Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:19]1[C:20]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:18])[CH:10]=2)=[O:5])C.[OH-].[Na+]>CO>[F:34][C:31]([F:32])([F:33])[C:28]1[CH:27]=[CH:26][C:25]([C:20]2[C:19]([C:17]([NH:16][C:11]3[CH:10]=[C:9]4[C:14]([CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]4)=[CH:13][CH:12]=3)=[O:18])=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
To a solution of 7[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid ethyl ester (50 g, 114.5 mmol, 1 equiv) and methanol (750 mL, 15 volumes) was slowly added 1 N sodium hydroxide (220 mL, 4.4 volumes). After stirring at room temperature for 2 hours, the reaction was concentrated in vacuo. Water (750 mL) was added to the residue and the pH was adjusted to 5.0 using 1 N hydrochloric acid (250 mL). The resulting slurry was stirred for 30 minutes and the precipitated solids were collected by filtration and dried in vacuo and then dissolved in methanol (75 mL) and ethyl acetate (675 mL). The solution was dried over sodium sulfate and filtered, and concentrated in vacuo. The residue was slurried in ethyl acetate (250 mL). The solids were collected by filtration to give 7-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-3-carboxylic acid (28.1 g, 60 %).
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][S:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[CH3:11][C:12]1[CH:13]=C(O)[CH:15]=[C:16]([CH:18]=1)[OH:17]>>[OH:17][C:16]1[C:15]2[C:2]3[CH2:6][CH2:5][S:4][C:3]=3[C:7](=[O:8])[O:9][C:10]=2[CH:11]=[C:12]([CH3:13])[CH:18]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: COC(=O)C1SCCC1=O
Product: Cc1cc(O)c2c3c(c(=O)oc2c1)SCC3

Procedure:
Following a procedure similar to that described in Example 1B hereinabove, methyl 3-oxo-2,3,4,5-tetrahydrothiophene-2-carboxylate is reacted with 5-methylresorcinol to give 1,2-dihydro-9-hydroxy-7-methyl-4-oxo-4H-thieno[2,3-c] [1]benzopyran.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:37][CH:38]1[CH2:42][N:41]([CH2:43][CH3:44])[N:40]([CH2:45][CH3:46])[CH2:39]1>C(Cl)(Cl)Cl>[CH2:45]([N:40]1[CH2:39][CH:38]([NH:37][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:2]=2[OH:1])[CH2:42][N:41]1[CH2:43][CH3:44])[CH3:46]
Reactant: O=C(O)c1ccc(O)cc1O
Reactant: CCN1CC(N)CN1CC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CCN1CC(NC(=O)c2ccc(O)cc2O)CN1CC
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a solution of 2,4- dihydroxybenzoic acid (1.00 g) in tetrahydrofuran anhydride (20 ml) were added 1-hydroxybenzotriazole (1.05 g) and N,N'-dicyclohexyl carbodiimide (1.34 g) while being cooled with ice. After the resulting mixture was stirred for 30 minutes, 4-amino-1,2-diethylpyrazolidine (0.93 g) was added thereto and the mixture was stirred for one night at room temperature. The reaction solution, with chloroform added thereto, was washed with brine and then dried over sodium sulfate anhydride. The resulting organic layer was concentrated under a vacuum and thus formed residue was purified by silica gel column chromatography (chloroform: methanol=20:1) so as to yield 1.17 g (65%) of N-(1,2-diethyl-4-pyrazolidinyl)-2,4- dihydroxybenzamide.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][CH:3]=1.[CH2:12](O)/[CH:13]=[CH:14]/[CH3:15]>>[CH2:12]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)/[CH:13]=[CH:14]/[CH3:15]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: C/C=C/CO
Product: C/C=C/COc1ccc(C(=O)O)cc1
Yield: 91.4 %

