Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21].O.[NH2:30][NH2:31].O>CN(C=O)C>[C:12]1([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:30][N:31]=[C:19]([CH:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:21])[C:3]=3[C:4]2=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C(=O)c1c(O)c2cccnc2n(-c2ccccc2)c1=O)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1ccccc1)c1n[nH]c2c1c(=O)n(-c1ccccc1)c1ncccc21
Temperature: 105 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-hydroxy-1-phenyl-3-(2-phenylpropionyl)-1,8-naphthyridin-2(1H)-one (370 mg, 1.0 mmol) produced in Synthesis Example 8 in DMF (8 mL) was added hydrazine monohydrate (purity of 80%, 160 μL), and the mixture was stirred at 100 to 110° C. for 3 hours. To the reaction solution was added water. The resulting precipitate was separated by filtration, washed with water, and dried to give 5-phenyl-3-(1-phenylethyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one as a form of crystal (306 mg, yield 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.CO[CH:10]1[CH2:14][CH2:13][CH:12](OC)O1>C(O)(=O)C>[N:5]1[CH:6]=[CH:7][C:2]([N:1]2[CH:10]=[CH:14][CH:13]=[CH:12]2)=[CH:3][CH:4]=1
Reactant: Nc1ccncc1
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: c1ccn(-c2ccncc2)c1

Procedure:
A 1-liter 3-neck flask equipped with stirrer, condenser, heating mantle, addition funnel and thermometer is charged with 47 g (0.5 mole) of 4-aminopyridine and 66 g (0.5 mole) of 2,5-dimethoxytetrahydrofuran. These materials are mixed together and 210 ml of glacial acetic acid is added dropwise with stirring over ten minutes while maintaining the temperature at less than 20°C.
Reaction SMILES: C(OC(N1CCC(C([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]4[NH:33][C:32]5[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=5[N:30]=4)[CH:23]=3)[CH2:18][CH2:17]2)=O)CC1)=O)(C)(C)C.CC[O:40][CH2:41][CH3:42]>C(Cl)Cl>[NH:33]1[C:32]2[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=2[N:30]=[C:29]1[C:24]1[CH:23]=[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:42]3([CH:41]=[O:40])[CH2:20][CH2:21][NH:16][CH2:17][CH2:18]3)[CH2:17][CH2:18]2)[CH:27]=[CH:26][C:25]=1[F:28]
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(c3ccc(F)c(-c4nc5ccccc5[nH]4)c3)CC2)CC1
Solvent: ClCCl
Product: O=CC1(N2CCN(c3ccc(F)c(-c4nc5ccccc5[nH]4)c3)CC2)CCNCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72 %

Procedure:
To a solution of 4-{4-[3-(1H-Benzoimidazol-2-yl)-4-fluoro-phenyl]-piperazine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester (0.08 g, 0.16 mmol) in DCM (1 mL) 2M HCl in Et2O (3.0 mL) was added and the resulting suspension was stirred at room temperature for 3 days. The reaction was concentrated under reduced pressure, water (8 mL) was added and the solution was concentrated under reduced pressure. The solid was purified by preparative HPLC. HPLC fractions were neutralized with K2CO3 and concentrated. DCM (5 mL) and water (5 mL) were added, organic phase was separated and concentrated to give 44 mg of the title compound (72%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[N:22]([CH:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[N:25]=3)[CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[N:22]([CH:33]4[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]4)[CH:23]=[C:24]([C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)[N:25]=3)[CH:18]=[CH:17][N:16]=2)[CH2:12][CH2:13]1
Reactant: CN1CCC(n2cc(-c3ccc(F)cc3)nc2-c2ccnc(NC3CCN(Cc4ccccc4)CC3)n2)CC1
Agent: [Pd]
Product: CN1CCC(n2cc(-c3ccc(F)cc3)nc2-c2ccnc(NC3CCNCC3)n2)CC1
Reaction time: 18 h

