Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20](F)[N:19]=4)[C:11]=3[CH:10]=2)[CH:6]=[N:5][CH:4]=1)[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]1>CS(C)=O>[C:34]([O:33][C:32](=[O:38])[NH:31][C@H:27]1[CH2:28][CH2:29][CH2:30][N:25]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([N:17]3[C:11]4[CH:10]=[C:9]([C:7]5[CH:6]=[N:5][CH:4]=[C:3]([CH2:1][CH3:2])[N:8]=5)[N:14]=[CH:13][C:12]=4[CH:15]=[N:16]3)[N:19]=2)[CH2:26]1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CCc1cncc(-c2cc3c(cn2)cnn3-c2cccc(F)n2)n1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Solvent: CS(C)=O
Product: CCc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)n1
Temperature: 95 °C
Yield: 69.5 %

Procedure:
A solution containing 6-(6-ethylpyrazin-2-yl)-1-(6-fluoro-2-pyridyl)pyrazolo[4,3-c]pyridine (75 mg, 0.23 mmol) and tert-butyl N-[(3S)-3-piperidyl]carbamate (234 mg, 1.17 mmol) in methyl sulfoxide 2.0 mL was heated 95° C. The reaction was quenched with water then extracted with EtOAc. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by flash chromatography (EtOAc/Heptane eluted at 65% EtOAc) to give (S)-tert-butyl(1-(6-(6-(6-ethylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)piperidin-3-yl)carbamate (80 mg) in 68% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([O:11][CH3:12])[CH:5]=1.CCN(CC)CC.[Cl:21][C:22]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:23]=1[C:24](Cl)=[O:25]>ClCCl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:24](=[O:25])[C:23]2[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:22]=2[Cl:21])=[C:6]([O:11][CH3:12])[CH:5]=1
Reactant: COC(=O)c1ccc(N)c(OC)c1
Reactant: O=C(Cl)c1cc(F)ccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)c2cc(F)ccc2Cl)c(OC)c1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A dry, 3-L, 3-necked, round-bottomed flask equipped with a thermometer and addition funnel was charged a solution of 33 (96 g, 0.53 mol, 1.0 equiv.) and Et3N (88 ml, 0.64 mol, 1.2 equiv.) in dichloromethane (1.2 L). The solution was cooled to 0° C. by an ice bath and 2-chloro-5-fluoro-benzoyl chloride (110 g, 0.57 mol, 1.05 equiv.) was added drop-wise over 40 min at 0° C. After the addition, the reaction mixture was stirred at 0° C. for further 1.5 h. The organic layer was washed with brine three times, dried over MgSO4, filtered, and evaporated to yield 4-(2-chloro-5-fluoro-benzoylamino)-3-methoxy-benzoic acid methyl ester 34 as a white solid. 1H NMR (400 MHz, CDCl3) δ: 8.84 (s, 1H), 8.61 (d, 1H), 7.75 (dd, 1H), 7.60 (d, 1H), 7.55 (dd, 1H), 7.45 (dd, 1H), 7.20-7.13 (m, 1H), 3.97 (s, 3H), 3.93 (s, 3H). MS (ES) m/z 338.0 (MH)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34][C:35](=[O:45])[NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43]I)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35](=[O:45])[NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][C:13]1[CH:12]=[CH:11][C:10]([N:16]2[CH2:17][C:18](=[O:29])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[S:20]2(=[O:22])=[O:21])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: CC(C)(C)OC(=O)Nc1ccccc1CI
Product: CC(C)(C)OC(=O)Nc1ccccc1Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and (2-iodomethylphenyl)-carbamic acid tert-butyl ester analogous to Example 57, step B.
Reaction SMILES: [Cl:1][C:2]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:21])[CH:3]=1.C1(C)C=CC=CC=1.Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH:41]=[CH:40][CH:39]=[N:38]2)=[CH:33][CH:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.C(OCC)(=O)C.O.C(O)C>[N:37]1([C:34]2[CH:35]=[CH:36][C:31]([CH2:30][C:11]3[C:2]([Cl:1])=[CH:3][C:4]([OH:21])=[C:5]([CH:10]=3)[C:6]([O:8][CH3:9])=[O:7])=[CH:32][CH:33]=2)[CH:41]=[CH:40][CH:39]=[N:38]1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(Cl)cc1O
Reactant: BrCc1ccc(-n2cccn2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(Cl)cc1O
Temperature: 100 °C
Reaction time: 8 h
Yield: 37.7 %