Procedure:
A reaction similar to that described in Example 1 (1a) was conducted using methyl 4-hydroxybenzoate (5.00 g, 32.9 mmol) and trans-crotyl alcohol (manufactured by Fluka, 2.37 g, 32.9 mmol) to give 5.78 g of the title compound (white powder, yield: 91%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][CH:24]=1)(=[O:21])[CH3:20]>>[CH3:18][C:13]1=[N:14][NH:15][C:16](=[O:17])/[C:12]/1=[C:4]1\[NH:5][C:6]2[C:11]([C:2]([S:29][C:26]3[CH:25]=[CH:24][C:23]([NH:22][C:19](=[O:21])[CH3:20])=[CH:28][CH:27]=3)=[CH:3]\1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Reactant: CC(=O)Nc1ccc(S)cc1
Product: CC(=O)Nc1ccc(SC2=C/C(=C3/C(=O)NN=C3C)Nc3ccccc32)cc1

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and 4-actamidothiophenol using the procedure described in Example 6. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.94 (s, 3H) 2.11 (s, 3H) 6.77 (s, 1H) 7.65-7.69 (m, 3H) 7.83-7.93 (m, 3H) 7.99 (d, J=8.08 Hz, 1H) 8.16 (d, J=8.34 Hz, 1H) 10.35 (s, 1H); ESI-MS: m/z calc'd for C21H18N4O2S 390.12. found 391.2 (M+H)+.
Reaction SMILES: [OH-].[K+].S(O)(O)(=O)=O.[C:8]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)(=[NH:10])[NH2:9].[C:24]([CH:27]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:28](OCC)=[O:29])(=O)[CH3:25]>C(O)C.C1(C)C=CC=CC=1>[CH2:17]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[N:9]=[C:28]([OH:29])[C:27]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:24]([CH3:25])[N:10]=2)[CH2:12][CH2:13]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)CC(C(C)=O)C(=O)OCC
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1c(C)nc(N2CCN(Cc3ccccc3)CC2)nc1O
Reaction time: 0.5 h
Yield: 17.6 %

Procedure:
Potassium hydroxide (3.1 g) was added to 200 ml of ethanol, and the mixture was stirred for 30 minutes. Then, 12.4 g of 1-amidino-4-benzylpiperazine sulfate was added. The mixture was stirred at room temperature for 10 minutes. To the solution was added 12.4 g of diethyl acetylsuccinate. The mixture was refluxed for 2 hours. Then, 200 ml of toluene was added, and the mixture was refluxed for 3 hours. After the reaction, ethanol was evaporated, and the residue was poured into 50 ml of an aqueous solution of hydrochloric acid. NaHCO3 was added to the solution to neutralize it. The precipitated solid was washed with water and dried over P2O5 to give 2.55 g (yield 15%) of 2-(4-benzylpiperazino)-5-ethoxycarbonylmethyl-4-hydroxy-6-methylpyrimidine as a white solid.
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)([CH3:6])[CH2:4][F:5].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH2:41][CH2:42][O:43][CH3:44])[N:36]=[CH:35][N:34]=[C:33]2[S:45][C:46]1[CH:47]=[C:48]([CH:50]=[CH:51][CH:52]=1)[NH2:49].C(N(CC)C(C)C)(C)C>C1COCC1>[F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13]([NH:49][C:48]2[CH:50]=[CH:51][CH:52]=[C:46]([S:45][C:33]3[C:32]4[C:37](=[CH:38][C:39]([O:40][CH2:41][CH2:42][O:43][CH3:44])=[C:30]([O:29][CH3:28])[CH:31]=4)[N:36]=[CH:35][N:34]=3)[CH:47]=2)=[O:21])[N:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:8]=1)([CH3:6])[CH2:4][F:5]
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)nn4-c4ccccc4)c3)c2cc1OC
Yield: 28 %

