Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([OH:20])=O)[CH:8]=1)=[O:5].[CH3:32][C:33]1[C:37]([NH2:38])=[CH:36][NH:35][N:34]=1.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C>CN(C=O)C>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([NH:38][C:37]2[C:33]([CH3:32])=[N:34][NH:35][CH:36]=2)=[O:20])[CH:8]=1)=[O:5]
Reactant: Cc1n[nH]cc1N
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1n[nH]cc1NC(=O)c1cc(NC(=O)c2cc(-c3ccccn3)c(Cl)cc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of 5-(2,4-dichloro-5-(pyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 111, 210 mg, 0.46 mmol), 3-methyl-1H-pyrazol-4-amine (68 mg, 0.69 mmol) and DIPEA (0.32 mL, 1.85 mmol) in anhydrous DMF (4 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (264 mg, 0.69 mmol). The reaction was stirred at room temperature for 1 hour under nitrogen. The reaction was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was collected, washed with brine (15 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by elution through an SCX-2 column using MeOH followed by 7N ammonia in MeOH, followed by purification using silica gel column chromatography eluting with EtOAc followed by 10% MeOH in DCM to afford the title compound (170 mg, 69%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[CH:16]([F:18])[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][C:24](=[O:36])[NH:25][C:26]1([C:34]#[CH:35])[CH2:31][O:30][C:29]([CH3:33])([CH3:32])[O:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C.CC#N.CC#N.Cl[Pd]Cl.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[C:19]([O:23][C:24](=[O:36])[NH:25][C:26]1([C:34]#[C:35][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:10]([CH:16]([F:18])[F:17])[CH:11]=2)[CH2:31][O:30][C:29]([CH3:33])([CH3:32])[O:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: FC(F)c1cc(Br)ccc1OCc1ccccc1
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Agent: Cl[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)NC1(C#Cc2ccc(OCc3ccccc3)c(C(F)F)c2)COC(C)(C)OC1
Yield: 79.2 %

Procedure:
Compound 51-2 (9.48 g), (5-ethynyl-2,2-dimethyl-1,3-dioxan-5-yl)carbamic acid t-butyl ester (7.34 g) synthesized according to the known method (e.g., Tetrahedron vol. 57 (2001) 15 pages 6531-6538), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (868 mg), bis(acetonitrile)palladium(II) dichloride (157 mg) and cesium carbonate (25.6 g) were stirred in acetonitrile (200 ml) at 80° C. for 8 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the object product (11.1 g) as a pale-brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH2:27]([NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:28][C:29]#[CH:30]>CN(C=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:30]#[C:29][CH2:28][CH2:27][NH:31][C:32](=[O:37])[C:33]([CH3:35])([CH3:34])[CH3:36]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: C#CCCNC(=O)C(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)NCCC#Cc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Yield: 101.9 %

