Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:34])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[C:27]([CH3:32])[C:26]=4[F:33])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[NH2:35][C:36]1[CH:37]=[C:38]([O:42][CH2:43][CH2:44][N:45]([CH3:47])[CH3:46])[CH:39]=[CH:40][CH:41]=1>CC(O)C.Cl.C(Cl)Cl>[CH3:46][N:45]([CH3:47])[CH2:44][CH2:43][O:42][C:38]1[CH:37]=[C:36]([NH:35][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:18]=[C:19]([NH:23][C:24](=[O:34])[C:25]5[C:30]([F:31])=[CH:29][CH:28]=[C:27]([CH3:32])[C:26]=5[F:33])[CH:20]=[CH:21][CH:22]=4)=[N:10][N:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: CN(C)CCOc1cccc(N)c1
Reactant: Cc1ccc(F)c(C(=O)Nc2cccc(-c3nn4ccccc4c3-c3ccnc(Cl)n3)c2)c1F
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: Cc1ccc(F)c(C(=O)Nc2cccc(-c3nn4ccccc4c3-c3ccnc(Nc4cccc(OCCN(C)C)c4)n3)c2)c1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a suspension of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluoro-3-methylbenzamide (100 mg, 0.21 mmol) (prepared in a manner similar to that described in Example 186) and {2-[(3-aminophenyl)oxy]ethyl}dimethylamine (47 mg, 0.26 mmol) in 2-propanol (3 mL) was added 2 drops of concentrated HCl. The reaction was stirred at 80° C. overnight. After 16 h, the mixture was diluted with DCM, washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and adsorbed onto silica. The crude product was purified by column chromatography to generate the title compound in 86% yield (112 mg, 0.18 mmol). 1H NMR (400 MHz, d6-DMSO) δ 10.90 (s, 1H), 9.55 (s, 1H), 8.86 (d, J=6.7 Hz, 1H), 8.51 (d, J=8.6 Hz, 1H), 8.28 (d, J=5.2 Hz, 1H), 8.01 (s, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.45-7.52 (m, 4H), 7.36 (d, J=7.3 Hz, 1H), 7.27 (d, J=8.1 Hz, 1H), 7.12-7.16 (m, 3H), 6.53 (d, J=5.1 Hz, 1H), 3.97 (t, J=5.6 Hz, 2H), 2.58 (t, J=5.8 Hz, 2H), 2.26 (s, 3H), 2.17 (s, 6H). MS (ESI) m/z=620 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].C(=O)([O-])O.[Na+].[CH2:22](O)[CH3:23]>>[CH2:22]([O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:14]([Cl:16])=[N:15][C:7]=1[NH2:6])[CH3:23]
Reactant: Nc1nc(Cl)ccc1C(=O)O
Reactant: CCO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1ccc(Cl)nc1N
Temperature: 65 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To ethanol (20 mL) were added concentrated sulfuric acid (10 mL) and 2-amino-6-chloro-nicotinic acid (6.3 g, 27 mmol, purity: 75%) described in Manufacturing Example 26-1-1 on an ice bath, which was stirred overnight at 65° C. The reaction mixture was gradually cooled, after which a sodium hydrogencarbonate aqueous solution was added to neutralize the mixture. The precipitated solids were filtered to obtain the title compound (4.1 g, 74%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[OH:10].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1ccc(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C)c(Oc2ccc([N+](=O)[O-])cc2)c1
Yield: 96.4 %

Procedure:
To a solution of 2-methyl-5-(methyloxy)phenol (Intermediate 12, 1.5 g) and 1-fluoro-4-nitrobenzene (1.4 g, 10.0 mmol) in acetonitrile (100 mL) was added potassium carbonate (2.1 g, 15.2 mmol) and the mixture was stirred at reflux for 5 hours. The resulting mixture was concentrated and partitioned between ethyl acetate (3 times 30 mL) and water (100 mL). The combined ethyl acetate layers were dried over sodium sulphate, filtered and concentrated under vacuum. The crude product thus obtained was purified by column chromatography on silica gel (EtOAc:PE=1:20) to afford the title compound as a solid (2.5 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[H-].[Na+].I[CH2:18][CH2:19][CH3:20].O>CN(C=O)C>[CH2:18]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13])[CH2:19][CH3:20]
Reactant: CCCI
Reactant: CC(=O)c1cc2c(cc1O)OCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1cc2c(cc1C(C)=O)CCCO2
Reaction time: 0.17 h
Yield: 114.9 %

