Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1.C(N(CC)CC)C.[CH:22]1([C:25]2[CH:26]=[C:27]([NH2:30])[NH:28][N:29]=2)[CH2:24][CH2:23]1>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:30][C:27]2[NH:28][N:29]=[C:25]([CH:22]3[CH2:24][CH2:23]3)[CH:26]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][N:3]=1
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: Clc1ncc(-c2ccccc2)c(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Clc1ncc(-c2ccccc2)c(Nc2cc(C3CC3)n[nH]2)n1
Yield: 60 %

Procedure:
To 2,4-Dichloro-5-phenyl-pyrimidine (187 mg, 0.83 mmol) and triethylamine (255 μL, 1.83 mmol) in ethanol (25 mL) was added 5-Cyclopropyl-2H-pyrazol-3-ylamine (142 mg, 1.16 mmol) and the solution was heated to 80 C for 14 h. The solvent was removed in vacuum, and the title compound was obtained by flash chromatography (0-2% methanol in dichloromethane) to give: 150 mg (60% yield). HPLC tr=6.68 min (87%), LCMS m/e 312.1 (M+H), 310.0 (M-H).
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[C:11]1([C:21](Cl)=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.[NH2:24][C:25]1[CH:26]=[C:27]([CH:38]=[CH:39][N:40]=1)[C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[C:11]1([C:21]([NH:24][C:25]2[CH:26]=[C:27]([CH:38]=[CH:39][N:40]=2)[C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Agent: O=C(Cl)c1ccccc1F
Product: O=C(NCc1ccccc1)c1ccnc(NC(=O)c2cccc3ccccc23)c1
Yield: 20 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with 1-naphthoyl chloride to react with 2-amino-N-benzylisonicotinamide, 2-(1-naphthamido)-N-benzylisonicotinamide was obtained as a colorless solid in 20% yield: mp 65-67° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 9.70 (s, 1H), 8.72 (s, 1H), 8.29-8.22 (m, 1H), 7.95 (d, J=8.3 Hz, 1H), 7.97-7.84 (m, 1H), 7.76 (d, J=5.2 Hz, 1H), 7.69 (d, J=5.2 Hz, 1H), 7.50-7.31 (m, 7H), 7.28-7.24 (m, 2H), 7.08 (t, J=5.8 Hz, 1H), 4.59 (d, J=5.7 Hz, 2H); MS (ES+) m/z 382.5 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH2:16])[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1.Cl[C:18]1[CH:19]=[CH:20][C:21]2[O:26][C:25]([CH3:28])([CH3:27])[C:24](=[O:29])[NH:23][C:22]=2[CH:30]=1.NC1C=C(Cl)C=CC=1O.BrC(C)(C)C(Br)=O>>[CH3:27][C:25]1([CH3:28])[C:24](=[O:29])[NH:23][C:22]2[CH:30]=[C:18]([NH:16][C:14]3[N:15]=[C:8]4[C:7]([C:5]5[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=5)=[N:12][CH:11]=[CH:10][N:9]4[N:13]=3)[CH:19]=[CH:20][C:21]=2[O:26]1
Reactant: Cn1cc(-c2nccn3nc(N)nc23)cn1
Reactant: CC1(C)Oc2ccc(Cl)cc2NC1=O
Agent: CC(C)(Br)C(=O)Br
Agent: Nc1cc(Cl)ccc1O
Product: Cn1cc(-c2nccn3nc(Nc4ccc5c(c4)NC(=O)C(C)(C)O5)nc23)cn1