Procedure:
Using the procedure described in Example 159B, phenyl 3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate described in Example 167B (0.186 g, 0.5 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (0.143 g, 0.4 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) at 50° C. for 6 hours, which was purified by silica gel chromatography with EtOAc/hexane as eluants and preparative HPLC(C18 column and 55-70% MeCN/H2O with 0.05% AcOH) to afford 1-[3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}urea as solid (0.072 g, 28%). 1H NMR (300 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.68 (s, 1H), 8.56 (s, 1H), 7.80 (s, 1H), 7.56 (m, 4H), 7.33-7.47 (m, 5H), 7.24 (d, 1H), 6.51 (s, 1H), 4.71 (m, 2H), 4.55 (m, 2H), 4.33 (m, 2H), 3.99 (s, 3H), 3.77 (m, 2H), 3.34 (s, 3H), 1.31 (s, 3H); LC-MS (ESI) m/z 635 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:12]([O:16][C:17](=[O:29])[NH:18][CH2:19][C:20]1[C:21]([O:27][CH3:28])=[N:22][CH:23]=[C:24]([NH2:26])[CH:25]=1)([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>C(Cl)Cl>[C:12]([O:16][C:17](=[O:29])[NH:18][CH2:19][C:20]1[C:21]([O:27][CH3:28])=[N:22][CH:23]=[C:24]([NH:26][S:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)(=[O:10])=[O:9])[CH:25]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=S(=O)(Cl)c1cccnc1Cl
Reactant: COc1ncc(N)cc1CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ncc(NS(=O)(=O)c2cccnc2Cl)cc1CNC(=O)OC(C)(C)C
Yield: 95 %

Procedure:
The title compound (2.12 g, 4.94 mmol) was prepared from 2-chloropyridine-3-sulfonyl chloride (1.10 g, 5.20 mmol), tert-butyl(5-amino-2-methoxypyridin-3-yl)methylcarbamate (IntA34) (1.45 g, 5.72 mmol) and pyridine (1.26 mL, 15.6 mmol) in DCM (20 mL) at rt using the methods of (IntC1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[N:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:18]=[CH:19][C:20]2[C:21]3[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27][C:22]=3[N:23]([CH3:26])[C:24]=2[CH:25]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][N:12]([C:17]2[CH:18]=[CH:19][C:20]3[C:21]4[CH2:30][N:29]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:28][CH2:27][C:22]=4[N:23]([CH3:26])[C:24]=3[CH:25]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1cc(OCc2ccccc2)cn[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(-n4ncc(OCc5ccccc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 43.6 %

Procedure:
5-(Benzyloxy)pyridazin-3(2H)-one (100 mg, 0.5 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (180 mg, 0.5 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (106 mg, 43%) as a solid: ESI MS m/z 487 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Cl[C:11]1[N:16]=[C:15]([C:17]2[CH:29]=[CH:28][C:20]3[N:21]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:23][C:19]=3[CH:18]=2)[CH:14]=[CH:13][N:12]=1>CN(C=O)C.[H-].[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:11]2[N:16]=[C:15]([C:17]3[CH:29]=[CH:28][C:20]4[N:21]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:23][C:19]=4[CH:18]=3)[CH:14]=[CH:13][N:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(S)cc1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Sc2nccc(-c3ccc4nc(NC(C)=O)sc4c3)n2)cc1
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 37.2 %