Procedure:
Use a method similar to the General Procedure 3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (425 mg, 1 mmol) with N-but-3-ynyl-2,2-dimethyl-propionamide (306 mg, 2 mmol) in DMF (10 mL). Purify by chromatography on silica gel eluting with cyclohexane/EtOAc (85:15 to 0:100 gradient) to obtain 7-chloro-6-[4-(2,2-dimethyl-propionylamino)-but-1-ynyl]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (437 mg, 99%).
Reaction SMILES: C(O)(=O)C(O)=O.C1(C(C2C=CC=CC=2)=C2CCN(CCCOC3C=CC=CC=3)CC2)C=CC=CC=1.Cl.[F:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]([C:53]2[CH:58]=[CH:57][C:56]([F:59])=[CH:55][CH:54]=2)([OH:52])[CH2:45][CH:46]2[CH2:51][CH2:50][CH2:49][NH:48][CH2:47]2)=[CH:40][CH:39]=1.Cl[CH2:61][CH2:62][CH2:63][O:64][C:65]1[CH:70]=[CH:69][C:68]([C:71](=[O:73])[CH3:72])=[CH:67][C:66]=1[O:74][CH3:75].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].[C:84]([OH:91])(=[O:90])/[CH:85]=[CH:86]/[C:87]([OH:89])=[O:88]>C(O)CCC>[C:84]([OH:91])(=[O:90])/[CH:85]=[CH:86]/[C:87]([OH:89])=[O:88].[F:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]([C:53]2[CH:54]=[CH:55][C:56]([F:59])=[CH:57][CH:58]=2)([OH:52])[CH2:45][CH:46]2[CH2:51][CH2:50][CH2:49][N:48]([CH2:61][CH2:62][CH2:63][O:64][C:65]3[CH:70]=[CH:69][C:68]([C:71](=[O:73])[CH3:72])=[CH:67][C:66]=3[O:74][CH3:75])[CH2:47]2)=[CH:40][CH:39]=1
Reactant: OC(CC1CCCNC1)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C(O)C(=O)O
Solvent: CCCCO
Product: COc1cc(C(C)=O)ccc1OCCCN1CCCC(CC(O)(c2ccc(F)cc2)c2ccc(F)cc2)C1
Yield: 35 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.7 g (0.012 mole) of the base of [α,α-bis(4-fluoropheny]-3-piperidineethanol hydrochloride [1:1], 2.8 g free (0.012 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone, 4.3 g (0.04 mole) of anhydrous sodium carbonate and 0.5 g of potassium iodide in 100 ml of 1-butanol gave a gum as residue. The gum was purified by column chromatography on 120 g of Florisil®. Fractions eluted with 20-60% acetone in benzene were combined and concentrated to give a gum. This gum was converted to the fumaric acid salt and the solid was recrystallized from ethyl acetate-acetonitrile to yield 2.6 g (35%) of the title compound as a white solid, mp 133°-136° C.
Reaction SMILES: [C:1]([N:9]=[C:10]=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:14][Si](C)(C)C)=[N-]>C(#N)C>[C:2]1([C:1]2[O:8][CH2:14][C:10](=[O:11])[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC#N
Product: O=C1COC(c2ccccc2)=N1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a solution of benzoyl isocyanate (2 g, 12.2 mmol) in acetonitrile (40 mL) was added rapidly (diazomethyl)trimethylsilane (2M solution in hexane, 7.34 mL, 14.7 mmol) at 0-5° C., whereby the temperature rose to 15° C. (bubbling). The mixture was stirred at 0-5° C. for 1 h. Following solvent evaporation, the product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as yellow solid (1.84 g with 90% purity, 10.3 mmol, 84.0%) which was used without further purification for the next step.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[Br:9][C:10]1[N:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>CO>[Br:9][C:10]1[N:15]=[C:14]([I:1])[C:13]([OH:16])=[CH:12][CH:11]=1
Reactant: Oc1ccc(Br)nc1
Reactant: O=C1CCC(=O)N1I
Solvent: CO
Product: Oc1ccc(Br)nc1I
Reaction time: 3 h
Yield: 36.6 %