Procedure:
8-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine is coupled with 6-chloro-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one, available by reaction of 2-amino-4-chlorphenol with 2-bromo-2-methyl-propanoyl bromide under basic conditions, using general procedure 2 gave the title compound as a solid.
Reaction SMILES: O[CH:2]([C:4]1[N:5]=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)[CH3:3].S(Cl)([Cl:16])=O>ClCCl>[Cl:16][CH:2]([C:4]1[N:5]=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1)[CH3:3]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1cc2c(cn1)CCCC2
Solvent: ClCCl
Product: CC(Cl)c1cc2c(cn1)CCCC2
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
3-(1-Hydroxyethyl)-5,6,7,8-tetrahydroisoquinoline (360 mg, 2.0 mmole) was dissolved in 4 ml dichloromethane in a 25 ml one neck round bottom flask under nitrogen. The solution is cooled to 0° C., is treated dropwise with thionyl chloride (218 μl, 3.0 mmole) in 3 ml dichloromethane, and is stirred 2 h at 0° C. followed by 1.5 h at room temperature. The mixture is recooled to 0° C., is quenched with 20 ml saturated sodium bicarbonate, and the layers are separated. The aqueous layer is extracted with 4×10 ml dichloromethane and the combined organics are dried over potassium carbonate. The dried organics are concentrated in vacuo to an amber oil. The crude material is chromatographed over 30 g silica gel (230-400 mesh), eluting with 20% acetone/hexane, while collecting 5 ml fractions. Fractions 11-16 are combined and concentrated to afford 339 mg (87%) of 3-(1-chloroethyl)-5,6,7,8-tetrahydroisoquinoline.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([C:8]([S:11](=[O:16])(=[O:15])[N:12]([CH3:14])[CH3:13])=[CH:9][N:10]=2)[CH:7]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C(#N)C>[ClH:1].[CH3:13][N:12]([CH3:14])[S:11]([C:8]1[N:6]2[CH:7]=[C:2]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:3]=[CH:4][C:5]2=[N:10][CH:9]=1)(=[O:16])=[O:15]
Reactant: CN(C)S(=O)(=O)c1cnc2cnc(Cl)cn12
Reactant: C1CNCCN1
Solvent: CC#N
Product: CN(C)S(=O)(=O)c1cnc2cnc(N3CCNCC3)cn12
Product: Cl

Procedure:
The crude product from Step A is reacted with piperazine (2 g) in refluxing acetonitrile for 18 hours and the mixture cooled and concentrated under vacuum, and the residue partitioned between dilute sodium hydroxide and chloroform. The chloroform extract is dried over sodium sulfate, filtered and concentrated under vacuum to a residue which is purified by chromatography on silica gel and crystallized from ethanolic hydrogen chloride to give 3-(N,N-dimethylsulfamoyl)-6-(1-piperazinyl)imidazo[1,2-a]pyrazine hydrochloride.
Reaction SMILES: [I:1]I.N(OCCCC)=O.[CH3:10][N:11]1[CH:15]=[C:14]([C:16]2[CH:22]=[CH:21][C:19](N)=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=2)[CH:13]=[N:12]1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CS(C)=O.C(#N)C>[I:1][C:19]1[CH:21]=[CH:22][C:16]([C:14]2[CH:13]=[N:12][N:11]([CH3:10])[CH:15]=2)=[CH:17][C:18]=1[N+:23]([O-:25])=[O:24]
Reactant: II
Reactant: Cn1cc(-c2ccc(N)c([N+](=O)[O-])c2)cn1
Agent: CCCCON=O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC#N
Solvent: ClCCl
Product: Cn1cc(-c2ccc(I)c([N+](=O)[O-])c2)cn1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 94.5 %

