 0.025 mmol) and hydroxylamine hydrochloride (6.86 mg, 0.099 mmol) in EtOH (5 ml) was added 0.01 ml of HCl (2 N) and the mixture was stirred in a sealed tube at 80° C. overnight. The mixture was evaporated to dryness and dissolved in H2O again, which was neutralized immediately by NaHCO3 until pH reached about 9. The resulted precipitate was filtered quickly. The precipitate was dissolved in DCM/MeOH (10/1) and washed again by water. The organic phase was dried over Na2SO4, filtered and evaporated to give the title compound (6.8 mg, yield 60.1%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6][CH:5]=1.[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]3[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:12]2=[O:17])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N2C(=O)c3ccccc3C2=O)nc1
Yield: 59 %

Procedure:
A solution of 6-aminonicotinic acid methyl ester (1.1 g, 7.2 mmol) and phthalic anhydride (1.2 g, 7.9 mmol) in anhydrous toluene was heated at reflux overnight in a Dean-Stark apparatus until no more water was collected. The reaction mixture was concentrated under vacuum. The residue was dissolved in ethyl acetate (50 mL) and was washed with brine and water. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to give 6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-nicotinic acid methyl ester (1.2 g, 60%), which was directly used in the next step without further purification. 1H NMR (300 MHz, d-DMSO) δ 9.12 (d, J=1.5 Hz, 1H), 8.52 (dd, J=2.1, 8.4 Hz, 1H), 8.03-7.92 (m, 4H), 7.72 (d, J=7.8 Hz, 1H), 3.91 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@@H:11]([C:20]([OH:22])=O)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([CH:30]([NH2:34])[CH2:31][CH2:32][CH3:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@@H:11]([C:20]([NH:34][CH:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:31][CH2:32][CH3:33])=[O:22])[NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC(N)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4.27 g of N-(tert-butoxycarbonyl)aspartic acid-4-benzyl ester (manufactured by PEPTIDE INSTITUTE, INC.) and 2.1 mL of 1-phenylbutyl amine were dissolved in 40 mL of DMF, and then 2.70 g of WSC hydrochloride and 1.93 g of HOBt were added thereto, and the reaction solution was stirred at room temperature for 6 hours. The reaction solution was added with water, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried with magnesium sulfate, and then distilled under reduced pressure to remove ethyl acetate, and then dried under vacuum, thereby to give 3.94 g of Compound 1.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:10]3[CH:16]=[CH:15][C:14](=[O:17])[CH:13]=[CH:12][C:11]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=1>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[C:32]([C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:21]2[CH2:20][CH2:19][N:18]([C:9]3[N:10]4[CH:16]=[CH:15][C:14](=[O:17])[CH:13]=[CH:12][C:11]4=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[CH2:23][CH2:22]2)=[CH:27][CH:28]=1)#[N:33]
Reactant: O=c1ccc2c(-c3ccccc3)cc(N3CCNCC3)n2cc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(CN2CCN(c3cc(-c4ccccc4)c4ccc(=O)ccn34)CC2)cc1
Yield: 12.9 %

Procedure:
By working as in Example 2, but starting with 1-phenyl-3-(1-piperazinyl)-7H-pyrrolo[1,2-a]azepin-7-one (3.05 g), α-bromo-p-toluonitrile (2.35 g) and 4-dimethylaminopyridine (1.48 g) in solution in chloroform (80 cc), 3-[4-(4-cyanobenzyl)-1-piperazinyl]-1-phenyl-7H-pyrrolo[1,2-a]azepin-7-one (0.54 g), m.p. 196° C., is obtained after recrystallization in ethanol (25 cc).