Procedure:
1-(7-Hydroxychroman-6-yl)ethanone (3.0 g, 15.6 mmol) was dissolved in DMF (20 ml). Sodium hydride (60% oil base, 686 mg, 1.1 equivalent weight) was added thereto while ice cooling, and then stirred for 10 minutes. 1-Iodopropane (2.92 g, 1.1 equivalent weight) was added to the mixture and then stirred at room temperature for 3 hours. Water was added to the reaction mixture, followed by extraction using ethyl acetate. The thus-obtained organic layer was concentrated to dryness under reduced pressure, and the residue was then purified using silica gel column chromatography (n-hexane:ethyl acetate=1:0→0:1). The purified product was concentrated to dryness under reduced pressure, giving a white powder of 1-(7-propoxychroman-6-yl)ethanone (4.2 g, yield: quantitative).
Reaction SMILES: [CH2:1]([S:4][C@:5]1([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)[CH2:9][N:8](C(OCC2C=CC=CC=2)=[O:11])[C@H:7]([C:20]([O:22][CH3:23])=[O:21])[CH2:6]1)[CH:2]=[CH2:3].I[Si](C)(C)C.CO>C(#N)C>[OH2:11].[CH2:1]([S:4][C@:5]1([C:24]2[CH:25]=[CH:26][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:28][CH:29]=2)[CH2:9][NH:8][C@H:7]([C:20]([O:22][CH3:23])=[O:21])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)OC)N(C(=O)OCc2ccccc2)C1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CO
Product: C=CCS[C@]1(c2ccc(-c3ccccc3)cc2)CN[C@H](C(=O)OC)C1
Product: O
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
To an iced solution of (2S,4R)-1-benzyl 2-methyl 4-(allylthio)-4-(biphenyl-4-yl)pyrrolidine-1,2-dicarboxylate (1.85 g, 3.79 mmol) in acetonitrile (20 mL) was added iodotrimethylsilane (0.810 mL, 5.69 mmol). The formed light brown solution was stirred at room temperature for 2 h. Cooled with ice bath, quenched with methyl alcohol (7.68 mL, 190 mmol). The formed light brown solution was purified by prep-HPL, and the collected fractions were evaporated on speed-vac system. The yellow residue was taken up in DCM, washed with sat. Na2CO3 and brine, dried over MgSO4, filtered, evaporated in vacuo to afford the desired product (2S,4R)-methyl 4-(allylthio)-4-(biphenyl-4-yl)pyrrolidine-2-carboxylate (664 mg, 1.878 mmol, 49.5% yield) as a viscous oil. 1H NMR (500 MHz, MeOD) δ ppm 2.93-3.08 (m, 3H) 3.11-3.20 (m, 1H) 3.77-3.88 (m, 1H) 3.92-3.99 (m, 3H) 4.04 (d, J=12.21 Hz, 1H) 4.72-4.80 (m, 1H) 5.02 (d, J=9.77 Hz, 1H) 5.09 (dd, J=16.94, 1.37 Hz, 1H) 5.54-5.70 (m, 1H) 7.35-7.42 (m, 1H) 7.43-7.56 (m, 4H) 7.60-7.68 (m, 2H) 7.69-7.77 (m, 2H). LC-MS (retention time; 2.21 min, method A), MS m/z 354 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:7]([CH3:15])([CH3:14])[O:8][SiH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH2:6])[CH3:2].CO[CH2:19][N:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:21][Si](C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:5]1([C:7]([CH3:15])([CH3:14])[O:8][SiH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:6][CH2:19][N:20]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:21]1)=[O:16])[CH3:2]
Reactant: C=C(C(=O)OCC)C(C)(C)O[SiH2]C(C)(C)C
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(C(C)(C)O[SiH2]C(C)(C)C)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
To a cold solution of 2-(tert-butyl-dimethyl-silanyloxymethyl)-acrylic acid ethyl ester (463 mg, 1.89 mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzyl-amine (540 μl, 2.11 mmol) in dichloromethane (3 ml) was added at 0° C. trifluoroacetic acid (26 μl, 0.34 mmol). The resulting solution was warmed to room temperature in two hours. The crude product was purified by column chromatography on silica get eluting with a solution of ethyl acetate in hexanes (1:10, 1:5) to give the title compound (490 mg, 69%).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:13][C:14]([CH3:19])([CH3:18])[CH2:15][CH2:16][NH2:17].[CH2:20](N(CC)CC)[CH3:21].Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:17][CH2:16][CH:15]2[CH2:21][CH2:20][CH2:13][C:14]2([CH3:19])[CH3:18])=[O:10])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)CCN
Reactant: CCN(CC)CC
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(C(=O)NCC2CCCC2(C)C)cc1
Reaction time: 18 h
Yield: 65.8 %