Procedure:
To a solution of methyl 4-chloro-2-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.15 g) in a mixed solvent of toluene (4.00 mL)-ethanol (0.80 mL)-water (0.80 mL) were added 1-(4-(bromomethyl)phenyl)-1H-pyrazole (0.11 g), tetrakis(triphenylphosphine)palladium(0) (0.06 g) and tripotassium phosphate (0.26 g), and the mixture was stirred overnight at 100° C. under argon atmosphere. The reaction mixture was allowed to be cooled to room temperature, water and ethyl acetate were added thereto, and the mixture was partitioned. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.06 g).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=3)[C:25]([O:27]CC)=[O:26])[C:17]2=[O:33])=[N:13][C:12]=1[CH3:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCCC1.O>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:23]=[C:24]([CH:30]=[CH:31][CH:32]=3)[C:25]([OH:27])=[O:26])[C:17]2=[O:33])=[N:13][C:12]=1[CH3:34])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc(CN2CCN(c3nc(C)c(C(=O)NCc4ccccc4)s3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(N2CCN(Cc3cccc(C(=O)O)c3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 97 %

Procedure:
To a solution of ethyl 3-((3-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoate (0.093 g, 0.19 mmol) in tetrahydrofuran (5 mL) and water (2.5 mL) was added lithium hydroxide monohydrate (0.032 g, 0.77 mmol) at ambient temperature. The resulting reaction mixture was heated to reflux for 14 hours. The solvent was removed in metro, and the residue was neutralized to pH 3˜4 with 10% hydrochloric acid solution. The resulting precipitate was filtered, washed with water (30 mL), hexane (30 mL) and dried to afford the title compound as a colorless solid in 97% yield (0.083 g): mp 120-123° C. (water); 1H NMR (300 MHz, DMSO-d6) δ 13.10 (br s, 1H), 8.49 (t, J=6.0 Hz, 1H), 7.91-7.88 (m, 2H), 7.40-7.38 (m, 2H), 7.32-7.16 (m, 5H), 4.48 (s, 2H), 4.35-4.33 (m, 2H), 4.01-3.96 (m, 2H), 3.48-3.42 (m, 2H), 2.44 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.5, 162.2, 157.8, 155.6, 151.3, 142.0, 140.1, 130.4, 130.1, 128.7, 128.2, 127.6, 127.1, 118.3, 47.1, 43.0, 42.4, 42.2, 17.5; MS (ES+) m/z 451.2 (M+1).
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](Cl)(=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C>ClCCl>[C:1]1([CH:7]2[O:12][CH2:11][CH2:10][N:9]([C:13](=[O:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCC(=O)Cl
Reactant: c1ccc(C2CNCCO2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC(=O)N1CCOC(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.6 %

Procedure:
A solution of 2-phenylmorpholine (326 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and hexanoyl chloride (336.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:4). The fractions containing 1-(2-phenylmorpholin-4-yl)hexan-1-one are collected and the solvent is removed in vacuo to give 437 mg of colorless oil.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][CH:10]=[N:9][C:8]=2[N:7]([CH2:15][CH2:16][CH3:17])[C:5]1=[O:6])[CH2:2][CH3:3].Cl[CH2:19][P:20](=[O:23])([CH3:22])[CH3:21]>>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[N:11]([CH2:19][P:20](=[O:23])([CH3:22])[CH3:21])[CH:10]=[N:9][C:8]=2[N:7]([CH2:15][CH2:16][CH3:17])[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2[nH]cnc2n(CCC)c1=O
Reactant: CP(C)(=O)CCl
Product: CCCn1c(=O)c2c(ncn2CP(C)(C)=O)n(CCC)c1=O

