Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:7])([SH:6])[CH3:5].Cl.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][CH:11]=1.C(N(CC)CC)C.Cl>CN(C=O)C.C(Cl)Cl.CCOCC>[CH3:5][C:4]([SH:6])([CH3:7])[CH2:3][NH:2][C:9]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:16]
Reactant: O=C(Cl)c1cccnc1
Reactant: CC(C)(S)CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(S)CNC(=O)c1cccnc1
Temperature: 0 °C

Procedure:
1-Amino-2-methylpropane-2-thiol hydrochloride (1.10 g, 6.18 mmol) was dissolved in DMF and nicotinoyl chloride hydrochloride (1.14 g, 8.03 mmol) was slowly added as a solid. The mixture was cooled to 0° C. and triethylamine (3.0 mL, 21.63 mmol) was slowly added. The mixture was stirred for one half hour at 0° C., allowed to warm to room temperature, and stirred overnight. The reaction mixture was diluted with methylene chloride, washed with saturated sodium bicarbonate, brine, and dried over magnesium sulfate. The volatiles were removed under reduced pressure to give a pink oil. An excess of hydrogen chloride in ether was added to precipitate 831 mg. (55%) of the title compound, mp. 163-165° C. 1H NMR (300 MHz, DMSO) δ9.00 (br s, 1H), 8.71 (dd, 1H, J=2.0, 4.9), 8.20 (dt, 1H, J=2.0, 7.9), 7.51 (dd, 1H, J=4.9, 7.9), 3.44 (d, 2H, J=6.3), 1.32 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([C@H:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][C@H:19]2[F:25])[CH3:17])=[O:15])[C@:11]([CH2:32][OH:33])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:10]=1.C1C=C(Cl)C=C(C(OO)=[O:42])C=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([C@H:18]2[CH2:23][CH2:22][N+:21]([CH3:24])([O-:42])[CH2:20][C@H:19]2[F:25])[CH3:17])=[O:15])[C@:11]([CH2:32][OH:33])([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN1CC[C@H](N(C)C(=O)N2CC(c3cc(F)ccc3F)=C[C@@]2(CO)c2ccccc2)[C@H](F)C1
Solvent: ClCCl
Product: CN(C(=O)N1CC(c2cc(F)ccc2F)=C[C@@]1(CO)c1ccccc1)[C@H]1CC[N+](C)([O-])C[C@H]1F
Reaction time: 0.5 h

Procedure:
To a solution of 20 mg (0.044 mmol) of 3-1 in 1 mL of CH2Cl2 at 0° C. was added 11 g (˜0.048 mmol) of mCPBA. The ice-bath was removed and the reaction was stirred for 30 min. The mixture was partitioned with EtOAc and saturated aqueous NaHCO3, separated, washed with H2O, brine, dried over Na2SO4 and concentrated by rotary evaporation. The residue was loaded onto a silica gel column and eluted with EtOAc—20:1:1 EtOH/NH4OH/H2O to provide 9-1 as a white foam. Data for 9-1: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (nm, 3H), 6.25 (s, 1H), 5.0-4.9 (m, 2H), 4.7. (m, 1H), 4.5 (m, 1H), 4.3-4.2 (m, 1H), 4.0 (m, 2H), 3.7 (m, 1H), 3.4-3.3 (m, 2H), 3.3 (s, 3H), 3.2 (s, 3H), 2.5-1.9 (bs, 2H), 1.8 (m, 1H) ppm. HRMS (ES) calc'd M+H for C25H28F3N3O3: 476.2156. Found: 476.2165.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[OH:11].NC1C=CC=C(Cl)C=1O>>[NH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[OH:11]
Reactant: Cc1cccc([N+](=O)[O-])c1O
Agent: Nc1cccc(Cl)c1O
Product: Cc1cccc(N)c1O

