Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[OH-].[K+].N1C2C(=CC=CC=2)C(=O)C1=[O:17].[F:26][C:27]([F:39])([F:38])[C:28]1[CH:29]=[C:30]([C:34](=O)[CH2:35][CH3:36])[CH:31]=[CH:32][CH:33]=1.Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:34]([C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([F:26])([F:38])[F:39])[CH:29]=1)[C:35]([CH3:36])=[C:5]2[C:6]([OH:11])=[O:17]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: CCC(=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(-c2cccc(C(F)(F)F)c2)nc2ccc(F)cc2c1C(=O)O
Yield: 91 %

Procedure:
5-Fluoroisatin (61.3 g, 371 mmol) was dissolved in ethanol (564 mL) to provide a dark red solution. KOH (125 g, 2226 mmol) was dissolved in water (226 mL) and the solution was added slowly to the isatin solution. 1-[3-(Trifluoromethyl)phenyl]-1-propanone (75 g, 371 mmol) was added, and the solution was heated to reflux for 1 h. The reaction mixture was cooled in an ice bath and neutralized with concentrated HCl (208 mL, 2597 mmol). The precipitate was collected by filtration, washed with water (100 mL), and air dried. The solid material was crushed and resuspended in 1:1 ethanol/water (800 mL). The slurry was refluxed for 30 min. The solid was collected by filtration, washed with 1:1 ethanol/water (100 mL), and dried. The solid material was crushed and resuspended in 1:1 ethanol/water (800 mL). The slurry was refluxed for 30 min. The solid was collected by filtration, washed with 1:1 ethanol/water (100 mL), and dried in a vacuum oven at 50° C. for 6 h to afford 6-fluoro-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (118.3 g, 91% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 14.41 (br. s., 1H), 8.19 (dd, J=5.65, 9.16 Hz, 1H), 7.94-8.00 (m, 2H), 7.89 (d, J=8.03 Hz, 1H), 7.72-7.81 (m, 2H), 7.53 (dd, J=2.76, 9.79 Hz, 1H), 2.41 (s, 3H); MS (m/z) 350.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]([CH3:11])([C:4](=[O:10])[CH:5]([CH3:9])[C:6]([CH3:8])=[CH2:7])[CH3:3].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:3][C:2]([CH3:11])([C:4](=[O:10])[C:5]([CH3:9])=[C:6]([CH3:8])[CH3:7])[CH3:1]
Reactant: C=C(C)C(C)C(=O)C(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)=C(C)C(=O)C(C)(C)C
Reaction time: 24 h

Procedure:
30.8 g (0.2 mole) of 2,2,4,5-tetramethyl-5-hexen-3-one were heated to 100° in 100 ml of toluene in the presence of 3.08 g of p-toluenesulfonic acid. After 24 h, the mixture was cooled down and extracted with ether. After neutralizing with an aqueous solution saturated with NaHCO3, the organic phase was washed with water, then with a solution saturated with NaCl, and dried with Na2SO4. Evaporation and distillation of the residue, followed by fractional distillation, provided a fraction having B.p. 60°/1.06×103Pa NMR(1H, 360MHz): 1.18(s, 9H); 1.57(s, 3H); 1.66(s, 3H); 1.77(s, 3H) δppm MS:m/z:154(3, M+), 97(100), 69(62), 41(65), 39(20).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][CH:13]=[N:12][CH:11]=2)=[C:6]([O:15][CH3:16])[CH:5]=1)([O-])=O>[Pd].CCO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][CH:13]=[N:12][CH:11]=2)=[C:6]([O:15][CH3:16])[CH:5]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-c1cnco1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)ccc1-c1cnco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
In a 2 L hydrogenation flask was placed 1C (130.0 g, 0.6131 mol), Pd/C (10%, 26.2 g) and absolute EtOH (1280 mL). The mixture was hydrogenated at 35-45 psi H2 until the reaction was complete. The mixture was filtered over a pad of celite (20 g) and the cake was washed with EtOH (3×100 mL). The filtrate was concentrated to a volume of 350 mnL. Heptane (500 mL) was added to the resulting slurry. After stirring for 2 hours at room temperature, the slurry was filtered. The cake was washed with heptane (3×100 mL) and air-dried to give 80.0 g of 5-(4-amino-2-methoxyphenyl)oxazole (1D). Another 30.2 g of product was recovered from the mother liquor affording a total yield of 95%. 1H NMR (CDCl3) d 7.88 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.41 (s, 1H), 6.41 (dd, J=8.4, 2.1 Hz, 1H), 3.34 (d, J=2.1 Hz, 1H), 3.98 (bs, 2H), 3.94 (s, 3H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[C:36](=[O:40])[C:37]#[C:38][CH3:39]>>[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[C:36](=[O:40])/[CH:37]=[C:38](\[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])/[CH3:39]