Procedure:
4-Methoxythiophenol (0.168 ml, 1.36 mmol) was dissolved in DMF (1.0 mL) and NaH (60% in mineral oil), 66.8 mg, 1.67 mmol) was added. The reaction was stirred under nitrogen at RT for 65 minutes, then N-(6-(2-chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (48.0 mg, 158 μmol) was added, and the reaction solution was stirred overnight under nitrogen at RT and quenched with water. The suspension was filtered, and the solid was washed with water, MeOH, and Et2O, then collected. The layers of the biphasic filtrate were separated, and the aqueous phase was extracted with 10:1 DCM/MeOH (2×25 mL; 10 mL; 2×25 mL). Organic extracts were combined with the solid, concentrated, and purified on HPLC (10% to 95% MeCN/water with 0.1% TFA over 30 minutes) to afford N-(6-(2-(4-methoxyphenylthio)pyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (24 mg, 38% yield). MS (ESI pos. ion) m/z: 409. Calculated exact mass for C20H16N4O2S2: 408. 1H NMR (400 MHz, DMSO-d6): 12.52 (s, 1H), 8.65 (s, 1H), 8.61 (d, J=8.5 Hz, 1H), 7.80 (m, 2H), 7.58 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H), 4.85 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C@H:22]([CH3:33])[CH2:23][O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27](SC)[N:26]=3)[CH2:17][CH2:16]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].OO.C(=O)(O)[O-:37].[Na+]>C(O)(=O)C>[C:1]([C:5]1[N:6]=[C:7]([N:15]2[CH2:20][CH2:19][N:18]([CH2:21][C@H:22]([CH3:33])[CH2:23][O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([OH:37])[N:26]=3)[CH2:17][CH2:16]2)[CH:8]=[C:9]([CH:11]2[CH2:14][CH2:13][CH2:12]2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: CSc1nccc(OC[C@@H](C)CN2CCN(c3cc(C4CCC4)nc(C(C)(C)C)n3)CC2)n1
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@H](COc1ccnc(O)n1)CN1CCN(c2cc(C3CCC3)nc(C(C)(C)C)n2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1 g of (S)-2-tert-butyl-4-cyclobutyl-6-{4-[2-methyl-3-(2-methylsulfanyl-pyrimidin-4-yloxy)-propyl]-piperazin-1-yl}-pyrimidine (2.12 mmol) were dissolved in 10 ml of acetic acid. 2 g of aqueous hydrogen peroxide (17.6 mmol, 30% in water) were added at 0° C. The reaction mixture was stirred for 15 h at room temperature, poured onto water and the aqueous phase was adjusted to alkaline pH with saturated sodium bicarbonate solution. After extraction with ethyl acetate, the organic phase was dried over magnesium sulfate, filtered, and the solvent evaporated. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (2%). Fractions containing the product were combined, the solvent was evaporated, and the residue treated with acetonitril, filtered and dried to yield 0.36 g of the title compound as a white solid.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[CH3:9][C:10]1([CH3:38])[C@@H:15]([OH:16])[C@H:14]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[C:13]2[CH:27]=[C:28]([S:31]([C:34]([F:37])([F:36])[F:35])(=[O:33])=[O:32])[CH:29]=[CH:30][C:12]=2[O:11]1>C(Cl)Cl.O>[N+:7]([O-:8])([O:16][C@H:15]1[C@H:14]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[C:13]2[CH:27]=[C:28]([S:31]([C:34]([F:37])([F:35])[F:36])(=[O:33])=[O:32])[CH:29]=[CH:30][C:12]=2[O:11][C:10]1([CH3:38])[CH3:9])=[O:6]
Reactant: O=[N+]=O
Reactant: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](N2Cc3ccccc3C2=O)[C@@H]1O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](N2Cc3ccccc3C2=O)[C@@H]1O[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 26.6 %