Procedure:
The title substance was prepared from 5 g (0.0186 mol) of 1,3-dipropyl-xanthine and 2.8 g (0.0224 mol) of chloromethyldimethylphosphine oxide analogously to Example 67.
Reaction SMILES: C[O:2][CH2:3][C:4]1[C:8]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[O:10])=[C:7]([CH3:22])[N:6]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[N:5]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][CH2:3][C:4]1[C:8]([C:9]([N:11]2[CH2:12][CH2:13][CH:14]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:15][CH2:16]2)=[O:10])=[C:7]([CH3:22])[N:6]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[N:5]=1
Reactant: COCc1nn(-c2cccc(C(F)(F)F)c2)c(C)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(C(=O)N2CCC(N3CCCC3)CC2)c(CO)nn1-c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 18.7 %

Procedure:
To a solution of 99 mg (0.22 mmol) [3-methoxymethyl-5-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (Example 155D]) in 1.8 ml of CH2Cl2 was treated at −30° C. with 0.28 ml BBr3 (1M in dichloromethane, 0.28 mmol). The reaction was warmed up (0° C. for 1 h) and stirred 1.5 h at 0° C. The reaction was treated with saturated NaHCO3-solution. The mixture was extracted with EtOAc (3×), the organic phase was washed with a NaCl solution (10%), dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography over silica gel with CH2Cl2/MeOH 2.5% to 10%, to give 18 mg (19%) of the title compound as light yellow foam. MS: 437.3 (MH+).
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=[CH:4]1)=O.[CH3:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([CH3:26])[C:22]=1[N+:23]([O-:25])=[O:24])[C:17](O)=[O:18].CNC>O1CCCC1>[CH3:1][N:3]([CH3:4])[C:17](=[O:18])[C:16]1[CH:15]=[C:14]([CH3:13])[C:22]([N+:23]([O-:25])=[O:24])=[C:21]([CH3:26])[CH:20]=1
Reactant: Cc1cc(C(=O)O)cc(C)c1[N+](=O)[O-]
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)N(C)C)cc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1,1′-Carbonyldiimidazole (914 mg) is added to a solution of 3,5-dimethyl-4-nitrobenzoic acid (1 g) in tetrahydrofuran (10 mL). The mixture is stirred for 3 hours at room temperature, dimethylamine (7.7 mL, 2 M in tetrahydrofuran) is added and the mixture is stirred for further 30 minutes. After concentration the mixture is diluted with ethyl acetate and washed with hydrochloric acid (0.2 M), saturated aqueous NaHCO3 solution and brine. The organic phase is dried (Na2SO4) and concentrated to give the title compound. Yield: 1 g; LC (method 20): tR=5.11 min; Mass spectrum (ESI+): m/z=223 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:19])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH2:5]2.C([O-])(=O)C.[K+].Br[C:26]1[C:30]2[C:31]([NH2:35])=[N:32][CH:33]=[CH:34][C:29]=2[S:28][CH:27]=1.C([O-])(O)=O.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.C(OCC)(=O)C.O.O1CCOCC1>[C:13]1([CH2:12][C:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:26]4[C:30]5[C:31]([NH2:35])=[N:32][CH:33]=[CH:34][C:29]=5[S:28][CH:27]=4)=[CH:10][CH:9]=3)[CH2:5][CH2:6]2)=[O:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cc1ccccc1)N1CCc2cc(Br)ccc21
Reactant: Nc1nccc2scc(Br)c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1nccc2scc(-c3ccc4c(c3)CCN4C(=O)Cc3ccccc3)c12
Temperature: 100 °C
Reaction time: 48 h