Procedure:
Iodine (3.5 g, 14 mmol), acetonitrile (40 ml), and test-butyl nitrite (0.82 mL, 6.9 mmol) were combined under N2 in a 3-neck round bottom flask fitted with reflux condenser and an addition funnel. The mixture was stirred at rt. To the addition funnel was added a solution of 4-(1-methyl-1H-pyrazol-4-yl)-2-nitroaniline (1.0 g, 4.6 mmol) dissolved in DCM (20 mL) and DMSO (2 mL). This solution was added dropwise to flask at rt. The reaction was placed in a 60° C. oil bath and after 5-10 minutes bubbles began appearing. The reaction was stirred for an additional 2 h at 60° C. and then the heat was turned off and the reaction stirred at rt overnight. Aqueous sodium sulfite solution was added and the mixture was extracted with EtOAc (3×). Combined organic layers were dried over anhydrous MgSO4, filtered, concentrated onto silica gel and purified by flash chromatography using 20-60% EtOAc/hexanes. 1.43 g (95%) of 4-(4-iodo-3-nitrophenyl)-1-methyl-1H-pyrazole was isolated as a yellow solid. MS (ESI): 330, 331 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([CH2:12][C:13]([OH:15])=O)[N:4]=1.Cl.[Br:19][C:20]1[C:21]([C@H:28]([NH2:38])[CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=2)=[N:22][C:23]([S:26][CH3:27])=[N:24][CH:25]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:19][C:20]1[C:21]([C@H:28]([NH:38][C:13](=[O:15])[CH2:12][N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:1])([F:17])[F:16])=[N:4]2)[CH2:29][C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[CH:31]=2)=[N:22][C:23]([S:26][CH3:27])=[N:24][CH:25]=1
Reactant: CSc1ncc(Br)c([C@H](N)Cc2cc(F)cc(F)c2)n1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(Br)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2-(3-(Trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid (124 mg, 0.5 mmol) and 11F (200 mg, 0.5 mmol) were dissolved in 3 mL of DMF and cooled down to 0° C. To it were added N,N-diisopropylethylamine (435 μL, 2.5 mmol) and HATU (228 mg, 0.6 mmol). The reaction mixture was stirred at 0° C. for 5 minutes, and then partitioned between EtOAc and 5% LiCl aqueous solution. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated. The residue was dissolved in methylene chloride and to it added hexanes. The precipitate was collected by vacuum filtration and dried under high vacuum overnight to afford the title compound 11G. MS (m/z) 592.25 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[C:20]2[C:16](=[CH:17][N:18]([CH3:21])[N:19]=2)[C:15]([CH2:22][OH:23])=[CH:14][CH:13]=1.C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl>[Cl:11][C:12]1[C:20]2[C:16](=[CH:17][N:18]([CH3:21])[N:19]=2)[C:15]([CH:22]=[O:23])=[CH:14][CH:13]=1
Reactant: Cn1cc2c(CO)ccc(Cl)c2n1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc2c(C=O)ccc(Cl)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of oxalyl chloride (2.93 mL, 34.6 mmol) in 30 dichloromethane (50 mL) was added dimethyl sulfoxide (3.68 mL, 51.9 mmol) at −78° C. To the reaction mixture was added a solution of (7-chloro-2-methyl-2H-indazol-4-yl)methanol (3.40 g, 17.3 mmol) in dichloromethane (10 mL), and the mixture was stirred for 2 hr. To the reaction mixture was added triethylamine (14.6 mL, 104 mmol) at −78° C., and the mixture was stirred for 30 min. The reaction mixture was warmed to room temperature, and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the aqueous layer was extracted with dichloromethane. The combined extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by recrystallization (hexane/dichloromethane) to give the title compound (3.07 g, yield 91%).
Reaction SMILES: C(OC(=O)C)(=O)C.[Br:8][C@@:9]1([O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@@H:21]([F:29])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]1[O:12][C:13](=[O:15])[CH3:14])[OH:10]>N1C=CC=CC=1>[Br:8][C@@:9]1([O:23][C@H:22]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[C@H:21]([F:29])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]1[O:12][C:13](=[O:15])[CH3:14])[OH:10]
Reactant: CC(=O)OC[C@H]1O[C@@](O)(Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1F
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@](O)(Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1F
Yield: 44 %

Procedure:
100 mg (0.55 mmol) of 3 are reacted with 3.5 ml of pyridine and 3.5 ml of acetic anhydride in analogy to the preparation of compound 2. 89 mg (44%) of 4 are obtained as an amorphous solid.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[C:7]([C:9](N)=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-:20].[K+].O>C(O)C>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[C:7]([C:9]([OH:20])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [OH-]
Reactant: NC(=O)c1ccc(-c2ccccc2)c(C(F)(F)F)c1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(-c2ccccc2)c(C(F)(F)F)c1
Temperature: 90 °C
Yield: 47.8 %

