Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[CH:11]([C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:20])[OH:12])([O-])=O.C([O-])=O.[NH4+]>CO.[Pt]=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[CH:11]([C:13]1[C:14]([Cl:20])=[CH:15][CH:16]=[CH:17][C:18]=1[Cl:19])[OH:12]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(O)c1c(Cl)cccc1Cl
Agent: O=[Pt]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1ccc(Cl)cc1C(O)c1c(Cl)cccc1Cl
Temperature: 50 °C
Reaction time: 5 h
Yield: 38.8 %

Procedure:
To 3.9 g of (2-nitro-5-chlorophenyl)(2,6-dichlorophenyl)methanol dissolved in 37 ml of methanol are added 5.25 g of ammonium formate and 0.374 g of platinum oxide. The mixture is left for 5 hours at room temperature and then heated at 50° C. for 18 hours. The resulting mixture is filtered through Celite and the filtrate is concentrated. The residue is taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 90/10 (v/v) cyclohexane/ethyl acetate mixture to give 1.378 g of the expected product.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[CH3:22][C:23]1[C:37]([CH3:38])=[CH:36][C:26]2[NH:27][C:28]([C:30]3[C:34]([NH2:35])=[CH:33][NH:32][N:31]=3)=[N:29][C:25]=2[CH:24]=1.[N:39]1([CH2:44][C:45](O)=[O:46])[CH:43]=[N:42][N:41]=[N:40]1>CN(C)C=O>[CH3:38][C:37]1[C:23]([CH3:22])=[CH:24][C:25]2[NH:29][C:28]([C:30]3[C:34]([NH:35][C:45](=[O:46])[CH2:44][N:39]4[CH:43]=[N:42][N:41]=[N:40]4)=[CH:33][NH:32][N:31]=3)=[N:27][C:26]=2[CH:36]=1
Reactant: O=C(O)Cn1cnnn1
Reactant: Cc1cc2nc(-c3n[nH]cc3N)[nH]c2cc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc2nc(-c3n[nH]cc3NC(=O)Cn3cnnn3)[nH]c2cc1C
Reaction time: 72 h
Yield: 9.2 %

Procedure:
A stirred solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (295.7 mg) and diisopropylethylamine (269 μl) in dimethylformamide (10 ml) were treated with 3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine [100 mg, Example 233(c)] and 2-(1H-1,2,3,4-tetraazol-1-yl) acetic acid (197.8 mg). The reaction mixture was stirred for 72 hours then treated further with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (295.7 mg), diisopropylethylamine (269 μl) and 2-(1H-1,2,3,4-tetraazol-1-yl) acetic acid (197.8 mg). Stirring was continued for a further 48 hours then the reaction mixture was partitioned between ethyl acetate and water. The organic phase was evaporated and the residue was treated with 1N potassium hydroxide in a mixture of methanol and tetrahydrofuran (1:4, 8 ml). After 1 hour this mixture was extracted with ethyl acetate. The extract was washed with brine, then dried over magnesium sulfate and then evaporated to dryness. The residue was subjected to preparative HPLC to give N-[3-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-2-(1H-1,2,3,4-tetraazol-1-yl)-acetamide (13.7 mg) as an off-white solid. MS: 338.14 (M+H)+. HPLC (METHOD B1): RT=7.26 minutes. (b) N-[3-(5,6-Dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-yl]-isonicotinamide
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[CH3:17])[S:13][CH2:12][CH2:11][C:10]2([CH3:19])[CH3:18])(C)C.[OH-].[K+]>C(O)(C)C>[CH3:18][C:10]1([CH3:19])[C:9]2[C:14](=[CH:15][C:16]([CH3:17])=[C:7]([C:6]#[CH:5])[CH:8]=2)[S:13][CH2:12][CH2:11]1
Reactant: Cc1cc2c(cc1C#C[Si](C)(C)C)C(C)(C)CCS2
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: C#Cc1cc2c(cc1C)SCCC2(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 380 mg (1.69 mmol) of trimethylsilyl (4,4,7-trimethyl-thiochroman-6-yl) ethyne, (Compound 67) 4 ml of isopropanol and 2.5 ml of aqueous 1N potassium hydroxide was degassed under nitrogen and stirred at room temperature for 16 h. The mixture was concentrated under vacuum and extracted with 2×10 ml of ether. The ether extracts were combined and washed successively with water and saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo to give the title compound as a yellow oil. PMR (CDCl3): & 1.31 (6H, s), 1.88-1.96 (2H, m), 2.35 (3H, s), 3.00-3.08 (2H, m), 3.25 (1H, s), 6.94 (1H, s), 7.47 (1H, s).