Procedure:
A mixture of 5-[(2-(1-benzyl-4-piperidinylamino)pyrimidin-4-yl]-4-(4-fluorophenyl)-1-(1-methylpiperdin-4-yl)imidazole (0.50 g, 0.95 mmol) and 10% palladium on carbon (10%) was stirred under an atmosphere of H2 for 18 h. The catalyst was removed by filtration and the filtrate was evaporated under reduced pressure. The residue was recrystallized from EtOAc/hexanes to afford the title compound as a whim solid; yield 0.98 g (24%): mp=201°-203° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[N:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]2=[N:20][C:19]=1[CH3:27]>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:17][C:18]2[N:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]3=[N:20][C:19]=2[CH3:27])[N:5]=[C:4]([OH:9])[CH:3]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cc1nc2ccccn2c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2c(C)nc3ccccn23)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (522 mg, 3.7 mmol) was dissolved in anhydrous DMF (20 mL), then were added potassium carbonate (1.52 g, 11.0 mmol) and 3-(bromomethyl)-2-methylimidazo[1,2-a]pyridine (5.5 mmol) in DMF (10 mL). The mixture was stirred overnight at room temperature. The solid was removed by filtration washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 4-12% DCM/MeOH to afford 6-methyl-2-[({2-methylimidazo[1,2-a]pyridin-3-yl}methyl)sulfanyl]pyrimidin-4-ol (165 mg, 16% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.23 (s, 3H), 2.42 (s, 3H), 4.84 (s, 2H), 6.01 (s, 1H), 6.94 (dt, J=6.8 Hz, J=1.4 Hz, 1H), 7.21-7.26 (m, 1H), 7.47 (td, J=9.0 Hz, J=1.0 Hz, 1H), 8.43 (td, J=6.8 Hz, J=1.2 Hz, 1H); LRMS (ES+) m/z 287 (80%, M+1).
Reaction SMILES: N.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:4]=1[NH:14][N:15]=[C:16]([CH2:19][C:20]#[N:21])[C:17]#[N:18]>O.C(O)C>[NH2:21][C:20]1[N:14]([C:4]2[C:3]([Cl:2])=[CH:8][C:7]([C:9]([F:11])([F:12])[F:10])=[CH:6][C:5]=2[Cl:13])[N:15]=[C:16]([C:17]#[N:18])[CH:19]=1
Reactant: N#CCC(C#N)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: N
Solvent: O
Solvent: CCO
Product: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reaction time: 0.17 h
Yield: 98.7 %

Procedure:
Ammonia (20 microliters of an 8% ammonia solution in water) was added to a mixture of the above 2-(2,6-dichloro-4-trifluoromethylphenylhydrazono)-succinonitrile (0.077 g) in ethanol (1 ml) and water (0.2 ml) at 0° C. After 10 minutes, the mixture was extracted (dichloromethane) and evaporated to give 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.076 g, 97% yield). Purity 98% (by hplc).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:14](=[O:15])[C@@H:13]2[CH2:16][C@H:9]1[CH2:10][CH2:11][C@@H:12]2[NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[BH4-].[Na+]>C1COCC1>[CH2:21]([O:20][C:18]([NH:17][C@H:12]1[CH2:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:16][C@H:13]1[CH2:14][OH:15])=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CO)C1
Reaction time: 5 h
Yield: 102.6 %

Procedure:
(1R,2S,5R)-2-Benzyloxycarbonylamino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester (500 mg, 1.3 mmol) was dissolved in THF (10 mL) and water (2.2 mL) prior to the addition of NaBH4 (252.4 mg). After 5 h, the reaction was quenched with saturated NaHCO3 solution and extracted with EtOAc (2×). The organic extracts were combined, dried (MgSO4), filtered, and concentrated in vacuo to afford tert-butyl (1R,3R,4S)-4-benzyloxycarbonylamino-3-(hydroxymethyl)cyclohexylcarbamate (505 mg). MS (ES+)=375.4 (M+H)+.
Reaction SMILES: C[O-].[Na+].[O:4]1[CH:8]=[CH:7][C:6]([CH:9]=O)=[CH:5]1.[N+:11]([CH3:14])([O-:13])=[O:12].CCOCC>CO>[N+:11]([CH:14]=[CH:9][C:6]1[CH:7]=[CH:8][O:4][CH:5]=1)([O-:13])=[O:12]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccoc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: O=[N+]([O-])C=Cc1ccoc1
Temperature: 0 °C
Yield: 69 %