Procedure:
In a sealed tube, to 5-bromo-1-(phenylacetyl)-2,3-dihydro-1H-indole (0.658 g, 2.081 mmol), bispinacolatodiboron (0.634 g, 2.497 mmol) and potassium acetate (0.613 g, 6.24 mmol) was added 1,4-Dioxane (15 mL) and the mixture was degassed with N2 for 10 minutes. PdCl2(dppf)-CH2Cl2 Adduct (0.085 g, 0.104 mmol) was added and the reaction mixture was stirred for 48 hours at 100° C. The mixture was cooled to room temperature and treated with 5 mL of water, 3-bromothieno[3,2-c]pyridin-4-amine (0.524 g, 2.289 mmol) and NaHCO3 (175 mg). The mixture was degassed with N2 for 10 minutes. PdCl2(dppf)-CH2Cl2 Adduct (0.085 g, 0.104 mmol) was added and the reaction mixture was stirred overnight at 100° C. The mixture was poured onto water and ethyl acetate, then filtered. The filtrate was poured into a separatory funnel. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% CHCl3 to 90:10:1 CHCl3/CH3OH/NH4OH) afforded a few fractions containing the desired product with impurity. The fractions were combined and evaporated. To the resulting residue was dissolved in MeOH/CH2Cl2 (1 mL/5 mL). Then dry loaded and purified by Analogix silica 25/14, gradient 0-100% EtOAc/hexane. The compound came out at 95% EtOAc. The fractions with the pure compound were combined. The solvents were evaporated and the resulting residue was triturated in EtOAc to give off-white solid (280 mg) of the title compound 3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]thieno[3,2-c]pyridin-4-amine. LC-MS (ES) m/z=386.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.16 (d, J=8.3 Hz, 1H) 7.82 (d, J=5.6 Hz, 1H) 7.41 (s, 1H) 7.19-7.38 (m, 8H) 5.41 (br. s., 2H) 4.25 (t, J=8.6 Hz, 2H) 3.89 (s, 2H) 3.23 (t, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=1.CC1(C)C(C)(C)OB([C:23]2[CH2:32][CH2:31][C:26]3([O:30][CH2:29][CH2:28][O:27]3)[CH2:25][CH:24]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.O1CCOCC1>[O:27]1[C:26]2([CH2:31][CH2:32][C:23]([C:2]3[CH:3]=[N:4][N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=3)=[CH:24][CH2:25]2)[O:30][CH2:29][CH2:28]1
Reactant: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1cc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(C2=CCC3(CC2)OCCO3)cn1
Temperature: 160 °C
Yield: 56.7 %

Procedure:
To a 10-20 mL microwave vessel was charged 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (0.60 mmol, 166 mg), 4,4,5,5-tetramethyl-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (0.84 mmol, 224 mg), K3PO4 (1.80 mmol, 382 mg), PdCl2(dppf).CH2Cl2 (0.06 mmol, 50 mg) and 9:1 Dioxane:H2O (15 mL). The suspension was sonicated to break up salts, flushed with argon, sealed, and heated to 160° C. for 45 minutes in microwave synthesizer. The reaction was concentrated in vacuo, and the residue purified via silica gel chromatography (0% to 60% ethyl acetate in hexanes) to yield 4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (115 mg, 0.34 mmol, 57% yield) as clear oil.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH:10]([CH:12]([OH:14])[CH3:13])[CH2:9][N:8]1[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])=[O:6])[CH:2]=[CH2:3].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CC(O)C>CC(C)=O>[C:12]([CH:10]1[CH2:11][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[N:8]([C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])[CH2:9]1)(=[O:14])[CH3:13]
Reactant: C=CCOC(=O)N1CC(C(C)O)CN1C(=O)OCC=C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: C=CCOC(=O)N1CC(C(C)=O)CN1C(=O)OCC=C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of 1,2-bis(allyloxycarbonyl)-4-(1-hydroxyethyl)pyrazolidine (13 g) in acetone (260 ml) was added dropwise Jones Reagent (2.67N, 34 ml) at 0° C. After stirring for 1 hour, to the reaction mixture was added dropwise 2-propanol (200 ml) and the reaction mixture was stirred at 0° C. for 1 hour. The precipitate was filtered off and the filtrate was evaporated to give a residual oil, which was extracted with ethyl acetate and the organic layer was separated, washed with brine, and dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (300 ml) eluting with a mixture of hexane and ethyl acetate (1:1, V/V) to give 4-acetyl-1,2-bis(allyloxycarbonyl)pyrazolidine (9.18 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[N:26][NH:27]2)=[C:23]([NH:30][C:31]([C:33]2[N:34]=[C:35]([CH3:38])[S:36][CH:37]=2)=[O:32])[CH:22]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]1[C:10]2[C:5](=[C:6]([C:21]3[CH:29]=[C:28]4[C:24]([CH:25]=[N:26][NH:27]4)=[C:23]([NH:30][C:31]([C:33]4[N:34]=[C:35]([CH3:38])[S:36][CH:37]=4)=[O:32])[CH:22]=3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Cc1nc(C(=O)Nc2cc(Br)cc3[nH]ncc23)cs1
Reactant: OB(O)c1cccc2cnccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1nc(C(=O)Nc2cc(-c3cccc4cnccc34)cc3[nH]ncc23)cs1
Temperature: 150 °C