Reaction SMILES: [S:1]([C:4]1[S:8][C:7]([NH:9][C:10]2[N:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)=[N:6][CH:5]=1)[C:2]#N.SC[C@H]([C@@H](CS)O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].ClC1[CH:40]=[CH:39][N:38]=[C:37]([C:41]([O:43][CH3:44])=[O:42])[C:36]=1[F:45]>CO.CN(C=O)C>[F:45][C:36]1[C:37]([C:41]([O:43][CH3:44])=[O:42])=[N:38][CH:39]=[CH:40][C:2]=1[S:1][C:4]1[S:8][C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][OH:17])=[CH:14][N:15]=2)=[N:6][CH:5]=1
Reactant: N#CSc1cnc(Nc2ccc(CO)cn2)s1
Reactant: COC(=O)c1nccc(Cl)c1F
Agent: O=P([O-])([O-])[O-]
Agent: O[C@H](CS)[C@H](O)CS
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1nccc(Sc2cnc(Nc3ccc(CO)cn3)s2)c1F
Temperature: 23 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
(6-(5-Thiocyanatothiazol-2-ylamino)pyridin-3-yl)methanol (1.0 g, 3.78 mmol) was dissolved in methanol (30 mL) and treated with dithiothreitol (0.582 g, 3.78 mmol). The reaction was stirred at 23° C. for 1 hour. DMF (30 mL) was then added, followed by K3PO4 (0.321 g, 1.51 mmol) and methyl 4-chloro-3-fluoropicolinate (0.788 g, 4.16 mmol). The reaction was stirred at 23° C. for 1 hour, then methanol was evaporated. The title material was precipitated by adding water (˜150 mL), collected by filtration and dried under high vacuum to give the title material (1.287 g, 87%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 3.34 (2H, s), 4.46 (2H, d, J=5.05 Hz) 5.22 (1H, t, J=5.56 Hz), 7.10 (1H, d, J=8.34 Hz), 7.15 (1H, t, J=5.31 Hz), 7.74 (1H, dd, J=8.59, 2.27 Hz), 7.84 (1H, s), 8.24 (1H, d, J=1.52 Hz), 8.33 (1H, d, J=5.05 Hz), 11.89 (1H, s). LC/MS (M+H)+: 393. HPLC ret. time (Condition N): 4.319 min.