Procedure:
A freshly prepared solution of sodium methoxide (prepared by dissolving sodium (0.46 g, 20 mmol) in MeOH (5 mL)) was added very slowly via a double ended needle to a solution of 3-furaldehyde (1.73 mL, 20 mM) and nitromethane (1.08 mL, 20 mmol) in MeOH (4 mL) cooled to 0° C. The mixture was stirred at 0° C. an addition 5 min, then Et2O (10 mL) was added. The resultant salt was collected via filtration, thoroughly washed with Et2O, taken up in a minimum amount of water then the solution was added to an ice cold solution of 25% HCl (80 mL). The solid that formed was collected by filtration and washed with water, then the moist product was taken up in CHCl3/MeOH and solvents removed to give 3-(2-nitrovinyl) furan (69%) as a pale yellow solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[F:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1>C(N(CC)CC)C>[CH:10]1[C:11]([O:14][C:4]([CH2:3][CH2:2][Cl:1])=[O:5])=[CH:12][CH:13]=[C:8]([F:7])[CH:9]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=C(Cl)CCCl
Solvent: CCN(CC)CC
Product: O=C(CCCl)Oc1ccc(F)cc1
Temperature: 60 °C
Yield: 97.8 %

Procedure:
3-Chloropropionyl chloride (391.5 g) and 3 drops of triethylamine is added to 4-fluorophenol (308.3 g) under stirring at 60° C. After heating to 100° C. for 1.5 hrs, distillation gives 544.7 g of (I) boiling at 126°-130° C. 10 mm Hg.
Reaction SMILES: Cl.Cl.[Cl:3][CH2:4][C:5](=[NH:7])[NH2:6].Cl[C:9](=[CH2:12])[C:10]#[N:11].C(N(CC)CC)C>C(O)C>[Cl:3][CH2:4][C:5]1[N:6]=[C:10]([NH2:11])[CH:9]=[CH:12][N:7]=1
Reactant: N=C(N)CCl
Reactant: C=C(Cl)C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Nc1ccnc(CCl)n1
Yield: 18 %

Procedure:
A solution of 2-chloroacetimidamide dihydrochloride 124 (250.0 g, 1.51 mol), 2-chloroacrylonitrile 125 (171 g, 1.95 mol) and triethylamine (490 g, 4.8 mol) in anhydrous ethanol (600 mL) was heated at reflux for 30 min. The solvent was removed in vacuo and the residue was purified by flash chromatography (dichloromethane:methanol=30:1) to give 126 (39.0 g, 18% yield).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=[O:3].[C:23]([NH:31][CH:32]1[C:38](=[O:39])[N:37]2[CH:40]([C:44]([NH:46][CH:47]([CH:56]([OH:68])[CH2:57][O:58][CH2:59][C:60]3[C:65]([Cl:66])=[CH:64][CH:63]=[CH:62][C:61]=3[Cl:67])[CH2:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:45])[CH2:41][CH2:42][CH2:43][N:36]2[C:35](=[O:69])[CH2:34][CH2:33]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl.CCOC(C)=O>[C:23]([NH:31][CH:32]1[C:38](=[O:39])[N:37]2[CH:40]([C:44]([NH:46][CH:47]([C:56](=[O:68])[CH2:57][O:58][C:59](=[O:3])[C:60]3[C:65]([Cl:66])=[CH:64][CH:63]=[CH:62][C:61]=3[Cl:67])[CH2:48][C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])=[O:45])[CH2:41][CH2:42][CH2:43][N:36]2[C:35](=[O:69])[CH2:34][CH2:33]1)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(O)COCc1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(=O)COC(=O)c1c(Cl)cccc1Cl
Reaction time: 1 h
Yield: 69.5 %