Procedure:
2-Amino-6-methylphenol was prepared from 2-methyl-6-nitrophenol (0.500 g, 3.26 mmol) in a manner similar to that described for 2-amino-6-chlorophenol. The compound was formed as a black solid (0.030 g, 8%). RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 100 Å, 5 μm, 250×4.6 mm column) tr=5.78 min., 86%; m/z 123 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH:30]1[C:38]2[C:33](=[CH:34][C:35]([NH2:39])=[CH:36][CH:37]=2)[CH:32]=[N:31]1.CCN=C=NCCCN(C)C.CN1C=CN=C1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]3[N:29]=[CH:28][S:27][C:14]=3[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:39][C:35]3[CH:34]=[C:33]4[C:38](=[CH:37][CH:36]=3)[NH:30][N:31]=[CH:32]4)=[O:22])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2nc(-c3cccc(C(=O)O)c3)nc3scnc23)cc1OC
Reactant: Nc1ccc2[nH]ncc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: ClCCl
Product: COc1ccc(Nc2nc(-c3cccc(C(=O)Nc4ccc5[nH]ncc5c4)c3)nc3scnc23)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.1 %

Procedure:
To a mixture of 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid (82 mg, 0.2 mmol) and 1H-indazol-5-amine (27 mg, 0.2 mmol) in 5 mL of DCM was added EDCI (80 mg, 0.6 mmol) followed by N-methylimidazole (50 mg, 0.6 mmol). The mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc to give 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(1H-indazol-5-yl)benzamide (20 mg, 19%) as white solid. 1H NMR (300 MHz, DMSO): δ 13.01 (s, 1H), 10.46 (s, 1H), 10.14 (s, 1H), 9.42 (s, 1H), 8.99 (s, 1H), 8.62 (d, 1H, J=7.8 Hz), 8.29 (s, 1H), 8.13-8.10 (m, 2H), 7.88 (s, 1H), 7.74-7.69 (m, 2H), 7.58-7.55 (m, 2H), 7.01 (d, 1H, J=8.7 Hz), 3.84 (s, 3H), 3.75 (s, 3H). LC-MS: 524 [M+H]+, tR=1.50 min. HPLC: 95.85% at 214 nm, 95.63% at 254 nm, tR=4.60 min.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1([NH:26][C:27](=[O:30])[CH2:28]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([NH:26][C:27](=[O:30])[CH2:28][N:17]2[CH2:18][CH2:19][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:9][CH:10]=3)[CH2:15][CH2:16]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CBr)Nc1ccccc1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Product: O=C(CN1CCC(c2ccc(Oc3ccccc3)cc2)CC1)Nc1ccccc1

Procedure:
The compound (4) synthesized in Reference Example 4 and the compound (23) synthesized in Reference Example 23 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[NH:15][N:14]=[C:13]([CH:16]3[CH2:18][CH2:17]3)[CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.CC1(C)C(C)(C)[O:23][B:22](B2OC(C)(C)C(C)(C)O2)[O:21]1.C([O-])(=O)C.[K+]>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].O1CCOCC1>[CH:16]1([C:13]2[CH:12]=[C:11]([NH:10][C:4]3[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([B:22]([OH:23])[OH:21])[CH:3]=3)[NH:15][N:14]=2)[CH2:18][CH2:17]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Cn1cc(Br)cc(Nc2cc(C3CC3)n[nH]2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: Cn1cc(B(O)O)cc(Nc2cc(C3CC3)n[nH]2)c1=O
Temperature: 105 °C
Reaction time: 4 h

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 126d (205 mg, 0.665 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.0 g, 4.0 mmol), dioxane (16 mL), PdCl2(dppf) (54.3 mg, 0.066 mmol), and potassium acetate (0.39 mg, 4.0 mmol). After bubbling argon through the resulting mixture for 30 minutes, it was stirred at 105° C. for 4 h under argon atmosphere. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure to afford crude 126e, which was used without further purification. MS: [M+H]+ 275.
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([C:13]([O:15][CH3:16])=[O:14])[C@H:11]([C:17]([O:19]C)=[O:18])[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.S(=O)(=O)(O)O>P([O-])([O-])([O-])=O>[CH2:1]([N:8]1[C@@H:12]([C:13]([O:15][CH3:16])=[O:14])[C@@H:11]([C:17]([OH:19])=[O:18])[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]1=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1[C@H](C(=O)OC)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1[C@@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 90.3 %