Procedure:
4-Acetylbenzoic acid (200 mg, 1.20 mmol) and amine 2 (from Example 1, 199 mg, 1.22 mmol) were dissolved in 5 mL of dichloromethane and triethylamine (187 μL, 1.34 mmol) and 4-dimethylaminopyridine (15 mg, 0.12 mmol) were added. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (398 mg, 1.34 mmol) was added and the mixture was stirred for 18 hours. The reaction was diluted with ethyl acetate and washed with hydrochloric acid (1.0 M, aq.), sodium bicarbonate (sat'd., aq.) and sodium chloride (sat'd., aq.). The organic layer was dried over magnesium sulfate, filtered and the solvent removed to yield 216 mg (65%) of a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]2[CH:8]([NH:25][CH:26]3[CH2:29][CH2:28][CH2:27]3)[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=O.CO.[NH3:32]>>[CH:26]1([NH:25][CH:8]2[C:7]3[S:6][C:5]([C:3]([NH2:32])=[O:2])=[N:14][C:13]=3[C:12]3[CH:15]=[C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])[CH:17]=[CH:18][C:11]=3[O:10][CH2:9]2)[CH2:29][CH2:28][CH2:27]1
Reactant: COC(=O)c1nc2c(s1)C(NC1CCC1)COc1ccc(C#CC(C)(C)O)cc1-2
Reactant: N
Solvent: CO
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)sc1C(NC1CCC1)CO2
Yield: 54 %

Procedure:
A solution of 4-Cyclobutylamino-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (80 mg, 0.19 mmol), in methanol-ammonia (5 mL) was stirred at room temperature for 0.5 h. Then the mixture was filtered to afford 4 Cyclobutylamino-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide (42 mg, 54%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[C:9]1([O:17][CH3:18])[C:10](=[CH:13][CH:14]=[CH:15][CH:16]=1)[O:11][CH3:12]>>[OH:8][CH:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[C:16]1[CH:15]=[CH:14][CH:13]=[C:10]([O:11][CH3:12])[C:9]=1[O:17][CH3:18]
Reactant: O=Cc1ccncc1
Reactant: COc1ccccc1OC
Product: COc1cccc(C(O)c2ccncc2)c1OC

Procedure:
In Scheme N, step a, 4-pyridinecarboxaldehyde (9) is reacted with lithiated veratrole to give 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]pyridine (10) as described previously in Scheme F, step d.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([Cu])#[N:13]>CC(N(C)C)=O.CCOC(C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]#[N:13])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Stir the mixture of 1,4-dibromo-2-nitro-benzene (3.56 mmol) and CuCN (3.74 mmol) in DMA (4 ml) at 100° C. for 5 hours. Cool to room temperature, dilute with EtOAc, filter through celite, wash the organic layer with brine, dry over Na2SO4, and concentrate under vacuum. Purify the residue by flash chromatography (4:1 hexanes/EtOAc) to give 4-bromo-2-nitro-benzonitrile.
Reaction SMILES: [C:1]([O:14][CH3:15])(=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:22][CH2:23][O:24][C:25]([CH2:27]Br)=[O:26]>CC(C)=O>[CH3:15][O:14][C:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([O:8][CH2:27][C:25]([O:24][CH2:23][CH3:22])=[O:26])=[C:4]([O:5][CH3:6])[CH:3]=1
Reactant: COC(=O)c1cc(OC)c(O)c(OC)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1c(OC)cc(C(=O)OC)cc1OC
Yield: 74.6 %