Procedure:
N-iodosuccinimide (6.47 g, 28.7 mmol) was added to a stirring solution of 6-bromopyridin-3-ol (5 g, 28.7 mmol) in MeOH (144 mL) at 45° C. It was allowed to stir for 3 hours. The mixture was concentrated and triturated with Et2O. The precipitate was discarded and the filtrate was concentrated and triturated with dichloromethane to give the expected product, 1 6-bromo-2-iodopyridin-3-ol (3150 mg, 10.50 mmol, 37% yield) by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.12 (1H, s), 7.42 (1H, d, J=8.28 Hz), 7.10 (1H, d, J=8.28 Hz). LC-MS retention time: 1.27 min; m/z (MH+): 300, 302. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:21]=[CH:20][C:8]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[C:7]([N+:22]([O-:24])=[O:23])[CH:6]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].O>CN(C=O)C>[C:25]([N:9]([S:10]([C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1)(=[O:12])=[O:11])[C:8]1[CH:20]=[CH:21][C:5]([O:4][CH3:3])=[CH:6][C:7]=1[N+:22]([O-:24])=[O:23])(=[O:27])[CH3:26]
Reactant: COc1ccc(NS(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N(C(C)=O)S(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
To a suspension of sodium hydride (60%, 0.08 g (2.00 mmol)) in DMF (3.0 ml), 4′-methoxy-2′-nitro-p-toluenesulfonanilide (0.50 g (1.55 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, acetic anhydride (0.20 ml (2.12 mmol)) was added dropwise. After one hour's stirring at room temperature, water was poured into the reaction mixture and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Crystals separated was added to diethyl ether, filtered and washed to give 0.51 g (90%) of the title compound as pale yellow crystals.
Reaction SMILES: COC([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=2)[CH:7]=[CH:6]1)=O.CNC>CCO>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][C:11]1[CH:12]=[C:13]2[C:8]([CH:7]=[CH:6][NH:5]2)=[CH:9][CH:10]=1)[CH3:19]
Reactant: CCOC(=O)Cc1ccc2ccn(C(=O)OC)c2c1
Agent: CNC
Solvent: CCO
Product: CCOC(=O)Cc1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-ethoxycarbonylmethyl-indole-1-carboxylic acid methyl ester (965 mg, 3.25 mmol) in EtOH (10 mL) was added dimethylamine (˜5.6 M in EtOH, 24.4 mL, 48.8 mmol) and the solution was stirred at RT overnight. EtOH was concentrated and the crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 85:15) to give the desired material. MS (UPLC): 204.2 [M+H]+, 221.2 [M+NH4]+, 248.2 [M+HCOO]−; tR (HPLC conditions f): 1.87 min.
Reaction SMILES: C([C:4]1[O:5][C:6]2[C:12]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])=[C:11]([F:26])[CH:10]=[C:9]([Cl:27])[C:7]=2[CH:8]=1)(O)=O>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[Cl:27][C:9]1[C:7]2[CH:8]=[CH:4][O:5][C:6]=2[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[C:11]([F:26])[CH:10]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3cc(C(=O)O)oc23)c1=O
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3ccoc23)c1=O
Temperature: 200 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
7.0 g (17 mmol) of 3-(2-carboxy-4-chloro-6-fluorobenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil and 5.0 g (79 mmol) of copper powder, were suspended in 50 ml of quinoline, followed by stirring at 200° C. for 1 hour. After completion of the reaction, the reaction solution was subjected to filtration. The filtrate was extracted with ethyl acetate. The organic layer was washed sequentially with a 10% hydrochloric acid aqueous solution and water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography, to obtain 3.5 g (yield: 56%) of the desired product as white crystals. Melting point: 127-128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH2:10][C:11](O)([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:10]=[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(COc3ccc(Cl)cc3)N=C2c2ccc(Cl)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2cc(COc3ccc(Cl)cc3)nc2-c2ccc(Cl)cc2)cc1

Procedure:
A mixture of 2-(4-chlorophenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-[(4-chlorophenoxy)methyl]-4,5-dihydro-1H-imidazole from Step 3 (750 mg, 1.5 mmol) and p-toluenesulfonic acid monohydrate (135 mg) in toluene (100 mL) was heated to reflux for 48 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude residue was redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture was purified by chromatography on silica gel using hexane/ethyl acetate (1/1) to give 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-[(4-chlorophenoxy)methyl]-1H-imidazole as a white solid: mp (DSC) 173° C. Anal. Calc'd for C23H18N2Cl2SO3.0.25 H2O: C, 57.81; H, 3.90; N, 5.86; Cl, 14.84. Found: C, 57.67; H, 3.83; N, 5.52; Cl, 15.17.
Reaction SMILES: [OH:1][C:2]([C:9]([F:12])([F:11])[F:10])([CH2:7][CH3:8])[C:3]([NH:5][NH2:6])=[O:4].Br[C:14]#[N:15]>O>[NH2:15][C:14]1[O:4][C:3]([C:2]([OH:1])([CH2:7][CH3:8])[C:9]([F:10])([F:11])[F:12])=[N:5][N:6]=1
Reactant: N#CBr
Reactant: CCC(O)(C(=O)NN)C(F)(F)F
Solvent: O
Product: CCC(O)(c1nnc(N)o1)C(F)(F)F
Reaction time: 3 h