Procedure:
Dess-Martin reagent (3.82 g; 9.0 mmol) was added to a stirred solution of the alcohol 215e (3.17 g; 4.5 mmol) in CH2Cl2 (100 ml). The mixture was sirred for 1 h, diluted with EtOAc (300 ml), then washed with a 1:1 mixture of sat. Na2S2O3 and sat. NaHCO3 (100 ml) followed by brine (100 ml). The mixture was dried (MgSO4) then concentrated. The residue was purified by flash chromatography to afford 2.2 g (70%) of 216e as a colourless solid: mp 102-107° C.; [α]D32 −82.5 (c 0.1, CH2Cl2); IR (KBr) 3374, 2937, 1739, 1661, 1525, 1433, 1275, 1260, 1152; 1H NMR (CDCl3) δ7.85-7.78 (2H, m), 7.57-7.32 (6H, m), 7.09 (1H, d, J=7.9), 7.01 (1H, d, J 7.3), 5.25-5.16 (1H, m), 5.16-5.05 (1H, m), 5.15 (1H, d), 5.03 (1H, d), 4.99-4.90 (1H, m), 4.68-4.54 (1H, m), 3.31-3.17 (1H, m), 3.17-2.72 (4H, m), 2.45-2.35 (1H, m), 2.30-1.66 (5H, m), 1.44 (9H, s); Anal. Calcd for C33H36Cl2N4O9.0.5H2O: C, 55.62; H, 5.23; N, 7.86; Cl, 9.95. Found: C, 55.79; H, 5.15; N, 7.80; Cl 9.81. MS (ES+) 729/7/5 (M+Na), 707/5/3 (M+1), 163 (100%).
Reaction SMILES: C([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[C:25]4[C:31]([C:32]5[C:33]([CH3:46])=[N:34][N:35]([CH2:38][C:39]6[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[CH:40]=6)[C:36]=5[CH3:37])=[CH:30][N:29]([S:47]([C:50]5[CH:56]=[CH:55][C:53]([CH3:54])=[CH:52][CH:51]=5)(=[O:49])=[O:48])[C:26]4=[N:27][CH:28]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[F:45][C:41]1[CH:40]=[C:39]([CH:44]=[CH:43][CH:42]=1)[CH2:38][N:35]1[C:36]([CH3:37])=[C:32]([C:31]2[C:25]3[C:26](=[N:27][CH:28]=[C:23]([C:20]4[CH:21]=[CH:22][C:17]([N:14]5[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][OH:8])[CH2:16][CH2:15]5)=[CH:18][CH:19]=4)[CH:24]=3)[N:29]([S:47]([C:50]3[CH:51]=[CH:52][C:53]([CH3:54])=[CH:55][CH:56]=3)(=[O:48])=[O:49])[CH:30]=2)[C:33]([CH3:46])=[N:34]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(CCOCc6ccccc6)CC5)cc4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(CCO)CC5)cc4)cnc32)cc1
Temperature: 70 °C
Yield: 157.1 %

Procedure:
5-(4-(4-(2-(benzyloxy)ethyl)piperazin-1-yl)phenyl)-3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (150 mg, 0.195 mmol) was dissolved in trifluoroacetic acid/toluene (5/5 ml) and heated to 70° C. for overnight. Solvents evaporated off to yield 208 mg of the crude titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH:16]=[C:15](OS(C(F)(F)F)(=O)=O)[N:14]([C@H:25]([C:27]2[CH:37]=[CH:36][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=2)[CH3:26])[N:13]=1.[CH3:38][O:39][C:40]1[CH:41]=[C:42]2[C:47](=[CH:48][CH:49]=1)[CH:46]=[C:45](B(O)O)[CH:44]=[CH:43]2.C(N(CC)CC)C.N#N>COCCOC.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[CH:16]=[C:15]([C:45]2[CH:44]=[CH:43][C:42]3[C:47](=[CH:48][CH:49]=[C:40]([O:39][CH3:38])[CH:41]=3)[CH:46]=2)[N:14]([C@H:25]([C:27]2[CH:28]=[CH:29][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:36][CH:37]=2)[CH3:26])[N:13]=1
Reactant: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(C(F)(F)F)ccc3F)cc2OS(=O)(=O)C(F)(F)F)cc1
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(C(F)(F)F)ccc3F)cc2-c2ccc3cc(OC)ccc3c2)cc1
Temperature: 100 °C

Procedure:
Ethyl 4-[(1S)-1-(3-[2-fluoro-5-(trifluoromethyl)phenyl]-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazol-1-yl)ethyl]benzoate (1.05 g, 1.90 mmol), 6-methoxy-2-naphthylboronic acid (0.43 g, 2.1 mmol), and triethylamine (0.53 ml, 3.8 mmol) were dissolved in DME (20 ml). After deoxygenation (vacuum-N2 cycles) Pd(PPh3)4 (85 mg, 4% mol) was added. The mixture was deoxygenated again and heated in microwave reactor to 100° C. for 15 min. The reaction mixture was filtered through a Celite pad, concentrated and purified by flash column chromatography (SiO2, 5-20% ethyl acetate in hexane gradient) to give ethyl 4-{(1S)-1-[3-[2-fluoro-5-(trifluoromethyl)phenyl]-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoate as colorless gel. NMR (500 MHz, CDCl3) δ: 1.38 (t, J=7.1 Hz, 3H); 1.99 (d, J=7.1 Hz, 3H); 3.96 (s, 3H); 4.37 (q, J=7.1 Hz, 2H); 5.64 (q, J=7.1 Hz, 1H); 6.87 (d, JF-H=4.2 Hz, 1H); 7.17 (d, J=2.5 Hz, 1H); 7.20 (dd, J=2.5 Hz, 8.9 Hz, 1H); 7.25 (t, J=9.5 Hz, 1H); 7.30 (d, J=8.4 Hz, 2H); 7.32 (dd, J=1.5 Hz, 8.4 Hz, 1H); 7.56 (m, 1H); 7.66 (d, J=1.5 Hz, 1H); 7.68 (d, J=8.9 Hz, 1H); 7.77 (d, J=8.4 Hz, 1H); 8.00 (d, J=8.4 Hz, 2H); 8.48 (dd, J=2.7 Hz, 6.8 Hz, 1H). MS C32H26F4N2O3 Cald: 562.19; Obsd (M+1): 563.33.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[OH:31][CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:37]4[CH2:38][CH2:39][N:34]([CH2:33][CH2:32][OH:31])[CH2:35][CH2:36]4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Reactant: OCCN1CCNCC1
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1CCN(CCO)CC1