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][CH2:7][C:6](=[O:9])[NH:5][C:4]1=[O:10].[C:26]1(=O)[O:31][C:29](=[O:30])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12.C([O-])(=O)C.[Na+]>C(O)(=O)C>[O:30]=[C:29]1[C:28]2[C:27](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:26](=[O:31])[N:2]1[C:3]1([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8][CH2:7][C:6](=[O:9])[NH:5][C:4]1=[O:10]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NC1(CCCCNC(=O)OCc2ccccc2)CCC(=O)NC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCC(CCCCNC(=O)OCc2ccccc2)(N2C(=O)c3ccccc3C2=O)C(=O)N1
Temperature: 130 °C
Reaction time: 7 h

Procedure:
To a suspension of 4 (0.12 g, 0.324 mmol), phthalic anhydride (0.060 g, 0.401 mmol), and sodium acetate (0.037 g, 0.434 mmol) was added acetic acid (1.5 mL) and the resulting mixture was stirred at 130° C. After 7 h, the mixture was quenched with sodium bicarbonate and extracted with DCM. The organic layer was dried over MgSO4 and concentrated. Purification by preparative HPLC afforded 12. Rf=0.32 (95:5 DCM:MeOH). 1H NMR (400 MHz, CDCl3) δ 8.05-7.64 (m, 5H), 7.44-7.27 (m, 4H), 5.16-5.00 (m, 2H), 4.90 (m, 1H), 3.34-3.09 (m, 3H), 2.92-2.77 (m, 1H), 2.77-2.45 (m, 3H), 2.36-2.18 (m, 1H), 2.17-1.99 (m, 1H), 1.38 (d, J=6.8 Hz, 2H). MS (ESI) m/z calcd for C25H26N3O6 [M+H]+ 464.5, found 464.3.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1C=CC=CC=1.[O:20]=[C:21]1[NH:25][CH:24]([C:26](Cl)=[O:27])[CH2:23][CH2:22]1>O>[CH2:1]([NH:13][C:26]([CH:24]1[CH2:23][CH2:22][C:21](=[O:20])[NH:25]1)=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C1CCC(C(=O)Cl)N1
Reactant: CCCCCCCCCCCCN
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCNC(=O)C1CCC(=O)N1

Procedure:
While cooling and stirring a mixture consisting of 9.2 gm (0.05 mol) of n-dodecylamine and 50 ml of pyridine, 17.3 gm (0.05 mol) of 5-oxo-2-pyrrolidine carboxylic acid chloride were added thereto in small portions, and the resulting mixture was stirred for one hour at room temperature. Thereafter, the reaction mixture was admixed with water, acidified and extracted with chloroform. The organic phase was separated, washed with water, dried and evaporated. The residue was recrystallized from ethyl acetate, yielding 9.0 gm (62% of theory) of the compound of the formula ##EQU5## which had a melting point of 114°-116°C.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][S:5][CH:4]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([NH:2][C:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][S:5][CH:4]=1)(=[O:21])[CH3:20]
Reactant: COC(=O)c1cscc1N
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cscc1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A mixture of methyl 3-aminothiophene-4-carboxylate hydrochloride (3.1 g, 16 mmol) and triethylamine (6.7 mL, 48 mmol), in methylene chloride (75 mL) was stirred 30 minutes and then chilled over wet ice. Acetyl chloride (1.4 mL, 19.2 mmol) was added and the reaction was warmed to ambient temperature and stirred 1 hour. The reaction was quenched with water and diluted with methylene chloride. The phases were separated and the aqueous layer was extracted with methylene chloride. The combined organic layer was washed with water, dried over magnesium sulfate, and concentrated to afford 2.85 g (91%) of methyl 3-acetamidothiophene-4-carboxylate as a brown oil which solidified on standing. The product was suitable for use without purification.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[C:6]2[O:28][CH:27]=[CH:26][C:7]=2[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)=[N:9][CH:10]=1.[CH3:29][O:30][CH2:31][CH2:32][C:33](O)=[O:34]>>[CH3:29][O:30][CH2:31][CH2:32][C:33]([NH:25][C@H:22]1[CH2:21][CH2:20][C@H:19]([CH2:18][CH2:17][N:14]2[CH2:13][CH2:12][N:11]([C:8]3[C:7]4[CH:26]=[CH:27][O:28][C:6]=4[C:5]([CH3:4])=[CH:10][N:9]=3)[CH2:16][CH2:15]2)[CH2:24][CH2:23]1)=[O:34]