Reaction SMILES: C([O:3][P:4]([CH:9]([NH:18][C:19]1[S:20][CH:21]=[C:22]([CH3:24])[N:23]=1)[P:10]([O:15]CC)(=[O:14])[O:11]CC)(=[O:8])[O:5]CC)C.CO>Cl>[CH3:24][C:22]1[N:23]=[C:19]([NH:18][CH:9]([P:4]([OH:5])(=[O:3])[OH:8])[P:10]([OH:14])(=[O:11])[OH:15])[S:20][CH:21]=1
Reactant: CCOP(=O)(OCC)C(Nc1nc(C)cs1)P(=O)(OCC)OCC
Agent: Cl
Solvent: CO
Product: Cc1csc(NC(P(=O)(O)O)P(=O)(O)O)n1

Procedure:
1.30 g (3.2 mmol) of 1-(4-methylthiazol-2-ylamino)methane-1,1-diphosphonic acid tetraethyl ester are heated in 20 ml of 1N hydrochloric acid at 100° for 20 hours. After cooling, 20 ml of methanol are added. During subsequent stirring, the product separates out in the form of fine white crystals. The filtrate is subsequently washed with methanol and petroleum ether. Yield: 615 mg (67% of the theoretical yield) of 1-(4-methylthiazol-2-ylamino)methane-1,1-diphosphonic acid of m.p. 294° (decomposition).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.CS(O)(=O)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[OH:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=O)=[CH:24][CH:23]=1.[OH-].[Na+]>>[Br:19][C:16]1[CH:17]=[CH:18][C:13]2[N:12]=[C:29]([CH2:28][C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)[O:20][C:14]=2[CH:15]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: Nc1ccc(Br)cc1O
Agent: CS(=O)(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Na+]
Product: Clc1ccc(Cc2nc3ccc(Br)cc3o2)cc1
Temperature: 120 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
Phosphorus pentachloride (2.27 g) was added to methanesulfonic acid (8 ml), and the mixture was stirred at 120° C. for 1 hour. To the solution were added 2-amino-5-bromophenol (1.50 g) and 4-chlorophenylacetic acid (1.36 g) and the mixture was stirred at 100° C. for 1 hour. The mixture was poured onto ice, neutralized with 8 N sodium hydroxide and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried over MgSO4. The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and the fraction eluted with ethyl acetate-hexane (1:4, v/v) was concentrated under reduced pressure. The resulting crystals were collected by filtration to obtain 6-bromo-2-(4-chlorobenzyl)benzoxazole (1.83 g, 71%).
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].CC([N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]2[C:32]3[C:27](=[C:28]([C:33]#[N:34])[CH:29]=[CH:30][CH:31]=3)[C:26]([NH:35][S:36]([C:39]3[S:40][C:41]([Cl:44])=[CH:42][CH:43]=3)(=[O:38])=[O:37])=[N:25]2)[CH:18]=1)C(=O)[O-])(C)C.C(N(CC)CC)C.C(OC(=O)C)(=O)C>C(Cl)Cl.O>[Cl:44][C:41]1[S:40][C:39]([S:36]([NH:35][C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]#[N:34])[N:24]([CH2:23][C:19]3[CH:18]=[C:17]([CH2:16][NH:12][C:1](=[O:2])[CH3:3])[CH:22]=[CH:21][CH:20]=3)[N:25]=2)(=[O:37])=[O:38])=[CH:43][CH:42]=1
Reactant: CC(C)(C)N(Cc1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(C#N)cccc32)c1)C(=O)[O-]
Reactant: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)NCc1cccc(Cn2nc(NS(=O)(=O)c3ccc(Cl)s3)c3c(C#N)cccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7 %

Procedure:
TFA (1 mL) was added to 1,1-dimethylethyl({3-[(3-{[(5-chloro-2-thienyl)sulfonyl]amino}-4-cyano-1H-indazol-1-yl)methyl]phenyl}methyl)carbamate (for a preparation see Intermediate 73) (630 mg, 1.13 mmol) in DCM (4 mL) and the reaction was stirred at room temperature for 30 min. LCMS showed the boc group was removed and the reaction mixture was concentrated. The residue was dissolved in DCM (7 mL), triethylamine (1.573 mL, 11.29 mmol) and acetic anhydride (0.128 mL, 1.355 mmol) were added, and the reaction mixture was stirred for 30 min. The reaction was treated with water (10 mL) and the product was extracted with DCM (2×30 mL). The combined organic layers were dried by passing through a hydrophobic frit and concentrated to afford the crude product as a yellow oil (0.57 g). The residue was purified by chromatography on Flashmaster (silica 