Reactant: CC#CC(=O)c1ccc(F)cc1F
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Product: C/C(=C/C(=O)c1ccc(F)cc1F)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 12) from 120 mg (0.33 mmol) of Intermediate 45 and 59 mg (0.33 mmol) of Intermediate 39 to yield 63 mg (35% yield) of Example 31: TLC (DCM/MeOH (4:1): Rf=0.72; 1H NMR (DMSO-d6, 400 MHz) δ11.37 (d, 1H, J=9.4), 7.87 (m, 2H), 7.72 (q, 1H, J=6.4), 7.43 (m, 3H), 7.14 (m, 4H), 6.79 (d, 2H, J=8.8), 5.25 (s, 1H), 4.13 (m, 3H), 3.18 (m, 1H), 2.85 (t, 2H, J=6.0), 2.77 (dd, 1H, J=14.0, 9.8), 2.29 (s, 3H), 1.62 (s, 3H) ; low resolution MS (ES−)m/e 545.1 (M-H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[C:3]=1[O:11][C:12]1[CH:13]=[C:14]([C:20]#[N:21])[CH:15]=[C:16]([CH:19]=1)[C:17]#[N:18].ClC1C=C(C=C(OC2C3N=NNC=3C=CC=2Cl)C=1)C#N.Br[CH2:43][C:44]1[C:52]2[C:47](=[N:48][CH:49]=[CH:50][CH:51]=2)[N:46](C(OC(C)(C)C)=O)[N:45]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]([CH2:43][C:44]3[C:52]4[C:47](=[N:48][CH:49]=[CH:50][CH:51]=4)[NH:46][N:45]=3)[N:7]=[N:8][C:4]=2[C:3]=1[O:11][C:12]1[CH:13]=[C:14]([C:20]#[N:21])[CH:15]=[C:16]([CH:19]=1)[C:17]#[N:18]
Reactant: N#Cc1cc(C#N)cc(Oc2c(Cl)ccc3[nH]nnc23)c1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Agent: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nnc23)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C#N)cc(Oc2c(Cl)ccc3c2nnn3Cc2n[nH]c3ncccc23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A partially purified product prepared in the manner described in Example 4A, step 5, except on a larger scale, was found to contain approximately 10 mol % 5-[(5-chloro-1H-1,2,3-benzotriazol-4-yl)oxy]isophthalonitrile in addition to 3-chloro-5-[(5-chloro-1H-1,2,3-benzotriazol-4-yl)oxy]benzonitrile. A solution of tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (Intermediate 1; 23 g, 74 mmol) in DMF (100 mL) was added to a suspension of the partially purified product (25 g, 82 mmol) and cesium carbonate (28 g, 86 mmol) in DMF (80 mL) at room temperature, and the resulting mixture was stirred for 1 hour at room temperature. The reaction mixture was then quenched with aqueous saturated ammonium chloride (200 mL), diluted with water (100 mL) and extracted with ethyl acetate (2×700 mL). The combined organic fractions were washed with dilute brine (3×500 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was adsorbed onto silica gel and subjected to automated silica gel chromatography eluting with a gradient of 25-50% ethyl acetate in hexanes to afford the crude title product. This mixture was then purified by reverse phase column chromatography eluting with 5-95% CH3CN/H2O (0.1% TFA) to yield the title compound. 1H NMR (DMSO-d6) δ 8.53 (dd, J=4.6 Hz, J=1.5 Hz, 1H), 8.22 (m, 1H), 8.15 (dd, J=8.2 Hz, J=1.5 Hz, 1H), 8.00 (m, 2H), 7.92 (d, J=8.9 Hz, 1H), 7.78 (d, J=8.9 Hz, 1H), 7.21 (dd, J=8.0 Hz, J=4.5 Hz, 1H), 6.39 (s, 2H). LRMS (M+1)=426.9.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C([O-])([O-])=O.[K+].[K+].O.[Cl:13][CH:14]([Cl:18])[C:15](Cl)=[O:16]>C1(C)C=CC=CC=1>[Cl:13][CH:14]([Cl:18])[C:15]([N:3]([O:4][CH3:5])[CH3:2])=[O:16]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CNOC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CON(C)C(=O)C(Cl)Cl
Temperature: 0 °C
Yield: 92.5 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (7.94 g, 81.4 mmol) and K2CO3 (17.2 g, 124.1 mmol) were added to a water (70 ml) and toluene (70 ml) mixture. The mixture was then cooled to 0° C. Dichloroacetyl chloride (10 g, 67.85 mmol) was added drop wise and the reaction was allowed to warm to room temperature overnight. The toluene was collected and then the aqueous layer was extracted with EtOAc (2×100 ml). The organic layers were dried over sodium sulfate and concentrated in vacuo to give the title product (10.8 g).