Reactant: COCCC(=O)O
Reactant: Cc1cnc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)c2ccoc12
Agent: Cl
Product: COCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3ncc(C)c4occc34)CC2)CC1

Procedure:
The title compound, white solid (79 mg, 61%), MS (ISP) m/z=429.4 [(M+H)+], mp 177° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(7-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate F) (136 mg, 0.3 mmol) and 3-methoxypropionic acid.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].BrC[CH2:23][C:24]([N:26]([CH:37]([CH3:39])[CH3:38])[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1)=[O:25].O>CN(C=O)C>[CH:37]([N:26]([C:27]1[CH:28]=[CH:29][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:31][CH:32]=1)[C:24](=[O:25])[CH2:23][NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:39])[CH3:38]
Reactant: CC(C)N(C(=O)CCBr)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccccc1Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N(C(=O)CNc1ccccc1Nc1ccccc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a stirred solution of 1.16 g (6.32 mmol) of N-Phenyl phenylenediamine in 15 mL of DMF is added 1.05 g (7.58 mmol, 1.2 equiv) of K2CO3 and 2.05 g (6.32 mmol) of Bromomethyl-N-isopropyl-N-(4-trifluoromethyl-phenyl) acetamide. The resulting mixture is stirred 1 h at RT then is heated to 50° C. for 16 h. The reaction mixture is then cooled to RT, poured into 100 mL H2O and extracted with Et2O (2×100 mL). The organic layers were washed in series with 1N HCl (2×80 mL), NaHCO3 (1×80 mL), and H2O (1×80 mL), dried (MgSO4), and the solvent removed in vacuo. Purification of the crude material by silica gel flash column chromatography using hexane/EtOAc 5/1 as eluent afforded 2.05 g of N-Isopropyl-2-(2-phenylamino-phenylamino)-N-(4-trifluoromethyl-phenyl)-acetamide as a light tan solid: 1H NMR (CDCl3, 400 MHz) δ7.72 (d, 2H, J=8.2), 7.26 (d, 2H, J=8.2), 7.15 (m, 3H), 6.95 (dd, 1H, J=7.7, 7.7), 6.80 (dd, 1H, J=7.1, 7.1), 6.74 (d, 2H, J=7.9), 6.68 (dd, 1H, J=7.4, 7.4), 6.29 (d, 1H, J=7.9), 5.20 (s, 1H), 5.00 (m, 1H), 3.40 (s, 2H), 1.06 (d, 6H, J=6.6); low resolution MS (FAB)m/e 427 (MH+); high resolution MS (C24H24F3N3O) Calc. 427.1871 Found 427.1871.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[B:11](OC(C)C)([O:16]C(C)C)[O:12]C(C)C.C([Li])CCC.Cl>C1(C)C=CC=CC=1.O1CCCC1>[C:4]([C:3]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:2]=1[B:11]([OH:16])[OH:12])#[N:5]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: N#Cc1cc(F)ccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: N#Cc1cc(F)ccc1B(O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Bromo-5-fluorobenzonitrile (6.00 g, 30.0 mmol) and triisopropyl borate (8.28 mL, 36.0 mmol) were dissolved in a mixture of toluene (48 mL) and tetrahydrofuran (12 mL), and the solution was cooled in a dry ice/acetone bath. A solution of n-butyllithium in hexanes (2.5M, 14.4 mL, 36.0 mmol) was added drop-wise over 1 hour, and the reaction was then allowed to warm to room temperature with stirring over 18 hours. The mixture was cooled in an ice bath and treated with a 2N aqueous hydrochloric acid solution until the pH reached 1, then allowed to warm to room temperature, at which time the layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed twice with water, once with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was recrystallized from ethyl acetate-heptane to provide (2-cyano-4-fluorophenyl)boronic acid as a white solid. Yield: 2.20 g, 13.3 mmol, 44%. 1H NMR (400 MHz, CD3OD) δ 7.43 (ddd, J=8.6, 8.6, 2.5 Hz, 1H), 7.55 (dd, J=8.8, 2.5 Hz, 1H), 7.69 (br s, 1H).