Procedure:
To a mixture of methyl syringate (100 grams, 472 mmol), anhydrous K2CO3 (250 grams, 1.809 mol) in anhydrous acetone (1200 mL) was added Ethyl bromo acetate (113 grams, 677 mmol) and refluxed for 48 hours. Acetone was distilled and water (1200 mL) was added. Crude 11 was filtered, dried, and recrystallized from toluene to give pure 11 (105 grams, 75%) as a white powder. The melting point was found to be 90.5-92.5° C. The structure was confirmed by I.R and NMR. IHNMR (CDCl3) δ 1.32 (t, 3H, CH2CH3), 3.88 (s, 3H, Ester), 3.90 (s, 6H, OCH3), 4.25 (q, 2H, CH2CH3), 4.69 (s, 2H, OCH2), 7.24 (s, 2H, Ar).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH:22]3[CH2:24][CH2:23]3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=1>>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:9]2[C:10]([CH:22]3[CH2:24][CH2:23]3)=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: COc1ccc(-n2cc(C(O)C3CCCCC3)c(C3CC3)n2)cc1
Product: COc1ccc(-n2cc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C3CC3)n2)cc1
Yield: 13.7 %

Procedure:
Using cyclohexyl[3-cyclopropyl-1-(4-methoxyphenyl)-1H-pyrazol-4-yl]methanol (0.5 g) synthesized in Example 46(1) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.38 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.11 g, 14%) was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=1.[C:28](=[O:31])([O-])[O-:29].[Na+].[Na+].Br[C:35]1[N:36]=[C:37]([N:40]2[CH2:45][CH2:44][O:43][CH2:42][CH2:41]2)[S:38][CH:39]=1>>[F:25][C:24]([F:27])([F:26])[C:28]([OH:29])=[O:31].[CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[CH:21]=[CH:20][N:19]=2)[CH:5]=[C:6]([C:35]2[N:36]=[C:37]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[S:38][CH:39]=2)[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Brc1csc(N2CCOCC2)n1
Agent: [Na+]
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2csc(N3CCOCC3)n2)c1
Product: O=C(O)C(F)(F)F
Temperature: 80 °C
Yield: 28 %

Procedure:
N-[3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)-pyrimidin-2-amine (100 mg, 0.264 mmol), sodium carbonate (33.5 mg, 0.316 mmol), 4-(4-bromo-1,3-thiazol-2-yl)morpholine (79 mg, 0.316 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl (7.1 mg, 0.01 mmol) and chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II) (10.5 mg, 0.013 mmol) were placed in a 4-mL vial. The vial was evacuated and back-filled with nitrogen (3×). 1,4-Dioxane (2 mL) and water (0.4 mL) were added and the reaction mixture heated to 80° C. for 16 hours. The reaction mixture was cooled to room temperature and filtered over celite with methanol (˜20 mL). Solvent evaporation gave a crude residue which was purified by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.1% trifluoroacetic acid (eluting with 40-100% MeCN), to give 20 mg (0.037 mmol, 14.2% yield) of N-{3-methyl-5-[2-(morpholin-4-yl)-1,3-thiazol-4-yl]phenyl}-4-(trifluoromethyl)pyrimidin-2-amine trifluoroacetate salt as a yellow solid. MS APCI [M+H]+ m/z 422.1. 1H NMR (500 MHz, d6-DMSO): 2.30 (s, 3H), 3.43 (t, J=4.9 Hz, 4H), 3.72 (t, J=4.9 Hz, 4H), 7.14 (s, 1H), 7.23 (d, J=4.9 Hz, 1H), 7.33 (s, 1H), 7.40 (s, 1H), 8.17 (s, 1H), 8.79 (d, J=4.9 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[S:3]([O:6][C:7]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22])(=[O:5])=[O:4].[CH:25]1([CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41]O)[CH:36]=2)[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27][CH2:26]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1.O>[CH:25]1([CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][O:13][C:11]3[CH:10]=[CH:9][C:8]([C:14]4[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=4[F:22])=[C:7]([O:6][S:3]([C:2]([F:23])([F:1])[F:24])(=[O:5])=[O:4])[CH:12]=3)[CH:36]=2)[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:27][CH2:26]1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ccc(O)cc2OS(=O)(=O)C(F)(F)F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(OS(=O)(=O)C(F)(F)F)c2)c1)C1CC1
Yield: 80.8 %