Procedure:
To hydrazide (34.07 g, 183 mmol) of step 2 in 275 mL of water was added KHCO3 (18.33 g, 183 mmol) followed by BrCN (19.39 g, 183 mmol) portionwise. After 3 h, the solid was filtered, washed with cold water and dried to afford the title compound. Additional compound could be recovered from the aqueous phase by extraction (ether-hexane, 1:1). 1H NMR (400 MHz, acetone-d6): δ 6.54 (s, 2H), 6.01 (s, 1H), 2.22 (m, 1H), 2.08 (m, 1H) and 0.99 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].CC([O-])(C)C.[K+].Cl[C:17]1[CH:26]=[CH:25][C:24]2[C:23](=[O:27])[NH:22][CH2:21][CH2:20][C:19]=2[N:18]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:6][C:17]1[CH:26]=[CH:25][C:24]2[C:23](=[O:27])[NH:22][CH2:21][CH2:20][C:19]=2[N:18]=1
Reactant: OCc1cccc(F)c1
Reactant: O=C1NCCc2nc(Cl)ccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NCCc2nc(OCc3cccc(F)c3)ccc21
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
3-Fluorobenzyl alcohol (1.66 g, 13.14 mmol) was dissolved into DMF (25 mL) and treated with KOtBu (3.2 g, 26.29 mmol) and stirred for 30 min. The mixture was treated with 2-chloro-7,8-dihydro-1,6-naphthyridin-5(6H)-one and heated to 100° C. overnight. The mixture was adsorbed onto silica and purified (0 to 80% EtOAc/Hexanes) to give a semi-pure solid. This material was further purified on RP-HPLC (eluting with 40-90% MeCN/H2O with 0.1% TFA modifier) to give 840 mg of the compound, 2-((3-fluorobenzyl)oxy)-7,8-dihydro-1,6-naphthyridin-5(6H)-one. 1H NMR (400 MHz, CDCl3) δ 8.44 (1H, d, J=7.6), 7.38 (1H, dd, J=14.6, 7.6), 7.24 (1H, d, 7.5), 7.22 (1H, d, J=9.6), 7.04 (1H, t, J=8), 6.79 (1H, d, J=8.4), 5.79 (1H, br s), 5.45 (2H, s), 3.64 (2H, t, J=6.4), 3.10 (2H, t, J=6.4); LC-MS (M+H)=273.2.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.[NH4+].[Cl-]>C1COCC1.C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][OH:13])=[CH:14][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCc1ccc(Oc2ccccc2)cc1
Yield: 92 %

Procedure:
A 0° C. solution of 4-phenoxybenzaldehyde (5.0 g, 25.2 mmol) in 10 mL THF under an atmosphere of dry N2 was treated with borane (1.0M in THF, 11.25 mL) for 1 hour. A saturated NH4Cl solution was added, and the mixture was diluted with ethyl acetate. The organic layer was washed with 1M HCl, 5% NaHCO3 and brine, dried and concentrated in vacuo to give the title compound in 92% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:27].[I:28]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[C:13]3[C:18]([C:19]=2[I:28])=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:27]
Reactant: II
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2ccccc21
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)c(I)c2ccccc21
Yield: 35.9 %

Procedure:
In a similar manner to Step 1 of Example 161, 4-chloro-7-(1-(tert-butoxycarbonyl)-indol-2-yl)isoindolinone (374 mg, 0.980 mmol) was dissolved in ethanol (26 mL), and the solution was treated with iodine (299 mg, 1.18 mmol) and silver sulfate (306 mg, 0.980 mmol), followed by purification by slurry using hexane and diisopropylether to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-3-iodoindol-2-yl]isoindolinone (179 mg, yield 36%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[CH3:13].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+].[OH-].[Na+]>CO.C(OCC)(=O)C>[CH2:16]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:15])[CH:11]=[C:12]([CH3:13])[CH3:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)=CC(=O)Nc1ccccc1CN
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)=CC(=O)Nc1ccccc1CNCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
The product of Example 1 (612 mg, 3.0 mmol) was placed in a 25 mL round bottom flask and dissolved in methanol (6 mL). To this solution was added benzaldehyde (0.32 mL, 3.0 mmol) and the mixture was stirred at room temperature for 1 hr. After this time sodium borohydride (170 mg, 4.5 mmol) was added slowly over 10 minutes, and the mixture was allowed to stir for an additional 20 minutes. 15 mL of 1N NaOH was then added to quench the reaction, and the mixture was transferred to a separatory funnel with ethyl acetate. An additional 25 mL of ethyl acetate was added and the organic layer was washed successively with 1N NaOH (3×15 mL), brine (1×15 mL), and then dried over magnesium sulfate, filtered, and evaporated. The product was purified by flash column chromatography with ethyl acetate-hexane (3:7 then 1:1) to yield 3-methyl-but-2-enoic acid [2-(benzylamino-methyl)-phenyl]-amide (839 mg, 95% yield) of a yellow oil. 1H NMR (250 MHz, CDCl3) 10.44 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 7.39-6.84 (m, 8H), 5.64-5.56 (m, 1H), 3.78 (s, 2H), 3.70 (s, 2H), 2.15 (s, 3H), 1.82 (s, 3H). The amine was then converted to the HCl salt with an excess of 1N HCl in ether to be used in further transformations.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH2:10][C:9](O)([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]2[CH:7]=[C:6]([N:19]=[N:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.C([O-])(=O)C1C=CC=CC=1.C1CCC(N=C=NC2CCCCC2)CC1>C1C=CC=CC=1.Cl[Cu]>[CH3:32][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]2[CH:7]=[C:6]([N:19]=[N:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)CC1(O)CCC(C)(C)c2ccc(N=Nc3ccc(C(=O)OCC)cc3)cc21
Agent: Cl[Cu]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)CC1=CCC(C)(C)c2ccc(N=Nc3ccc(C(=O)OCC)cc3)cc21
Temperature: 25 °C