Reaction SMILES: [C:1]([N:3]1[CH2:6][CH:5]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([CH3:30])=[C:16]([NH:18][C:19]([C:21]4[N:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]5=[N:23][CH:22]=4)=[O:20])[CH:17]=3)[N:8]=2)[CH2:4]1)#[N:2].Cl.[NH2:32][OH:33].CCN(C(C)C)C(C)C>C(O)C>[OH:33][N:32]=[C:1]([N:3]1[CH2:4][CH:5]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([CH3:30])=[C:16]([NH:18][C:19]([C:21]4[N:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]5=[N:23][CH:22]=4)=[O:20])[CH:17]=3)[N:8]=2)[CH2:6]1)[NH2:2]
Reactant: Cc1ccc(-c2noc(C3CN(C#N)C3)n2)cc1NC(=O)c1cnc2ccccn12
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2noc(C3CN(C(N)=NO)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 78 °C

Procedure:
A stirring mixture of N-(5-(5-(1-cyanoazetidin-3-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (82) (50 mg, 0.125 mmol), hydroxylamine HCl (13 mg, 0.188 mmol) and DIEA (44 uL, 0.250 mmol) in ethanol was heated at 78° C. for 2 hours. The solvent was concentrated and dried under high vacuum. Crude N-(5-(5-(1-(N′-hydroxycarbamimidoyl)azetidin-3-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (83) was used in the next step without further purification. MS m/z 433.17 (M+1)+.
Reaction SMILES: [C:1]1([C:7]2[C:15]([C:16]3[CH:17]=[N:18][C:19](S(C4C=CC=CC=4)(=O)=O)=[CH:20][CH:21]=3)=[C:10]3[CH:11]=[N:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][O-:32].[Na+]>CO.O1CCOCC1>[CH3:31][O:32][C:19]1[N:18]=[CH:17][C:16]([C:15]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:8][N:9]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=23)=[CH:21][CH:20]=1
Reactant: O=S(=O)(c1ccccc1)c1ccc(-c2c(-c3ccccc3)nn3ccncc23)cn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(-c2c(-c3ccccc3)nn3ccncc23)cn1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A mixture of 2-phenyl-3-[6-(phenylsulfonyl)-3-pyridinyl]pyrazolo[1,5-a]pyrazine (3.93 g) and sodium methoxide (5.2M MeOH solution, 10 mL) in MeOH (60 mL) and 1,4-dioxane (60 mL) was stirred at 85° C. for 1 h. The reaction mixture was concentrated in vacuo, and ice water was added, extracted, with EtOAc, washed with water and brine, dried over sodium sulfate, evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane-EtOAc 2:3) to give 3-(6-methoxy-3-pyridinyl)-2-phenylpyrazolo[1,5-a]pyrazine (2.37 g) as an oil.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:35])[N:24]([CH:32]([CH3:34])[CH3:33])[CH2:25][CH2:26][N:27]2[CH:31]=[N:30][CH:29]=[N:28]2)[CH:20]=[C:19]([Cl:36])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[Cl:36][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:18]=1)[C:23]([N:24]([CH:32]([CH3:33])[CH3:34])[CH2:25][CH2:26][N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)=[O:35]
Reactant: CC(C)N(CCn1cncn1)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(CCn1cncn1)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2-{3-chloro-5-[isopropyl-(2-[1,2,4]triazol-1-yl-ethyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.097 g) in dichloromethane (5 ml) was added trifluoroacetic acid (2 ml) and the mixture was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure and the residue subjected to preparative hplc to give the title compound (0.093 g) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][O:23][CH2:24][CH3:25])[N:14]([CH2:15][C:16]3([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl>FC(F)(F)C(O)=O.C(O)C.[Pt](=O)=O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][O:23][CH2:24][CH3:25])[N:14]([CH2:15][C:16]3([OH:21])[CH2:17][CH2:18][CH2:19][CH2:20]3)[C:10]=2[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCCC1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CCOCc1nc2c(N)nc3c(c2n1CC1(O)CCCC1)CCCC3
Temperature: 60 °C
Reaction time: 120 h

Procedure:
A mixture of 1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopentanol (prepared as described in Example 3, 0.50 g, 1.47 mmol) and platinum (IV) oxide (0.25 g) in trifluoroacetic acid (20 mL) was hydrogenated at 50 psi (3.5×105 Pa) for 5 d on a Parr apparatus. The reaction mixture was filtered through CELITE filter agent and the filtrate was treated with saturated aqueous NaOH until the pH=14, then was extracted with dichloromethane (3×100 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated to an oil that was purified by flash chromatography (silica gel, 10% methanol in dichloromethane). The appropriate fractions were combined and concentrated to yield a colorless oil. The oil was dissolved in ethanol and 2.7 M HCl in ethanol (1 mL) was added and the mixture was concentrated under reduced pressure. The resulting oil was dissolved in water and Na2CO3 was added until the pH=12. A gummy white solid formed and the mixture was heated at 60° C. for 20 min until a free flowing precipitate formed. The mixture was allowed to cool to rt and the precipitate was isolated by filtration and dried in a vacuum oven at 80° C. to provide 1-{[4-amino-2-(ethoxymethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopentanol as a white solid, mp 171-173° C. 1H NMR (300 MHz, DMSO-d6) δ 5.78 (br s, 2H), 4.77 (br s, 2H), 4.66 (s, 1H), 4.45 (br s, 2H), 3.46 (q, J=7.0 Hz, 2H), 2.95 (m, 2H), 2.66 (m, 2H), 1.82-1.36 (m, 12H), 1.11 (t, J=7.0 Hz, 3H); MS (ESI) m/z 345 (M+H)+; Anal. Calcd for C19H28N4O20.2 H2O: C, 65.57; H, 8.22; N, 16.10. Found: C, 65.78; H, 8.27; N, 15.70.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:14][CH2:15][C:16]1[C:17](Cl)=[N:18][CH:19]=[CH:20][CH:21]=1)[CH2:11][CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O>C1COCC1>[CH2:3]([N:10]1[CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[N:18][C:17]=2[O:13][CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCCN(CCc1cccnc1Cl)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CN2CCOc3ncccc3CC2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 76.7 %

Procedure:
Under a nitrogen atmosphere, to a suspension of sodium hydride (60% in oil, 0.24 g) in THF (5 mL) was added a solution of the compound (0.88 g) obtained in step 6 in THF (10 mL) at 0° C., and the mixture was stirred at 80° C. for 6 hr. The reaction mixture was cooled to 10° C., and poured into water. The resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 20→33% ethyl acetate/hexane) to give the title compound (0.59 g, 77%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15](OC3C=CC([N+]([O-])=O)=CC=3)=[O:16])[CH2:12][CH:11]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[OH:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:36]3[CH2:37][CH2:38][CH:33]([OH:32])[CH2:34][CH2:35]3)=[O:16])[CH2:12][CH:11]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)C1CC(c2ccc(CC)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CC(c2ccc(CC)cc2)CN(C(=O)N2CCC(O)CC2)C1
Temperature: 150 °C

Procedure:
370 mg (0.81 mmol) of 3-ethyl 1-(4-nitrophenyl) 5-(4-ethylphenyl)piperidine-1,3-dicarboxylate, 245 mg (2.42 mmol) of 4-hydroxypiperidine and 112 mg (0.81 mmol) of potassium carbonate were added to 9 ml of DMF and heated in a single-mode microwave (Emrys Optimizer) at 150° C. for 15 min. For work-up, water was added and the reaction solution was extracted with ethyl acetate. The organic phase was dried with sodium sulphate and concentrated under reduced pressure. The residue was purified by preparative HPLC. Yield: 208 mg (66% of theory)
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][C:4](=[N:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([OH:20])=[C:12]([C:21]3[NH:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[S:23](=[O:32])(=[O:31])[N:22]=3)[C:11]2=[O:33])[CH2:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][CH:4]([NH:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([OH:20])=[C:12]([C:21]3[NH:26][C:25]4[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=4[S:23](=[O:32])(=[O:31])[N:22]=3)[C:11]2=[O:33])[CH2:3]1
Reactant: CC1CC(=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)CC(C)C1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1CC(C)CC(Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3ccccc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 245A (0.064 g, 0.14 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.010 mL, 0.25 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.100 mL, 0.20 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water, and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with dichlrormethane to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.55 (m, 2 H) 0.87 (m, 6 H) 1.67 (m, 6 H) 3.05 (m, 1 H) 5.66 (dd, J=5.70, 3.86 Hz, 1 H) 7.05 (m, 1 H) 7.28 (t, J=8.27 Hz, 2 H) 7.51 (m, 2 H) 7.66 (d, J=7.72 Hz, 1 H) 7.73 (t, J=7.54 Hz, 1 H) 8.06 (dd, J=7.91, 1.29 Hz, 1 H). MS (ESI−) m/z 465 (M−H)−.