Procedure:
To a suspension of dimethyl cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylate (500 mg) in 0.1M phosphate buffer (pH 8.0, 50 ml) was added Pig Liver Esterase (manufactured by Sigma Lab., 1600 units, 10 mg). The mixture was stirred at room temperature for 30 hours. Chloroform (150 ml) was added to the mixture. Then, the mixture was adjusted to pH 2 with diluted sulfuric acid. The chloroform layer was separated from the aqueous layer, washed with water, dried over anhydrous magnesium sulfate and concentrated to give (4S,5R)-1,3-dibenzyl-5-methoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (435 mg). M.P., 141°-146° C. [α]D20 =+2.0° (c=1, CHCl3). [α]36520 =-21.6° (c=1, DMF).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:11]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([C:2]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][C:3]=2[C:11]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]3[C:12]=2[CH:13]=[CH:14][CH:15]=[N:16]3)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc(-c2oc3ccccc3c2Br)c2cccnc12
Reactant: OB(O)c1ccccc1
Product: COc1ccc(-c2oc3ccccc3c2-c2ccccc2)c2cccnc12

Procedure:
The title compound was prepared as a solid (0.202 g, 68%) by the coupling of 5-(3-bromo-1-benzofuran-2-yl)-8-methoxy-quinoline and phenyl boronic acid according to the procedure described in Step 1 of Example 1. Mass spectrum (+ESI, [M+H]+) m/z 352. 1H NMR (400 MHz, DMSO-d6): δ 8.87 (d, 1H, J=1.6 Hz), 8.13 (d, 1H, J=8.2 Hz), 7.73 (t, 2H, J=7.8 Hz), 7.68 (d, 1H, J=8.2 Hz), 7.38-7.52 (m, 3H), 7.21-7.38 (m, 6H), and 4.00 ppm (s, 3H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][S:7][CH:8]1[CH2:29][CH:11]2[N:12]([N:19]=[CH:20][CH:21]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[OH:22])[C:13](=[O:18])[N:14]([CH2:15][CH2:16][CH3:17])[CH:10]2[CH2:9]1)([OH:3])=[O:2].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:1]([CH2:4][CH2:5][CH2:6][S:7][CH:8]1[CH2:29][CH:11]2[N:12]([NH:19][CH2:20][CH:21]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[OH:22])[C:13](=[O:18])[N:14]([CH2:15][CH2:16][CH3:17])[CH:10]2[CH2:9]1)([OH:3])=[O:2]
Reactant: CCCN1C(=O)N(N=CC(O)C2CCCCC2)C2CC(SCCCC(=O)O)CC21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN1C(=O)N(NCC(O)C2CCCCC2)C2CC(SCCCC(=O)O)CC21
Reaction time: 1 h