Procedure:
A solution of (+/-) ethyl 4-[(5,5-dimethyl-8-hydroxy-8-carbethoxymethyl-5,6,7,8-tetrahydronaphth-2-yl)azo]benzoate 5 (Compound D1, 108 mg, 0.25 mmol), DCC (55.9 mg, 0.271 mmol) and CuCl (36.6 mg, 0.37 mmol) in 8 ml of dry benzene was heated under reflux for 7 days. After cooling to room temperature, the solids were filtered out and the solution was extracted with ethyl acetate. The combined organic layer was washed with brine and dried over Na2 SO4. The solvent was removed under reduced 11 pressure, the crude material was purified by flash chromatography (silica gel, 10% ethyl acetate in hexane) to afford the pure title compounds as red oils.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13](CC2C=CC(OC)=CC=2)[N:12]=[C:11]3[CH3:26])=[N:4][C:3]=1[N:27]1[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]1>FC(F)(F)C(O)=O>[NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[C:11]3[CH3:26])=[N:4][C:3]=1[N:27]1[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]1
Reactant: COc1ccc(Cn2nc(C)c3cc(-c4nnc(N)c(N5CCN(C(=O)OC(C)(C)C)CC5)n4)ccc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2ccc(-c3nnc(N)c(N4CCNCC4)n3)cc12
Yield: 85.8 %

Procedure:
A solution of 6-amino-3-[N-(4-methoxybenzyl)-3-methylindazol-5-yl]-5-(4-Boc-piperazin-1-yl)-[1,2,4]triazine 111 (0.016 g, 0.0302 mmol) in trifluoroacetic acid (2.5 mL) was heated in a microwave reactor at 120° C. for 40 minutes. The organic solvent was evaporated under reduced pressure. Methanol (1 mL) and dichloromethane (9 mL) were added. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to yield the desired 6-amino-3-(3-methylindazol-5-yl)-5-(piperazin-1-yl)-[1,2,4]triazine 1 (0.008 g, 0.0259 mmol).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]3[C:23]4[C:22](=[O:24])[NH:21][CH:20]=[N:19][C:18]=4[CH:17]=[C:16](Cl)[N:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH2:26]([NH2:29])[CH2:27][NH2:28]>>[NH2:28][CH2:27][CH2:26][NH:29][C:16]1[N:15]=[C:14]([NH:13][C:10]2[CH:11]=[N:12][C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[CH:8][CH:9]=2)[C:23]2[C:22](=[O:24])[NH:21][CH:20]=[N:19][C:18]=2[CH:17]=1
Reactant: NCCN
Reactant: O=c1[nH]cnc2cc(Cl)nc(Nc3ccc(N4CCOCC4)nc3)c12
Product: NCCNc1cc2nc[nH]c(=O)c2c(Nc2ccc(N3CCOCC3)nc2)n1
Temperature: 150 °C

Procedure:
A mixture of starting material 5-(6-morpholinopyridin-3-ylamino)-7-chloropyrido[4,3-d]pyrimidin-4(3H)-one (20 mg, 0.055 mmol) and ethylene diamine (200 uL, used as solvent as well) was heated at 150° C. overnight. The excess diamine was removed under reduced pressure, and the residue was subject to HPLC-MS for purification to the final product 7-(2-aminoethylamino)-5-(6-morpholinopyridin-3-ylamino)pyrido[4,3-d]pyrimidin-4(3H)-one.