Procedure:
116 mg of nitronium tetrafluoroborate were added to a solution of 300 mg of trans-3,4-dihydro-2,2-dimethyl-4-(1-oxoisoindolin-2-yl)-6-trifluoromethylsulfonyl-2H-1-benzopyran-3-ol (prepared as described in Preparation 13) in 5 ml of methylene chloride, and the resulting mixture was stirred at room temperature for 1.5 hours. At the end of this time, the reaction mixture was diluted with 20 ml of water and extracted with 15 ml of methylene chloride. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 1:4 by volume mixture of ethyl acetate and cyclohexane as the eluent, to afford 88 mg of the title compound as crystals, melting at 189.5°-190° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[N:9]2[CH:21]=[CH:22][CH:23]=[C:8]2[C:7]=1[OH:24])=[O:5])C.[NH2:25][CH2:26][C:27]([O-:29])=[O:28].[Na+]>>[Cl:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][N:10]1[C:11](=[O:12])[C:6]([C:4]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5])=[C:7]([OH:24])[C:8]2=[CH:23][CH:22]=[CH:21][N:9]12
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2cccc(Cl)c2)c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cccn2n(Cc2cccc(Cl)c2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 1-(3-chloro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 376 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]2)=[C:4]2[CH2:10][CH2:9][CH2:8][C:5]2=[N:6][CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[C:33]1[S:34][CH:35]=[C:36]([C:38](O)=[O:39])[N:37]=1.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>CN(C=O)C>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[C:33]1[S:34][CH:35]=[C:36]([C:38]([NH:1][C:2]2[C:3]([N:11]3[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:23])[CH3:22])[CH2:12]3)=[C:4]3[CH2:10][CH2:9][CH2:8][C:5]3=[N:6][CH:7]=2)=[O:39])[N:37]=1
Reactant: O=C(O)c1csc(-c2c(F)cccc2F)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCC3)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3c2CCC3)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.2 %

Procedure:
tert-Butyl [(3S)-1-(3-amino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (5.0 mg, 0.015 mmol) was mixed with 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (Example 2, step 2, 4.4 mg, 0.018 mmol), HATU (14 mg, 0.038 mmol), DMF (0.035 mL) and DIPEA (5.8 mg, 0.045 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was filtered, concentrated and purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to give the sub-title compound as a colorless gum (4.1 mg, 49%). LCMS calc. for C28H32F2N5O3S (M+H)+: m/z=556.2. Found: 556.1.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].C(N(CC)CC)C.S(O)(O)(=O)=O.[NH2:30][C:31]1[N:40]=[C:39]([NH2:41])[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([S:42](Cl)(=[O:44])=[O:43])[CH:37]=2)[N:32]=1>O>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:42]([C:36]2[CH:37]=[C:38]3[C:33](=[CH:34][CH:35]=2)[N:32]=[C:31]([NH2:30])[N:40]=[C:39]3[NH2:41])(=[O:43])=[O:44])[C:4]1=[O:17])#[N:13]
Reactant: Nc1nc(N)c2cc(S(=O)(=O)Cl)ccc2n1
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: O
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc4nc(N)nc(N)c4c3)C2=O)c1
Reaction time: 0.17 h
Yield: 25 %

Procedure:
To a solution of 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride (0.50 g, 2 mmol) in 8 mL of H2O is added triethyl amine (0.7 g, 7 mmol). After stirring for 10 minutes, 2,4-diamino-quinazoline-6-sulfonyl chloride sulfate salt (0.71 g, 2 mmol) is added. The solution is refluxed for 1 hour. After this time, the solution is cooled to ambient temperatures. The solution is filtered. The collected solid is dried under vacuum to give the title compound (0.22 g, 0.5 mmol) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[CH:5]([C:36]#[N:37])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:26]([NH:29][C:30]([NH:32][CH2:33][CH2:34][CH3:35])=[O:31])(=[O:28])=[O:27])=[CH:16][CH:15]=1)[C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2].C(N(CC)CC)C.[CH3:46][SH:47]>ClCCl>[NH2:37][C:36]([S:47][CH3:46])=[C:5]([N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:26]([NH:29][C:30]([NH:32][CH2:33][CH2:34][CH3:35])=[O:31])(=[O:28])=[O:27])=[CH:16][CH:15]=1)[C:7](=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11])[C:4]([O:3][CH2:1][CH3:2])=[O:38]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)NCCC)cc1)C(C#N)C(=O)OCC
Reactant: CS
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)NCCC)cc1)C(C(=O)OCC)=C(N)SC
Temperature: -20 °C