Procedure:
5-Isoquinolinylboronic acid (21 mg), 0.6M potassium carbonate solution (200 μl) and Pd(dppf)Cl2 (10 mg) in 1,4-dioxane (1 ml) were treated with a solution of N-(6-bromo-1H-indazol-4-yl)-2-methyl-1,3-thiazole-4-carboxamide (40 mg) in 1,4-dioxane (1 ml). The reaction vessel was sealed and heated under microwave irradiation at 150° C. for 30 min. After cooling the solvent was removed in vacuo. The sample was redissolved in methanol and loaded onto C18 reverse phase SPE (0.5 g). Product was eluted with acetonitrile/TFA (0.1%) (3×3 ml), and concentrated under a stream of nitrogen using blow down apparatus. Purification by mass directed preparative HPLC (Method C) gave the title compound.
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=2[C:7]=1[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]2[CH3:17])=[C:10]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:9]=1)[CH3:2].[NH:30]1[CH2:35][CH2:34][CH:33]([C:36]([OH:39])([CH3:38])[CH3:37])[CH2:32][CH2:31]1>>[CH2:1]([C:3]1[O:4][C:5]2[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=2[C:7]=1[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[C:13]([CH2:18][N:30]3[CH2:35][CH2:34][CH:33]([C:36]([OH:39])([CH3:38])[CH3:37])[CH2:32][CH2:31]3)[N:14]2[CH3:17])=[C:10]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:9]=1)[CH3:2]
Reactant: CC(C)(O)C1CCNCC1
Reactant: CCc1oc2ccccc2c1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Product: CCc1oc2ccccc2c1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1

Procedure:
Following General Procedure L for reductive amination, 2-(2-ethylbenzofuran-3-yl)-9-methyl-6-morpholino-9H-purine-8-carbaldehyde and 2-(piperidin-4-yl)propan-2-ol were reacted to give 430. [M+H]+ 519.6
Reaction SMILES: ClC1C=CC(C2(O)CCN(CCC=C3C4C(=NC=CC=4)OC4C=CC=C(OCC(OCC)=O)C=4C3)CC2)=CC=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2([OH:83])[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][CH:55]=[C:56]3[C:66]4[C:61](=[N:62][CH:63]=[CH:64][CH:65]=4)[O:60][C:59]4[CH:67]=[CH:68][CH:69]=[C:70]([O:71][CH2:72][C:73]5[CH:78]=[CH:77][C:76]([C:79]([O:81]C)=[O:80])=[CH:75][CH:74]=5)[C:58]=4[CH2:57]3)[CH2:49][CH2:48]2)=[CH:43][CH:42]=1>>[C:79]([C:76]1[CH:77]=[CH:78][C:73]([CH2:72][O:71][C:70]2[C:58]3[CH2:57][C:56](=[CH:55][CH2:54][CH2:53][N:50]4[CH2:49][CH2:48][C:47]([C:44]5[CH:43]=[CH:42][C:41]([Cl:40])=[CH:46][CH:45]=5)([OH:83])[CH2:52][CH2:51]4)[C:66]4[C:61]([O:60][C:59]=3[CH:67]=[CH:68][CH:69]=2)=[N:62][CH:63]=[CH:64][CH:65]=4)=[CH:74][CH:75]=1)([OH:81])=[O:80]
Reactant: COC(=O)c1ccc(COc2cccc3c2CC(=CCCN2CCC(O)(c4ccc(Cl)cc4)CC2)c2cccnc2O3)cc1
Agent: CCOC(=O)COc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Product: O=C(O)c1ccc(COc2cccc3c2CC(=CCCN2CCC(O)(c4ccc(Cl)cc4)CC2)c2cccnc2O3)cc1