Procedure:
In the mamner of Example 103, 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide and 4-(2-hydroxy-ethyl) piperazine was converted to 32.3 mg of the title compound (free base) and mass spectrum (electrospray, m/e): M+H 539.1, 42.2 mg of the title compound as the bis-trifluoroacetate salt); mass spectrum (electrospray, m/e): M+H 539.1.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.CON(C)[C:35](=[O:48])[C:36]1[CH:41]=[CH:40][N:39]=[C:38]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH:37]=1>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:35]([C:36]3[CH:41]=[CH:40][N:39]=[C:38]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[CH:37]=3)=[O:48])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CON(C)C(=O)c1ccnc(N2CCOCC2)c1
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccnc(N2CCOCC2)c1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (590 mg, 1.2 mmol) in THF (2 mL) was added isopropylmagnesium chloride (1.3 mL, 2.6 mmol) slowly at 0° C. One hour later, N-methoxy-N-methyl-2-morpholin-4-yl-isonicotinamide (300 mg, 1.2 mmol) was added and warmed up to RT while stirring overnight, quenched with water, extracted with ethyl acetate, concentrated and purified by flash column to give 4-chloro-N-[5-chloro-2-(2-morpholin-4-yl-pyridine-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[C:21]([O:33][CH3:34])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[NH:35]1[CH2:39][CH2:38][CH2:37][C@@H:36]1[CH2:40][OH:41]>>[CH3:34][O:33][C:21]1[CH:20]=[C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:35]4[CH2:39][CH2:38][CH2:37][C@@H:36]4[CH2:40][OH:41])[C:17]=23)[CH:24]=[CH:23][C:22]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: OC[C@H]1CCCN1
Reactant: COc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1ccccn1
Product: COc1cc(Nc2ncnc3[nH]nc(OCCN4CCC[C@@H]4CO)c23)ccc1OCc1ccccn1
Yield: 47 %