20 g cartridge), eluting with a gradient 25-100% EtOAc in DCM, followed by 0-30% MeOH in DCM) and the appropriate fractions were combined and concentrated to afford the title compound as a white solid (44 mg, 7%). Other fractions from the column were combined and concentrated to afford a yellow oil, (0.25 g), which was dissolved in MeOH (5 mL), potassium carbonate (300 mg) was added and the mixture was stirred at room temp for 30 min. LCMS showed one of the two acetyl groups was cleaved to afford more of the desired product. The mixture was concentrated and acidified with 2N HCl. The product was extracted with EtOAc (3×15 mL) and the combined organic layers were washed with saturated brine (5 mL), dried using a hydrophobic frit and evaporated in vacuo to give the crude product as a brown oil. The residue was dissolved in DMSO (1 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a Formic acid modifier (Method A). The solvent was evaporated in vacuo to give the title compound (70 mg, 12%). LCMS (System A) RT=0.92 min, ES+ve m/z 500/502 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:7]=2[CH:32]=1.C1(=O)[NH:37]C(=O)C2=CC=CC=C12.[K]>CN(C=O)C>[NH2:37][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[NH:8][C:7]=2[CH:32]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCCN(CCC)CCCCc1nc2ccc(CCl)cc2n1S(=O)(=O)c1ccc(C)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: CCCN(CCC)CCCCc1nc2ccc(CN)cc2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 55.4 %

Procedure:
The compound (113 mg) obtained in Example 114-3 was dissolved in DMF (2 ml) and added with potassium phthalimide (69.0 mg), followed by stirring at room temperature for 2 days. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform, followed by washing with water. After extraction with chloroform, the organic layer was washed with saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was dried under vacuum, and the dried product was dissolved in a 40% methylamine/methanol solution (1.5 ml), followed by stirring overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform, followed by washing with water and a 1 mol/l sodium hydroxide aqueous solution. After extraction with chloroform, the extract was washed with saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (39.8 mg) as a brown solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([Si:15]([CH3:29])([CH3:28])[O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][OH:25])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl.O>[C:11]([Si:15]([CH3:29])([CH3:28])[O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH:24]=[O:25])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(CCO)CCOCCO[Si](C)(C)C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CC=O)CCOCCO[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 93.6 %

Procedure:
Step B To a solution of oxalyl chloride (0.1 mL, 1 mmol) (Aldrich) in dichloromethane (5 mL) at −78° C. was added the solution of dimethyl sulfoxide (0.16 mL, 2.2 mmol) in dichloromethane (1 mL) dropwise. After 5 mins, the solution of 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pentan-1-ol (0.3 g, 1 mmol) in dichloromethane (1 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 15 min. Triethylamine (0.5 mL, 3.6 mmol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. Then water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pentanal as a yellow oil (Yield: 0.27 g, 94%).
Reaction SMILES: Cl[C:2]1[C:3]2[S:10][C:9]([S:11][CH3:12])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[OH:23].C([O-])([O-])=O.[K+].[K+]>O(C1C=CC=CC=1)C1C=CC=CC=1>[F:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[O:23][C:2]1[C:3]2[S:10][C:9]([S:11][CH3:12])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: CSc1cc2ncnc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CSc1cc2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 130 °C
Yield: 88 %