Procedure:
The compound (0.5 g) of Example 2 was dissolved in a mixture of methanol (5 ml) and acetic acid (5 ml) at 15° C. and to the stirred solution was added sodium cyanoborohydride (0.15 g). After one hour, the solution was concentrated in vacuo, water (20 ml) and chloroform (20 ml) were added and the organic phase separated and dried over anhy. sodium sulphate. Filtration and concentration of the filtrate in vacuo gave the desired produced (0.49 g).
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:34][CH2:33][S:32][CH2:31][CH2:30]4)=[C:25]([CH3:35])[CH:24]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:35][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[CH:29]1[CH2:34][CH2:33][S:32][CH2:31][CH2:30]1)[O:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:6]([OH:36])=[O:5])[CH2:14][CH2:13]2)=[CH:16][CH:17]=1
Reactant: Cc1cc(OCc2ccc(C3CCN(CCC(=O)OC(C)(C)C)CC3)cc2)ccc1C1CCSCC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCc2ccc(C3CCN(CCC(=O)O)CC3)cc2)ccc1C1CCSCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of crude 3-(4-{4-[3-Methyl-4-(tetrahydro-thiopyran-4-yl)-phenoxymethyl]-phenyl}-piperidin-1-yl)-propionic acid tert-butyl ester in dry DCM (7 mL) is added triethyl silane (5 eq., 4.442 mmol, 517 mg, 0.71 mL) followed by TFA (7 mL). The resulting mixture is stirred at room temperature for 1 hour. After concentration, the crude product is purified by preparative RP LC-MS to give 3-(4-{4-[3-methyl-4-(tetrahydro-thiopyran-4-yl)-phenoxymethyl]-phenyl}-piperidin-1-yl)-propionic acid as a tan solid. 1H NMR (DMSO-d6, 400 MHz) δ 7.44-7.38 (m, 2H), 7.30-7.21 (m, 2H), 7.13-7.05 (m, 1H), 6.83-6.72 (m, 2H), 5.02 (s, 2H), 3.61-3.52 (m, 2H), 3.15-3.05 (m, 2H), 2.89-2.75 (m, 5H), 2.72-2.60 (m, 3H), 2.33-2.20 (m, 3H), 2.06-1.88 (m, 6H), 1.77-1.61 (m, 1H); MS (ES+): (454.2, M+1)+.
Reaction SMILES: [Li].[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH:6]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=O)[C:5]=2[CH:4]=[CH:3]1.O.[OH-].[Na+]>O1CCCC1>[N:13]1([CH2:11][CH:6]2[C:5]3[CH:4]=[CH:3][O:2][C:10]=3[CH2:9][CH2:8][NH:7]2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(C1NCCc2occc21)N1CCCC1
Agent: [Li]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: c1cc2c(o1)CCNC2CN1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a suspension of lithium alumimium hydride (0.2 g) in dry tetrahydrofuran (30 ml) was added a solution of the product of stage (i) (0.58 g) in tetrahydrofuran (10 ml) and the mixture was stirred at ambient temperature for 1 h. Water (0.2 ml), aqueous sodium hydroxide (2M; 0.6 ml) and water (0.2 ml) were cautiously added and the mixture was filtered. The filtrate was evaporated, the residue was dissolved in dichloromethane (20 ml), dried and evaporated in vacuo to give the title compound as an oil (0.54 g). T.l.c. SiO2 dichloromethane/methanol/ammonia (75:10:2) Rf 0.5.
Reaction SMILES: [S:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([O:14]C)=O)(=O)(=O)[NH2:2]>[OH-].[Na+]>[S:1]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:11][C:12](=[O:14])[NH:2]1
Reactant: COC(=O)Cc1ccccc1S(N)(=O)=O
Agent: [Na+]
Agent: [OH-]
Product: O=C1Cc2ccccc2SN1
Yield: 96.4 %

Procedure:
A solution of 18 g of 2-sulfamoylphenylacetic acid, methyl ester, in 125 g of 10% aqueous sodium hydroxide was stirred at room temperature for 4 hours. The mixture was filtered and the filtrate acidified by the addition of concentrated hydrochloric acid with ice-water cooling. The resulting precipitate was collected by filtration, washed with water, and dried to afford 12.5 g of 2H-1,2-benzothiazin-3(4H)-one, 1,1-dioxide as an off-white powder, m.p. 190°-195° C. NMR (CDCl3 /DMSO-d6): δ 11.3 (1H, br s, NH), 7.85 (1H, br d), 7.3-7.7 (3H, m) and 4.0 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:26])[N:14]([C:19]4[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1.[CH3:27][N:28]1[C:32]([C:33](Cl)=[O:34])=[CH:31][C:30]([CH3:36])=[N:29]1>C1COCC1.CCN(CC)CC>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:26])[N:14]([C:19]4[CH:20]=[CH:21][C:22]([NH:25][C:33]([C:32]5[N:28]([CH3:27])[N:29]=[C:30]([CH3:36])[CH:31]=5)=[O:34])=[CH:23][CH:24]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Cc1ccn(-c2ccc(N)cc2)c(=O)c1N1CCc2nc(N)ncc2C1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2ccc(-n3ccc(C)c(N4CCc5nc(N)ncc5C4)c3=O)cc2)n(C)n1
Temperature: 40 °C
Reaction time: 5 h
Yield: 68.1 %