Reaction SMILES: [Na].[F:2][C:3]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:4]=1[NH:5][C:6](=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[SH:7].[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>CN(C)C=O>[F:2][C:3]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:4]=1[NH:5][C:6](=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[S:7][CH2:31][C:30]1[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=1
Reactant: CCOC(=O)C(C(=O)OCC)=C(S)Nc1ccc(F)c(F)c1F
Reactant: COc1ccc(CCl)cc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)=C(Nc1ccc(F)c(F)c1F)SCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Diethyl [(2,3,4-trifluoroanilino)(mercapto)methylene]malonate sodium salt (68.5 g) was dissolved in N,N-dimethylformamide (200 ml) and thereto p-methoxybenzyl chloride (28.9 g) was added dropwise at 3° to 5° C. over a period of 5 minutes. After the reaction mixture was stirred at room temperature for 1 hour and evaporated to dryness under reduced pressure, water was added to the residue and the mixture was extracted with chloroform. After the extract was washed with a NaCl solution and dried over magnesium sulfate, the solvent was distilled off under reduced pressure to give the title compound (82.9 g) as colorless solid, which was then recrystallized from a mixed solvent of haxane - benzene.
Reaction SMILES: [CH3:1][O:2][N:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl.[NH2:18][OH:19]>CO>[CH3:1][O:2][N:3]1[CH2:8][CH2:7][C:6](=[N:18][OH:19])[CH2:5][CH2:4]1
Reactant: CON1CCC(=O)CC1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CON1CCC(=NO)CC1

Procedure:
To a solution of 1-methoxy-piperidin-4-one [prepared according to Journal of Organic Chemistry (1961), 26, 1867-74] (258 g, 2.0 mol) and triethylamine (305.2 ml, 221.9 g, 4.4 mol) in methanol (3000 ml) was added hydroxylamine hydrochloride (277.6 g, 4.0 mol), and the reaction mixture heated at reflux for 1.5 hours. The solvent was evaporated, the residue diluted with diethyl ether and the suspension filtered. The filtrate was washed with water and brine, dried over sodium sulfate and concentrated. Yield: 286.25 g of 1-methoxy-piperidin-4-one oxime as a colorless, viscous oil. This material was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[C:47]([F:48])=[CH:46][CH:45]=[CH:44][C:27]=1[O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:32]3[CH:31]=[CH:30][C:29]([O:28][C:27]4[CH:44]=[CH:45][CH:46]=[C:47]([F:48])[C:26]=4[F:25])=[CH:34][CH:33]=3)[C:3]=12
Reactant: CC1(C)OB(c2ccc(Oc3cccc(F)c3F)cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4F)cc3)c3c(N)ncnc32)C1
Temperature: 90 °C
Reaction time: 12 h
Yield: 81.3 %

Procedure:
Into a 250 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (500 mg, 1.13 mmol, 1.00 equiv) in 1,4-dioxane/H2O (100/30 mL), 2-[4-(2,3-difluorophenoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (420 mg, 1.26 mmol, 1.1 equiv), sodium carbonate (240 mg, 2.26 mmol, 2.0 equiv), and Pd(PPh3)4 (65 mg, 0.06 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 90° C. in an oil bath. The resulting mixture was concentrated under vacuum and the residue was diluted with water. The resulting solution was extracted with dichloromethane and the organic layers were combined, washed with brine and filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was loaded onto a silica gel column and elution with dichloromethane/methanol (10/1) gave 480 mg (82%) of tert-butyl (3R)-3-[4-amino-3-[4-(2,3-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a white solid.