Procedure:
A mixture of 280 (210 mg, 0.97 mmol), 2-fluoro-4-nitrophenol (278 mg, 1.77 mmol) and K2CO3 (560 mg, 3.54 mmol) in Ph2O (10 mL) was heated at 130° C. 60 hours, cooled to room temperature and partitioned between EtOAc and water. Organic phase was collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by flash column chromatography with a gradient elution (hexane to hexane/EtOAc, 1:1) to afford the title compound 281 (288 mg, 88% yield) as a yellowish solid. MS (m/z): 338.1(M+H) (found).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([N:8]2[C:12]([CH3:13])=[N:11][C:10]([OH:14])=[N:9]2)[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[P:21](=[S:29])(Cl)([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24]>C(#N)C>[P:21](=[S:29])([O:14][C:10]1[N:11]=[C:12]([CH3:13])[N:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=2)[N:9]=1)([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24]
Reactant: CCOP(=S)(Cl)OCC
Reactant: Cc1nc(O)nn1-c1cccc(F)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOP(=S)(OCC)Oc1nc(C)n(-c2cccc(F)n2)n1
Temperature: 25 °C

Procedure:
A 3-neck, 500-ml flask was charged with 9 g (0.046 m) of 1-(6-fluoro-2-pyridinyl)-5-methyl-1H-1,2,-4-triazol-3-ol, 6.6 grams (0.048 m) of dry potassium carbonate and 150 ml of acetonitrile. The mixture was refluxed for 2 hours and then cooled to 25° C. To this mixture was added 8.67 g (0.46 m) of O,O-diethyl phosphorochloridothioate and the mixture was heated to 75° C. for 31/2 hours. The solid material which formed was removed by filtration and the acetonitrile was removed by evaporation under reduced pressure. The solid residue which remained was taken up in ethyl ether, washed with 2 percent sodium hydroxide and dried over sodium sulfate. The desired O,O-diethyl O-(1-(6-fluoro-2-pyridinyl)-5-methyl-1H-1,2,4-triazol-3-yl) phosphorothioate was crystallized from a 50:50 mixture of ethyl ether and hexane in a yield of 12.9 g (85 percent of theoretical). The product melted at 68°-70° C. and upon analysis was found to have carbon, hydrogen and nitrogen contents of 41.54, 4.66 and 16.05 percent, respectively, as compared to the theoretical contents of 41.62, 4.66 and 16.18 percent, respectively, as calculated for the above named compound. (Compound 2).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C1COCC1.Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([C:32]3[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][C:33]=3[F:42])[N:30]=[CH:31][C:24]=12>C(Cl)Cl>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:23]2[N:28]=[CH:27][N:26]=[C:25]3[N:29]([C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][C:33]=4[F:42])[N:30]=[CH:31][C:24]=23)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 500 mL round-bottomed flask equipped with a N2 inlet septum was placed a stir bar, NaH (60% in mineral oil, 1.8 g, 45.6 mmol) and 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1.53 g, 7.6 mmol). THF (anhydrous, 80 mL) was added to the mixture. The resulting suspension was stirred about 30 min at room temperature. 4-Chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (2.5 g, 7.6 mmol) was then added in one portion. The mixture was stirred overnight under N2 at room temperature and the resulting slurry turned slightly yellowish. The slurry was added CH2Cl2 and filtered. The filtrate was concentrated under vacuum to give the crude product. Column chromatography purification using 50% EtOAc/Hexane gave Compound A74 as an off-white solid. Exact mass calculated for C22H26FN5O5S: 491.16, found 492.1 (MH+).
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:20]=[C:19]2[C:14]([C:15]([OH:27])=[C:16]([O:23][C:24](=[O:26])[CH3:25])[C:17](=[O:22])[N:18]2[CH3:21])=[CH:13][CH:12]=1)([O-:10])=[O:9].[CH3:28][O:29][CH2:30]Cl>C1COCC1>[N+:8]([C:11]1[CH:20]=[C:19]2[C:14]([C:15]([O:27][CH2:28][O:29][CH3:30])=[C:16]([O:23][C:24](=[O:26])[CH3:25])[C:17](=[O:22])[N:18]2[CH3:21])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: CC(=O)Oc1c(O)c2ccc([N+](=O)[O-])cc2n(C)c1=O