Procedure:
A solution of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-1-(4-aminophenyl)-4-methylpyridin-2(1H)-one (26 mg, 0.078 mmol) in 3 mL of THF (3 mL) and NEt3 (3 mL) was treated with 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (16 mg, 0.105 mmol). The reaction was heated to 40° C. and allowed to stir for 5 h. The reaction was cooled and then extracted with EtOAc (3×˜10 mL) and water (˜10 mL). The combined organic layers were then washed with ˜20 mL of NaHCO3(aq). The organic layers were then dried over anhydrous Na2SO4 (s), filtered and the concentrated in vacuo. The crude mixture was purified over silica (EtOAc/Hexanes gradient). Following concentration of the appropriate fractions the title compound was isolated as a grey solid (25 mg, 76%). 1H NMR (DMSO) δ: 9.52 (s, 1H), 7.92 (s, 1H), 7.78(m, 1H), 7.45-7.52 (m, 2H), 7.44 (m, 1H), 7.24-7.32 (m, 2H), 6.65 (m, 1H), 6.28 (s, 2H), 6.17 (m, 1H), 3.96 (br. s, H), 3.29 (s, 2H), 2.66 (t, J=5.3 Hz, 2H), 2.35 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([Br:13])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].Br.CN1CCCC1=O.C(N(CC)C(C)C)(C)C.[Cl:31][C:32]1[N:37]=[C:36](Cl)[C:35]([Cl:39])=[CH:34][N:33]=1>>[Br:13][C:9]1[CH:10]=[C:11]([F:12])[C:2]([NH:1][C:34]2[C:35]([Cl:39])=[CH:36][N:37]=[C:32]([Cl:31])[N:33]=2)=[C:3]([CH:8]=1)[C:4]([NH:6][CH3:7])=[O:5]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CNC(=O)c1cc(Br)cc(F)c1N
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Br)cc(F)c1Nc1nc(Cl)ncc1Cl
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
2-Amino-5-bromo-3-fluoro-N-methyl-benzamide; hydrobromide (2.00 g, 6.10 mmol) was placed in N-methylpyrrolidinone (20.0 mL, 207 mmol) and N,N-diisopropylethylamine (3.19 mL, 18.3 mmol) was added. The reaction was stirred for 5 minutes and then 2,4,5-trichloro-pyrimidine (3.50 mL, 30.5 mmol) was added. The reaction was heated at 100° C. for 24 hours and then concentrated under reduced pressure. The residue was taken up in DCM (100 mL) and washed twice with water (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-40% EtOAc/hex as the eluting solvent to obtain 5-bromo-2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide as a tan solid (1.19 g, 50%). m.p.=246-249° C.; LCMS (m/e) 393 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 9.73 (s, 1H), 8.68-8.57 (m, 1H), 8.43 (s, 1H), 7.87 (d, 1H, J=9.6 Hz), 7.66 (s, 1H), 2.69 (d, 3H, J=3.9 Hz); 19F-NMR (d6-DMSO, 400 MHz)6-113.
Reaction SMILES: [C:1]([NH:5][C:6]1[N:10]2[CH:11]=[CH:12][N:13]=[CH:14][C:9]2=[N:8][C:7]=1[C:15]1[S:16][C:17]([C:20]#[CH:21])=[CH:18][CH:19]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[N:24]=1.CCN(CC)CC.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CC(=O)OCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([NH:5][C:6]1[N:10]2[CH:11]=[CH:12][N:13]=[CH:14][C:9]2=[N:8][C:7]=1[C:15]1[S:16][C:17]([C:20]#[C:21][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[N:24]=2)=[CH:18][CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccc(-c2nc3cnccn3c2NC(C)(C)C)s1
Reactant: Fc1cccc(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)Nc1c(-c2ccc(C#Cc3cccc(F)n3)s2)nc2cnccn12
Temperature: 50 °C
Yield: 30.2 %