Procedure:
To a solution of 2′-fluoro-4-hydroxy-5′-methoxybiphenyl-2-yl trifluoromethanesulfonate (1.30 g) in THF (30 mL) were added ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (1.02 g), triphenylphosphine (1.87 g) and a 40% solution of diethyl azodicarboxylate in toluene (3.2 mL), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.71 g) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([CH2:14][C:15](=[O:23])[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[O:25]=[C:26]1[CH:35]=[N:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]1[CH2:36][CH:37]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[C:1]([O:5][C:6](=[O:24])[N:7]([CH2:14][C:15](=[O:23])[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH:8]1[CH2:9][CH2:10][N:11]([CH2:37][CH2:36][N:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:34]=[CH:35][C:26]2=[O:25])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CC(=O)Nc1ccccn1)C1CCNCC1
Reactant: O=CCn1c(=O)cnc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N(CC(=O)Nc1ccccn1)C1CCN(CCn2c(=O)cnc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To 3 mL of dichloromethane solution containing 0.18 g of tert-butyl(2-oxo-2-(pyridin-2-ylamino)ethyl)(piperidin-4-yl)carbamate, 0.10 g of (2-oxoquinoxalin-1(2H)-yl)acetaldehyde and 30 μl of acetic acid were added and stirred at room temperature for 2 hours. To the reaction mixture, 0.17 g of sodium triacetoxyborohydride was added and stirred at the same temperature for 30 min. Chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=10:1] to give 0.26 g of tert-butyl(2-oxo-2-(pyridin-2-ylamino)ethyl)(1-(2-(2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a pale yellow foam.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[N:37]([CH3:38])[N:36]=[C:35]([CH3:39])[C:34]=1[S:40](Cl)(=[O:42])=[O:41]>N1C=CC=CC=1>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:34]4[C:35]([CH3:39])=[N:36][N:37]([CH3:38])[C:33]=4[Cl:32])(=[O:41])=[O:42])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4c(C)nn(C)c4Cl)cc3)nc21
Temperature: 23 °C
Reaction time: 3 h

Procedure:
8-(4-Amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione (20 mg, 0.047 mmol) was dissolved in pyridine (0.5 ml) and treated with 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (Maybridge, 16 mg, 0.07 mmol). The reaction was stirred at 23° C. for 3 h. The solvent was removed and the residue was purified by reverse phase HPLC. LCMS, m/z (M+H)=615.2.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][N:14]([C:33]1[CH:38]=[CH:37][N:36]=[C:35]([NH2:39])[N:34]=1)[C:15]1[CH:16]=[C:17]2[C:21](=[C:22]([C:24]3[S:28][C:27]4[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=4[CH:25]=3)[CH:23]=1)[NH:20][N:19]=[CH:18]2)C1C=CC=CC=1.C(O)=O>CO.[Pd]>[NH2:10][CH2:11][CH2:12][CH2:13][N:14]([C:15]1[CH:16]=[C:17]2[C:21](=[C:22]([C:24]3[S:28][C:27]4[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=4[CH:25]=3)[CH:23]=1)[NH:20][N:19]=[CH:18]2)[C:33]1[CH:38]=[CH:37][N:36]=[C:35]([NH2:39])[N:34]=1
Reactant: Nc1nccc(N(CCCNC(=O)OCc2ccccc2)c2cc(-c3cc4ccccc4s3)c3[nH]ncc3c2)n1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: NCCCN(c1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1)c1ccnc(N)n1
Temperature: 25 °C
Reaction time: 19 h
Yield: 16.4 %

Procedure:
A solution of {3-[(2-amino-pyrimidin-4-yl)-(7-benzo[b]thiophen-2-yl-1H-indazol-5-yl)-amino]-propyl}-carbamic acid benzyl ester (prepared from Example #F.8.1 using general procedures O and N, 0.169 g, 0.308 mmol) and formic acid (0.116 mL, 3.08 mmol) in methanol (2 mL) was added dropwise to a suspension of Palladium black (0.080 g, 0.752 mmol) in methanol (1.5 mL). The resulting mixture was allowed to stir at ambient temperature for about 19 hours. The resulting suspension was filtered though celite and the solvent was removed under reduced pressure. The resulting crude product was purified by reverse chromatography (Thermo Hypersil-Keystone 250×21.2 mm 8μ Hypersil® HS C18 column; 5% acetonitrile/0.1 M aqueous ammonium acetate −100% acetonitrile over 20 min, 100% acetonitrile hold 5 minutes, 21 mL/min) to afford N4-(3-amino-propyl)-N4-(7-benzo[b]thiophen-2-yl-1H-indazol-5-yl)-pyrimidine-2,4-diamine (0.021 g, 17% yield) as a green solid. RP-HPLC (Table 1, Method e) Rt 1.62 min.; m/z: (M+H)+ 416.1.