Reactant: COCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCOc1c(OC(C)=O)c(=O)n(C)c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
After addition of 1.87 g of triethylamine (18.5 mmol) to a mixture of 3.2 g of 7-nitro-3-acetoxy-4-hydroxy-1-methyl-2(1H)-quinolinone (11.5 mmol) in 64 ml of THF, 1.89 g of chloromethyl methyl ether (23.0 mmol) was dropped to the mixture, and stirred at room temperature for 1 hour. Filtration of the reaction mixture, the filtrate was concentrated under reduced pressure to give 3.6 g of 7-nitro-3-acetoxy-4-methoxymethoxy-1-methyl-2(1H)-quinolinone. In accordance with EXAMPLE 4, the obtained 7-nitro-3-acetoxy-4-methoxymethoxy-1-methyl-2(1H)-quinolinone was used instead of 7-nitro-3-acetoxy-4-hydroxy-1-methyl-2(1H)-quinolinone, 7-nitro-3-hydroxy-4-methoxymethoxy-1-methyl-2(1H)-quinolinone was provided. Then in accordance with EXAMPLE 2, 7-nitro-3-methoxy-4-methoxymethoxy-1-methyl-2(1H)-quinolinone was given by methylation reaction. Finally, to a mixture of the obtained 7-nitro-3-methoxy-4-methoxymethoxy-1-methyl-2(1H)-quinolinone in 40 ml of methanol was added 0.22 g of p-toluenesulfonic acid monohydrate and stirred at room temperature for 1 hour. To the reaction mixture was added water, extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was crystallized from THF and hexane to yield 1.45 g of the title compound (18). (yield=54%)
Reaction SMILES: [C:1]([NH:3][C:4](=[N:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1)OC1C=CC=CC=1)#[N:2].[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[N:37]=[C:36]([NH:38][NH2:39])[CH:35]=[CH:34][N:33]=2)[CH2:28][CH2:27]1>CN1CCCC1=O>[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[N:37]=[C:36]([N:38]3[C:1]([NH2:2])=[N:3][C:4]([NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:20][CH2:21][O:22][CH2:23][CH2:24]5)=[CH:17][CH:18]=4)=[N:39]3)[CH:35]=[CH:34][N:33]=2)[CH2:28][CH2:27]1
Reactant: N#CNC(=Nc1ccc(N2CCOCC2)cc1)Oc1ccccc1
Reactant: CN1CCN(c2nccc(NN)n2)CC1
Solvent: CN1CCCC1=O
Product: CN1CCN(c2nccc(-n3nc(Nc4ccc(N5CCOCC5)cc4)nc3N)n2)CC1
Temperature: 220 °C
Yield: 66.5 %

Procedure:
A mixture of N-cyano-N′-(4-morpholinopheny)-O-phenylisourea (0.10 g, 0.31 mmol) and [2-(4-Methyl-piperazin-1-yl)-pyrimidin-4-yl]-hydrazine (0.08 g, 0.34 mmol) in N-methylpyrrolidinone (3 mL) was heated in the microwave apparatus at 220° C. for 5 min. Purification by semi-preparative HPLC provided the title compound (0.09 g, 2% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:27][C@H:28]([C:32]([O:34]C)=[O:33])[CH:29]([CH3:31])[CH3:30])=[O:26])=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.CO.[Li+].[OH-].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:27][C@H:28]([C:32]([OH:34])=[O:33])[CH:29]([CH3:31])[CH3:30])=[O:26])=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)c(F)c2)cc1)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@H](NC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)c(F)c2)cc1)C(=O)O
Temperature: 50 °C

Procedure:
Methyl N-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-yl}carbonyl)-L-valinate (84.2 mg, 0.17 mmol) was suspended in THF (2.5 mL), MeOH (2.5 mL) and water (1 mL), and LiOH (40.7 mg, 1.70 mmol) was added. The reaction mixture was heated at 50° C. for 2 h. Upon cooling to rt, the reaction mixture was brought to pH 3 with 1N HCl and was extracted with EtOAc (3×25 mL). The combined organic phases were washed with water (2×50 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo. This yielded 72.3 mg (88%) of the title compound as a white solid. LC/MS m/z 482.3 (MH+), retention time 3.46 min. 1H NMR (400 MHz, DMSO-d6) δ 0.99 (dd, 6H), 2.19-2.24 (m, 1H), 4.30 (dd, H), 7.18 (t, 1H), 7.60-7.84 (m, 6H), 7.88 (d, 2H), 8.42 (d, 1H), 8.66 (t, 1H), 10.42 (s, 1H).