Procedure:
The reaction was split into 4, using a quarter of the reagents in each: to a mixture of 4-bromo-3-(trifluoromethyl)benzonitrile (4 g, 16.00 mmol), phenylboronic acid (3.90 g, 32.0 mmol) and potassium carbonate (6.63 g, 48.0 mmol) in N,N-dimethylformamide (DMF) (64 ml) was added palladium tetrakistriphenylphosphine(0) (1.849 g, 1.600 mmol). Each reaction was heated in the microwave at 150° C. for 30 min. The combined reaction mixtures were filtered through celite, washed with ethyl acetate and the solvent removed in vacuo. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL) and the organic phase washed with sodium bicarbonate solution (100 mL). The organic phase was dried (MgSO4), filtered and the solvent removed in vacuo. The brown oil was triturated with dichloromethane and filtered to give a pale yellow solid, 2-(trifluoromethyl)-4-biphenylcarboxamide (2.47 g) which was used without further purification. To 2-(trifluoromethyl)-4-biphenylcarboxamide (2 g, 7.54 mmol) in ethanol (80 ml) was added potassium hydroxide (4.23 g, 75 mmol) and water and the mixture heated to 90° C. for 18 h. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane (100 mL) and 2M HCl (100 mL). The organic phase was isolated and dried (phase separator) and the solvent removed in vacuo to give the crude product. Purification using the Biotage Horizon, reverse phase cartridge, eluting 5-100% MeCN in water to give an off-white solid the title compound (960 mg) (N2123-46-A5). MS (ES): C14H6F3O2 requires 266; found 265 (M−H+).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.CN1CCOCC1.N#N.[C:20]([NH:23][C@H:24]([C:40]([OH:42])=O)[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])(=[O:22])[CH3:21].C(N=C=NCCCN(C)C)C.[C:54]([O:58][C:59](=[O:83])[CH:60]([CH2:81][NH2:82])[CH2:61][C:62]1([C:67](=[O:80])[NH:68][C@H:69]2[CH2:74][CH2:73][C@@H:72]([C:75]([O:77][CH2:78][CH3:79])=[O:76])[CH2:71][CH2:70]2)[CH2:66][CH2:65][CH2:64][CH2:63]1)([CH3:57])([CH3:56])[CH3:55]>ClCCl>[C:54]([O:58][C:59](=[O:83])[CH:60]([CH:81]([C:40](=[O:42])[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])[NH:23][C:20](=[O:22])[CH3:21])[NH2:82])[CH2:61][C:62]1([C:67](=[O:80])[NH:68][C@H:69]2[CH2:70][CH2:71][C@@H:72]([C:75]([O:77][CH2:78][CH3:79])=[O:76])[CH2:73][CH2:74]2)[CH2:66][CH2:65][CH2:64][CH2:63]1)([CH3:56])([CH3:55])[CH3:57]
Reactant: CC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(CN)C(=O)OC(C)(C)C)CCCC2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(C(=O)OC(C)(C)C)C(N)C(=O)[C@H](CCCCNC(=O)OCc3ccccc3)NC(C)=O)CCCC2)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1-Hydroxybenztriazole (207 mg, 1.53 mmole) and N-methylmorpholine (235 mg, 2.36 mmole) were added to a stirred solution of N2 -acetyl-N6 -benzyloxycarbonyl-L-lysine (456 mg, 1.41 mmole) in dry dichloromethane at 0° C., followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (361 mg). The solution was stirred at 0° C. for 20 minutes and 3-{1-[(cis-4-ethoxycarbonylcyclohexyl)-carbamoyl]cyclopentyl}-2-(aminomethyl)propanoic acid t-butyl ester (500 mg, 1.18 mmole) in dichloromethane (10 ml) was added in one portion and the reaction mixture allowed to warm to room temperature and stirred for 16 hours. The solution was concentrated under vacuum to a volume of 10 ml and partitioned between ethyl acetate and water. The organic phase was washed with water (2×50 ml), 2M hydrochloric acid (50 ml, 2×25 ml), sodium bicarbonate solution (2×25 ml) and brine and then dried (MgSO4) and the solvent evaporated. The residue was chromatographed on silica eluting with ethyl acetate to give the title compound (610 g, 71%). Found: C,63.34; H,8.61; N,7.45. C39H60N4O9 (0.25H2O) requires C,63.48; H,8.33; N,7.59%.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([CH3:12])[C:8]([Cl:11])=[N:9][CH:10]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[ClH:11].[Cl:11][C:8]1[N:9]=[CH:10][C:5]([CH2:4][NH2:1])=[CH:6][C:7]=1[CH3:12]
Reactant: Cc1cc(CN=[N+]=[N-])cnc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CN)cnc1Cl
Product: Cl
Reaction time: 2 h