Procedure:
A solution of 8.5 g of the product of Stage B and 2.4 ml of triethylamine in 100 ml of dichloromethane was saturated with methanethiol by sweeping through the stirred solution cooled to -20° C. The temperature was allowed to rise and then the solution was maintained under a nitrogen pressure of 10 bars at 40° C. for 48 hours. After concentration, the residue was purified by chromatography on silica (eluant: dichloromethane-MeOH 20-1) to obtain 8.0 g of the expected product with an Rf (SiO2, dichloromethane-MeOH20-1)=0.39.
Reaction SMILES: [NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4](Cl)[CH:3]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:3]=1
Reactant: C1CNCCN1
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Product: Nc1cc(N2CCNCC2)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]

Procedure:
A solution 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1 mmol; see Example 154) was reacted with piperazine following the procedure described in Example 163 to afford 4-amino-N-(1H-indazol-6-yl)-5-nitro-2-piperazin-1-ylbenzamide. The product thus obtained was treated with BOC anhydride as in Example 163 to obtain 4-[5-amino-2-(1H-indazol-6-ylcarbamoyl)-4-nitro-phenyl]-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].Cl.[CH3:14]O>>[CH3:14][O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Agent: Cl
Product: COC(=O)Cc1ccc(O)c(Cl)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 3-chloro-4-hydroxyphenyl acetic acid (20 mmol) in methanol (50 mL) was added concentrated HCl solution (5 mL), and stirred for 1 h at 50° C. After excess solvents were removed under vacuum, the residue was dissolved in EtOAc (50 mL) and washed with sat. NaHCO3 solution (2×30 mL), brine (30 mL) and dried over anhydrous Na2SO4. This afforded methyl 3-chloro-4-hydroxy acetate 3 as a colorless oil (4.0 g, 99%). 1H NMR (CDCl3) 6.9-7.0 (d, 1H), 6.8-6.9 (d, 1H), 5.4 (s, 1H), 3.6 (s, 3H), 3.4 (s, 2H).
Reaction SMILES: [CH3:1][C@H:2]1[N:15]2[C:6]([CH2:7][O:8][C:9]3[C:14]2=[CH:13][C:12]([N+:16]([O-])=O)=[CH:11][CH:10]=3)=[N:5][NH:4][C:3]1=[O:19].[Cl-].[NH4+]>CO.C1COCC1.[Zn]>[NH2:16][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][C:6]1[N:15]2[C@H:2]([CH3:1])[C:3](=[O:19])[NH:4][N:5]=1
Reactant: C[C@@H]1C(=O)NN=C2COc3ccc([N+](=O)[O-])cc3N21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1C(=O)NN=C2COc3ccc(N)cc3N21
Temperature: 50 °C
Reaction time: 16 h
Yield: 112.6 %

Procedure:
To a solution of (R)-4-methyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (50 g, 191 mmol) and ammonium chloride (102 g, 1907 mmol) in MeOH (700 mL) and THF (700 mL) was added zinc powder (125 g, 1907 mmol) in portions. After addition, the reaction mixture was stirred at 50° C. for 16 h. The reaction mixture was cooled to ambient temperature and filtered. The filter cake was washed with hot MeOH (3×1 L) and the combined organic phase was concentrated in vacuo. The residue was washed with THF (3×500 mL) and the combined organic phase was concentrated to give the crude (R)-6-amino-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (50 g, 215 mmol, containing residual NH4Cl), which was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): δ 6.68 (d, J=8.4 Hz, 1H), 6.43 (d, J=2.4 Hz, 1H), 6.16 (dd, J=2.4, 8.4 Hz, 1H), 4.83 (br. s., 1H), 4.56-4.52 (m, 1H), 4.47-4.39 (m, 2H), 1.31 (d, J=6.5 Hz, 3H). LCMS (Table 1, Method 3) Rt=0.803 min; MS m/z: 233 [M+H]+.