Procedure:
500 mg (1.69 mmol) of tert-butyl-[2-(5-ethynyl-thiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-amine (synthesis described in Example 158 part b) were dissolved together with 355 mg (2.02 mmol) of 2-bromo-6-fluoro-pyridine in DMF (20 ml). 2.4 ml (16.9 mmol) of NEt3, 32 mg (0.17 mmol) of copper(I) iodide and 119 mg (0.17 mmol) bis(triphenylphosphine)-palladium(II) chloride were added to this solution. The reaction mixture was heated to 50° C. for 6 h. The mixture was then diluted with EA and combined with a 1M aq. Na2CO3 solution. The phases were separated and the aq. phase was extracted with EA. The combined organic phases were washed with a 1M aq. Na2CO3 solution, dried over MgSO4, filtered and evaporated under a vacuum. 200 mg (0.51 mmol, 30%) of N-tert-butyl-2-(5-((6-fluoropyridin-2-yl)ethynyl)thiophen-2-yl)imidazo[1,2-a]pyrazin-3-amine were obtained by CC (EA) of the group.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:31][CH3:32])=[C:10]([CH2:19][NH:20][C:21]([CH:23]([CH2:27][CH2:28][CH2:29][CH3:30])[C:24]([OH:26])=O)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:33][CH2:34][C:35]1[CH:36]=[CH:37][C:38]([F:62])=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]3[CH2:53][CH2:52][N:51](C(OC(C)(C)C)=O)[C@@H:50]([CH3:61])[CH2:49]3)[CH:42]=2)[CH:40]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH2:27]([CH:23]([C:24]([NH:33][CH2:34][C:35]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]3[CH2:53][CH2:52][NH:51][C@@H:50]([CH3:61])[CH2:49]3)[CH:42]=2)[C:38]([F:62])=[CH:37][CH:36]=1)=[O:26])[C:21]([NH:20][CH2:19][C:10]1[C:11]([NH:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[C:6]2[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]2=[N:8][C:9]=1[CH2:31][CH3:32])=[O:22])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCC(C(=O)O)C(=O)NCc1c(CC)nc2c(cnn2CC)c1NC1CCOCC1
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CN)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(C(=O)NCc1ccc(F)c(-c2cccc(CN3CCN[C@@H](C)C3)c2)c1)C(=O)NCc1c(CC)nc2c(cnn2CC)c1NC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
A mixture of 2-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]hexanoic acid, 1,1-dimethylethyl (2S)-4-{[5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (424 mg, 0.98 mmol), HBTU (535 mg, 1.41 mmol) and Et3N (0.82 mL, 5.89 mmol) in DCM (3 mL) was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were then washed with water followed by a brine wash. The organic layer was then concentrated under vacuum to give a crude residue: LC-MS m/z 841 (M+H)+. The crude residue was dissolved in 25% TFA in DCM (2 mL) and stirred at RT for 2 h. It was purified with a Gilson HPLC (with 0.1% TFA condition) eluting with 10 to 70% CH3CN in water at a flowrate of 20 mL/min. The fractions were combined and then converted to the free base with saturated NaHCO3. The organic layer was dried over sodium sulfate, filtered and then concentrated to give 2-butyl-N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-{[(3S)-3-methyl-1-piperazinyl]methyl}-3-biphenylyl)methyl]propanediamide as a solid (59 mg, 12%). LC-MS m/z 741 (M+H)+.
Reaction SMILES: [ClH:1].O1CCOCC1.[Br:8][C:9]1[CH:10]=[C:11]([CH:35]=[CH:36][CH:37]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH:15]1[CH2:27][O:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:13]>CO>[ClH:1].[ClH:1].[Br:8][C:9]1[CH:10]=[C:11]([C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH:15]2[CH2:27][O:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:13])[CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(Br)c2)C(COc2cccnc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1cccc(Br)c1)N1CCNCC1COc1cccnc1
Reaction time: 4 h

Procedure:
4 M HCl in 1,4-dioxane (5 mL, 20 mmol) was added to a solution of tert-butyl 4-(3-bromobenzoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (126 mg, 0.264 mmol) in MeOH (1 mL). After stirring for 4 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 95% MeCN/0.1% TFA in H2O/0.1% TFA gradient). This gave 80.5 mg (68%) of the desired product as a white solid upon conversion to the dihydrochloride salt. LC-MS: RT=3.91 min, [M+H]+=376.5.