Procedure:
To the solution of 5-(azidomethyl)-2-chloro-3-methylpyridine 30-3 (2.0 g, 11 mmol) in THF (20 mL) was added PPh3 (3.17, 12 mmol) slowly. After 2 hours, H2O was added to the reaction mixture and the reaction was stirred for additional 15 hours, and the solvent was removed. The crude product was partitioned between ethyl acetate (50 mL) and 0.2 N HCl (50 mL). The aqueous phase was dried to give (6-chloro-5-methylpyridin-3-yl)methanamine HCl salt 30-4 as a white solid.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.O1CCCCC1[O:31][CH2:32][CH2:33][N:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1.O1CCCCC1OC1CCCCO1.Cl>>[CH:20]([N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:37]5[CH:36]=[N:35][N:34]([CH2:33][CH2:32][OH:31])[CH:38]=5)[CH:24]=[CH:23][C:5]=4[C:6]=3[N:7]=2)=[N:18][C:17]([CH3:19])=[N:16]1)([CH3:22])[CH3:21]
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n(C(C)C)n1
Agent: C1CCC(OC2CCCCO2)OC1
Agent: Cl
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(-c4cnn(CCO)c4)ccc2-3)n(C(C)C)n1

Procedure:
Similarly to as described in General Procedure C: 8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. Subsequent to the Suzuki coupling, deprotection of the tetrahydropyranyl ether was accomplished by adding 2N HCl to the crude reaction mixture. Purification by reverse phase HPLC gave 287 as a colorless solid (53 mg). LCMS: 437.1.
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)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.O.[NH2:33][NH2:34]>CN(C=O)C>[N+:28]([C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:34][N:33]=2)=[CH:23][CH:24]=1)([O-:30])=[O:29]
Reactant: O=C(CCc1ccc([N+](=O)[O-])cc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(CCc3ccc([N+](=O)[O-])cc3)n[nH]c2c2cccnc2n1-c1ccccc1
Yield: 97.2 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-3-(4-nitrophenyl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (104 mg, 0.25 mmol, prepared in Synthetic Example 7) in DMF (2 ml) was added hydrazine monohydrate (80%, 40 μl, 11.0 mmol, 4.0 eq.), and the mixture was treated in the same manner as in Example 9 to give 3-[2-(4-nitrophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (100 mg, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][CH:17]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34][CH2:35][CH3:36])=[CH:29][N:28]=1>>[C:40]([O:39][C:37]([N:33]([C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:23](=[O:24])[CH2:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:17][CH:18]=2)=[N:28][CH:29]=1)[CH2:34][CH2:35][CH3:36])=[O:38])([CH3:41])([CH3:42])[CH3:43]
Reactant: COc1cc2ncnc(Oc3ccc(CC(=O)O)cc3)c2cc1OC
Reactant: CCCN(C(=O)OC(C)(C)C)c1ccc(N)nc1
Product: CCCN(C(=O)OC(C)(C)C)c1ccc(NC(=O)Cc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2)nc1