Procedure:
The procedure described in Example 55 was repeated using 2-[(4-{[3-methoxy-4-(pyridin-2-ylmethoxy)phenyl]amino}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)oxy]ethyl methanesulfonate and (R)-2-pyrrolidinemethanol to give the title compound in 47% yield; NMR Spectrum: 1.50 (m, 1H), 1.65 (m, 2H), 1.79 (m, 1H), 2.33 (q, 1H), 2.58 (m, 1H), 2.79 (dt, 1H), 3.15 (td, 1H), 3.27 (m, 1H), 3.41 (m, 1H), 3.81 (s, 3H), 4.40 (t, 2H), 4.43 (t, 1H), 5.16 (s, 2H), 7.00 (d, 1H), 7.27 (dd, 1H), 7.36 (m, 2H), 7.39 (d, 1H), 7.55 (d, 1H), 7.85 (td, 1H), 8.21 (s, 1H), 8.26 (s, 1H), 8.58 (d, 1H); Mass Spectrum: 492 (MH+).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH2:26][CH:27]2[CH2:32][CH2:31][CH:30]([C:33]([O:35]CC)=[O:34])[CH2:29][CH2:28]2)=[N:6][C:7]2[N:8]([N:11]=[CH:12][C:13]=2[C:14]2[CH:15]=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)[C:9]=1[NH2:10])(=O)[CH3:2].O.[NH2:39]N>CN1C(=O)CCC1>[CH3:2][C:1]1[C:4]2[C:5]([CH2:26][CH:27]3[CH2:28][CH2:29][CH:30]([C:33]([OH:35])=[O:34])[CH2:31][CH2:32]3)=[N:6][C:7]3[N:8]([N:11]=[CH:12][C:13]=3[C:14]3[CH:15]=[N:16][C:17]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][CH:19]=3)[C:9]=2[NH:10][N:39]=1
Reactant: NN
Reactant: CCOC(=O)C1CCC(Cc2nc3c(-c4ccc(-c5ccccc5)nc4)cnn3c(N)c2C(C)=O)CC1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1n[nH]c2c1c(CC1CCC(C(=O)O)CC1)nc1c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 20 mL scintillation vial was charged ethyl 4-((6-acetyl-7-amino-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)cyclohexanecarboxylate (Int-4o, 72 mg, 0.144 mmol). To this vial was added NMP (2 mL) followed by hydrazine monohydrate (1 mL). The reaction was stirred at room temperature for 18 hours. At 18 hours, the hydrazine monohydrate was removed in vacuo and the crude 4-((7-amino-6-(1-hydrazonoethyl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)cyclohexanecarbohydrazide (Int-4p) was transferred into 2-5 mL microwave vessel. The vial was sealed and heated to 200° C. for 45 minutes in microwave. After 45 minutes, the NMP was removed in vacuo using chlorobenzene as a cosolvent. The residue was dried on high vacuum over night. The crude 4-((3-methyl-6-(6-phenylpyridin-3-yl)-1H-dipyrazolo[1,5-a:4′,3′-e]pyrimidin-4-yl)methyl)cyclohexanecarbohydrazide (Int-4q) was taken up in 4 N HCl in 1,4-dioxane (2 mL). To this was added H2O (1 mL). This solution was stirred at 70° C. for 2 hours. After 2 hours, the solvent was removed in vacuo. The residue was purified via reverse-phase preparatory HPLC to yield 4-((3-methyl-6-(6-phenylpyridin-3-yl)-1H-dipyrazolo[1,5-a:4′,3′-e]pyrimidin-4-yl)methyl)cyclohexanecarboxylic acid (5) (m+H=467.23, retention time=3.66 min).
Reaction SMILES: Cl[C:2]1[N:3]([CH3:13])[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[N:14]1([C:2]2[N:3]([CH3:13])[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: C1CNCCN1
Reactant: Cn1c(Cl)c(C=O)c2ccccc21
Product: Cn1c(N2CCNCC2)c(C=O)c2ccccc21
Yield: 24 %

Procedure:
2-Chloro-1-methyl-1H-indole-3-carboxaldehyde (1.0 g, 5.5 mmol) is reacted with piperazine as described in Example 2 to yield the title compound (24%) as an orange-brown solid. MS 244 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][NH:9]C(OC(C)(C)C)=O)=[C:6]([F:17])[C:5]([CH2:18][NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:4][CH:3]=1.[F:26][C:27]([F:40])([F:39])[C:28]1[CH:38]=[CH:37][C:31]([C:32]([N:34]=[C:35]=[O:36])=O)=[CH:30][CH:29]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:18][NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:22])[CH3:23])=[C:6]([F:17])[C:7]=1[N:8]1[C:35](=[O:36])[NH:34][C:32]([C:31]2[CH:37]=[CH:38][C:28]([C:27]([F:40])([F:39])[F:26])=[CH:29][CH:30]=2)=[N:9]1
Reactant: CC(C)(C)OC(=O)NNc1c(Cl)ccc(CNC(=O)C(C)(C)C)c1F
Reactant: O=C=NC(=O)c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C(F)(F)F)cc3)[nH]c2=O)c1F
Yield: 73.5 %

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(6-chloro-2-fluoro-3-(pivalamidomethyl)phenyl)hydrazinecarboxylate (Intermediate-57, 0.050 g, 0.13 mmol), 4-(trifluoromethyl)benzoyl isocyanate (Intermediate-59, 0.060 g, 0.26 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.045 g of desired product. 1H NMR (400 MHz, DMSO d6): δ 1.12 (s, 9H), 4.30 (d, J=4.4 Hz, 2H), 7.41 (t, J=8 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.91 (d, J=8.4 Hz, 2H), 8.0 (d, J=8.2 Hz, 2H), 8.17 (t, J=5.8 Hz, 1H), 12.9 (br s, 1H); MS (m/z): 471.10 (M+H+).