Reaction SMILES: [CH:1]1[C:17]2[C:4]([CH:5]=[CH:6][C:7]3[C:16]=2[CH:15]=[C:14]2[C:9](=[CH:10][CH2:11][C:12](=[O:18])[CH2:13]2)[CH:8]=3)=[N:3][N:2]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(O)(=O)C>[C:19]([N:2]1[CH:1]=[C:17]2[C:4]([CH:5]=[CH:6][C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][C:16]=32)[CH2:13][C:12](=[O:18])[CH:11]=[CH:10]4)=[N:3]1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CC=c2cc3ccc4c(c3cc2C1)C=NN=4
Solvent: CC(=O)O
Product: CC(=O)n1cc2c(ccc3cc4c(cc32)CC(=O)C=C4)n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Due to limited solubility of Compound 1, purification of the same may be achieved by first derivatizing Compound 1 to a more soluble intermediate, such as the corresponding acetate, recrystallizing the intermediate, and then converting the intermediate to yield purified Compound 1 in good yield. More specifically, to solution of the pyrazoloanthrone (9.67 g, 43.9 mmol) in acetic acid (700 mL) is added acetic anhydride (12.4 mL, 132 mmol). The solution is heated to 80° C. for 5 hours and then cooled to room temperature. After 16 hours, the reaction is cooled to 0° C. for 2 hours. The reaction is then filtered to give the N-acetylpyrazoloanthrone intermediate. This intermediate is recrystallized in acetic acid to give the pure intermediate (5.96 g, 52%). 1H NMR (CDCL3) δ 10.6 (br s, 1H), 8.46 (d, 1H), 8.33 (d, 1H), 8.26 (d, 1H), 8.08 (d, 1H), 7.96–7.87 (m, 2H), 7.78 (t, 1H), 2.83 (s, 3H); ES-MS (m/z) 263 [M+1]+. To a solution of the pure intermediate (5.96 g, 23 mmol) in methanol (600 mL) is added ammonium hydroxide (60 mL). The reaction is stirred at room temperature for 16 hours and then filtered and dried in a vacuum oven. A second crop of crystals is recovered to give a total of 4.8 g of Compound 1 at greater than 98% purity. ES-MS (m/z) 221 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.I[CH2:16][CH3:17].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH2:16][CH3:17])=[O:13])[CH:6]=[CH:5]2
Reactant: CCI
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2cc(Br)ccc2c1
Yield: 97.3 %

Procedure:
A mixture of 6-bromo-2-naphthoic acid (6.18 g, 24.6 mmol), iodoethane (19.7 mL, 38.39 g, 246.1 mmol) and Cs2CO3 (12.03 g, 36.9 mmol) in acetonitrile (200 mL) under an atmosphere was heated to reflux overnight. The resulting mixture was filtered and evaporated. The solid was dissolved in ethyl acetate and washed with water (4×), brine and dried (Mg2SO4). The mixture was filtered and evaporated to give 6.68 g of ethyl 6-bromo-2-naphthoate (97%) as a solid. 1H NMR (500 MHz; CDCl3): δ 1.45 (t, J=7.0 Hz, 3H); 4.44 (q, J=7.0 Hz, 2H); 7.61 (dd, J1=2.0 Hz, J2=9.0 Hz, 1H); 7.79 (d, J=8.5 Hz, 1H); 7.82 (d, J =9.0 Hz, 1H); 8.00–8.11 (m, 2H); 857 (brs, 1H),
Reaction SMILES: O.C([O:5][CH2:6][C@:7]1([CH3:19])[O:12][C:11]2=[N:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][N:10]2[CH2:9][CH2:8]1)(=O)C.C([O-])([O-])=O.[K+].[K+].Cl>CO>[CH3:19][C@@:7]1([CH2:6][OH:5])[O:12][C:11]2=[N:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][N:10]2[CH2:9][CH2:8]1
Reactant: CC(=O)OC[C@@]1(C)CCn2cc([N+](=O)[O-])nc2O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@]1(CO)CCn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