Procedure:
Using a similar procedure to that described in Example 6, 2-[4-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]acetic acid was reacted with 2-amino-5-(N-tert-butoxycarbonyl-N-propylamino)pyridine to give N-[5-(N-tert-butoxycarbonyl-N-propylamino) pyridin-2-yl]-2-[4-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]acetamide; Mass Spectrum: M+H+ 574.
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[S:22][C:21]3[C:20]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:19][C:18]([Sn](CCCC)(CCCC)CCCC)=[N:17][C:16]=3[CH:15]=2)[CH2:9][CH2:8]1)([CH3:6])[C:3]([NH2:5])=[O:4].I[C:43]1[N:44]([CH3:52])[N:45]=[C:46]2[C:51]=1[CH:50]=[CH:49][CH:48]=[CH:47]2>O1CCOCC1.S1C=CC=C1C([O-])=O.[Cu+].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>[CH3:1][C:2]([N:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]2[S:22][C:21]3[C:20]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:19][C:18]([C:43]4[N:44]([CH3:52])[N:45]=[C:46]5[C:51]=4[CH:50]=[CH:49][CH:48]=[CH:47]5)=[N:17][C:16]=3[CH:15]=2)[CH2:11][CH2:12]1)([CH3:6])[C:3]([NH2:5])=[O:4]
Reactant: Cn1nc2ccccc2c1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: Cn1nc2ccccc2c1-c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Yield: 22.4 %

Procedure:
To a degassed mixture of 2-methyl-2-(4-((4-morpholino-2-(tributylstannyl)thieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)propanamide (270 mg, 0.389 mmol), 3-iodo-2-methyl-2H-indazole (95 mg, 0.368 mmol), copper(I) thiophene-2-carboxylate (70 mg, 0.368 mmol) in dioxane (2.3 mL) was added Pd(PPh3)4 (21 mg, 0.018 mmol). The reaction mixture was reacted in the CEM microwave at 140° C. for 30 min. The reaction mixture was then loaded onto a Biotage Isolute SPE SCX-2 column. The column was washed with MeOH and the desired product was then eluted with 2 M NH3 in MeOH and further purified by RP-HPLC to give 176 (44 mg, 29%). LCMS: M+H+=535.2. 1H-NMR (400 MHz, DMSO-d6): δ 8.40 (d, 1H), 7.67 (d, 1H), 7.47 (s, 1H), 7.31 (t, 1H), 7.19 (t, 1H), 7.06 (s, 1H), 6.93 (s, 1H), 4.60 (s, 3H), 4.06 (m, 4H), 3.88 (s, 2H), 3.84 (m, 4H), 2.49-2.62 (m, 8H), 1.08 (s, 6H)
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21](O)[CH3:22].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[CH2:21]([O:12][C:11](=[O:13])[C@H:10]([NH:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:22]
Reactant: CCO
Reactant: CC(C)(C)OC(=O)CN[C@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)[C@@H](Cc1ccccc1)NCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 44.5 %

Procedure:
(2R)-2-((tert-Butoxycarbonyl)methylamino)-3-phenylpropionic acid (4.0 g, 14.27 mmol) was dissolved in dichioromethane (5 ml) and ethanol (0.95 ml, 16.27 mmol). 4-Dimethylaminopyridine (0.19 g, 1.57 mmol) was added. The solution was cooled to 0° C. and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.98 g, 15.55 mmol) was added. The reaction mixture was stirred for 2 h at 0° C. for 16 h at room temp. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate/water (30 ml/30 ml). The phases were separated. The organic phase was washed with a saturated solution of sodium hydrogencarbonate and water and dried over magnesium sulfate. The crude product was purified by flash chromatography on silica (180 g) with ethyl acetate/heptane 1:2 to give 1.95 g of (2R)-2-((tert-butoxycarbonyl)methylamino)-3-phenylpropionic acid ethylester.