Procedure:
The titled compound was prepared by following the procedure of example 133, but replacing the product of example 48 with the product of example 301.
Reaction SMILES: Br[C:2]1[C:3]([CH3:16])=[C:4]([O:14][CH3:15])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[CH3:13].[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[CH3:15][O:14][C:4]1[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]([CH3:13])=[C:2]([N:27]2[CH2:28][CH2:29][N:24]([C:21]3[CH:22]=[CH:23][C:18]([CH3:17])=[CH:19][CH:20]=3)[CH2:25][CH2:26]2)[C:3]=1[CH3:16]
Reactant: COc1c(C)c(Br)c(C)c2c1OC(C)(C)C2
Reactant: Cc1ccc(N2CCNCC2)cc1
Product: COc1c(C)c(N2CCN(c3ccc(C)cc3)CC2)c(C)c2c1OC(C)(C)C2
Yield: 55 %

Procedure:
By using 5-bromo-7-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran (1.80 g, 6.31 mmol) synthesized in Reference example 94 and 1-(4-methylphenyl)piperazine (2.22 g, 12.6 mmol), the reaction was carried out in the same manner as Example 1 to synthesize the title compound 1.32 g (yield 55%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=2)[C:3]=1[CH2:21][CH2:22][CH3:23].[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C>[N:24]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=2)[C:3]=1[CH2:21][CH2:22][CH3:23])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(Cl)ncnc1Cn1ccnc1-c1cccc(F)n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(Cn2ccnc2-c2cccc(F)n2)ncnc1N=[N+]=[N-]

Procedure:
A solution of 103 (2.25 mmol) and NaN3 (731 mg, 11.25 mmol) in DMF (15 ml) is heated at 70° C. in a sealed tube overnight. The solvent is removed in vacuo and water (10 ml) and EtOAc (10 ml) are added to the residue. The layers are separated and the aqueous layer is extracted with EtOAc (2×10 ml). The combined extracts are washed with brine (15 ml) and dried with Na2SO4. The solvent is removed in vacuo and the resulting yellow oil (104) is used in the next step without further purification.
Reaction SMILES: N#N.[O:3]=[C:4]([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][CH:11]=[C:12]([C:14](Cl)=[O:15])[N:13]=1.[N-:18]=[N+:19]=[N-:20].[Na+]>CC(C)=O.O>[O:3]=[C:4]([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][CH:11]=[C:12]([C:14]([N:18]=[N+:19]=[N-:20])=[O:15])[N:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)CCCCc1nc(C(=O)Cl)co1
Agent: N#N
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)CCCCc1nc(C(=O)N=[N+]=[N-])co1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of this crude 2-(5-oxo-hexyl)-oxazole-4-carbonyl chloride was dissolved in dry acetone (19.0 mL). The solution was cooled to 0° C. and a solution of sodium azide (315 mg, 4.79 mmol) in H2O (2.2 mL) was added dropwise. The reaction mixture was stirred at 0° C. for 1.5 h. The mixture was concentrated under reduced pressure, and the residue was dissolved in CH2Cl2 and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a brown solid. LC-MS-conditions 02: tR=0.82 min.