Water (4 mL) was added dropwise to a stirred mixture of (R)-acetate 158 (427 mg, 1.67 mmol) and K2CO3 (256 mg, 1.85 mmol) in MeOH (36 mL). After stirring at room temperature for 4 h, the mixture was cooled in ice and treated with 0.1M HCl (37 mL, 3.70 mmol). The solvents were removed under reduced pressure and the residue was chromatographed on silica gel. Elution with 0-1% MeOH/CH2Cl2 firstly gave foreruns, and then further elution with 1-2.5% MeOH/CH2Cl2 gave [(7R)-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-yl]methanol (159) (343 mg, 96%) as a pale yellow solid that was used directly in the next step; 1H NMR [(CD3)2SO] δ 8.03 (s, 1H), 5.23 (br t, J=5.4 Hz, 1H), 4.13 (dt, J=13.0, 6.0 Hz, 1H), 4.05 (ddd, J=12.9, 8.1, 5.6 Hz, 1H), 3.54 (dd, J=11.6, 4.9 Hz, 1H), 3.48 (dd, J=11.6, 5.2 Hz, 1H), 2.21 (ddd, J=14.4, 8.1, 5.9 Hz, 1H), 2.00 (dt, J=14.4, 5.8 Hz, 1H), 1.32 (s, 3H); [α]D27−16.0° (c 1.00, DMF).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]([O:33]CC)=O)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])(=[O:20])=[O:19])=[C:13]([F:29])[CH:12]=3)[C:3]=12.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:30][C:31]([N:40]3[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]3)=[O:33])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=4[Cl:28])(=[O:19])=[O:20])=[C:13]([F:29])[CH:12]=3)[C:3]=12
Reactant: CN1CCNCC1
Reactant: CCOC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21
Product: CN1CCN(C(=O)Cn2nc(-c3ccc(NS(=O)(=O)c4cccc(Cl)c4Cl)c(F)c3)c3c(N)ncnc32)CC1

Procedure:
Ethyl 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate was treated with 1-methylpiperazine using the representative procedure for amide formation. Purification by preparative HPLC (25 to 100% CH3CN in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8Hypersi1HS C18, 250×21 mm column, Rt 6.4-7.0 min) afforded N1-(4-{4-amino-1-[2-(4-methylpiperazino)-2-oxoethyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-2,3-dichloro-1-benzenesulfonamide as a white solid (0.005 g, 0.009 mmol): RP-HP (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) Rt 6.83 min. 1H NMR (DMSO-d6, 400 MHz) δ 8.20 (s, 1H), 7.96 (d, 1H), 7.88 (d, 1H), 7.50 (t, 1H), 7.36 (m, 3H), 5.31 (s, 2H), 3.45 (m, 4H), 2.50 (m, 4H), 2.30 (s, 3H), MS: MH+ 593.
Reaction SMILES: [NH2:1][C:2]1[C:35]([C:36]([F:39])([F:38])[F:37])=[CH:34][C:5]([CH2:6][C@@H:7]([CH2:11][C:12](=[O:33])[N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:23]4[CH:24]=[N:25][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=5[C:22]=4[NH:21][C:20]3=[O:32])[CH2:15][CH2:14]2)[C:8]([OH:10])=O)=[CH:4][C:3]=1[Cl:40].[O:41]1[CH2:46][CH2:45][CH:44]([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:43][CH2:42]1>>[NH2:1][C:2]1[C:35]([C:36]([F:39])([F:37])[F:38])=[CH:34][C:5]([CH2:6][C@@H:7]([CH2:11][C:12]([N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[C:23]4[CH:24]=[N:25][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=5[C:22]=4[NH:21][C:20]3=[O:32])[CH2:17][CH2:18]2)=[O:33])[C:8]([N:50]2[CH2:49][CH2:48][N:47]([CH:44]3[CH2:45][CH2:46][O:41][CH2:42][CH2:43]3)[CH2:52][CH2:51]2)=[O:10])=[CH:4][C:3]=1[Cl:40]
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(n3c(=O)[nH]c4c5ccccc5ncc43)CC2)C(=O)O)cc1C(F)(F)F
Product: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(n3c(=O)[nH]c4c5ccccc5ncc43)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc1C(F)(F)F

Procedure:
Prepared analogously to Example 7i from 80 mg (0.14 mmol) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidin-1-yl]-butanoic acid and 26.0 mg (0.15 mmol) 1-(tetrahydropyran-4-yl)-piperazine.