Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([O:10]C)[C:7]([CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].B(Br)(Br)Br>C(Cl)Cl>[CH3:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(C)c(C=O)cc1C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(C=O)c(C)cc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.3 %

Procedure:
First step: To a stirring solution of 2,5-dimethyl-4-methoxybenzaldehyde (0.82 g, 5.0 mmol) at −20° C. in CH2Cl2 (10 mL) was added BBr3 (10 mL, 1M in CH2Cl2). The reaction mixture was stirred at room temperature for 16 hrs. It was added ice and diluted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:1) to afford 2,5-dimethyl-4-hydroxy-benzaldehyde as a yellow solid (0.43 g, 57%): 1H NMR (300 MHz, DMSO-d6): δ 10.41 (s, 1H), 9.99 (s, 1H), 7.56 (s, 1H), 6.69 (s, 1H), 2.51 (s, 3H), 2.14 (s, 3H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=20% ethyl acetate in hexanes; Rf=0.48.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.O.[OH-].[Na+].Cl.[CH3:17][C:18]([CH3:20])=[O:19]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:17][C:18](=[O:19])[CH3:20])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1ccc(C=O)cc1OC
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C=CC(C)=O)cc1OC
Yield: 17.75 %

Procedure:
To a solution of 3, 4-dimethoxybenzaldehyde (8.31 g, 50 mmol) in acetone (25 ml) and 95% ethanol (25 ml) was added water (200 ml) under stirring. During this time white precipitated solid was formed, and 10% sodium hydroxide aqueous solution (40 ml) was added dropwise under stirring below 10° C. Then the reaction mixture was stirred for 24 hr at room temperature, after the reaction completed, the reaction mixture was neutralized with 6N hydrochloric acid to adjust pH=7.0, the prepicitated yellow solid was collected by filtration and washed with ethanol, dried , then recrystallized from 95% ethanol to give 4.16 g of a pale yellow crystal, mp: 78-80° C., yield: 17.75%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=2)=[O:24])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CCNCc1cccc(O)c1
Product: CCN(Cc1cccc(O)c1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with 3-ethylaminomethyl-phenol
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1.Cl.Cl[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CN(C=O)C>[N:20]1([CH2:19][CH2:18][O:3][C:4]2[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: ClCCN1CCOCC1
Reactant: CCOC(=O)Cc1cccc(O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(OCCN2CCOCC2)c1
Reaction time: 0.25 h
Yield: 52.7 %

Procedure:
A suspension of 97% NaH (1.75 g, 0.07 mol) in DMF (50 mL) was stirred for 15 minutes then ethyl 3-hydoxyphenylacetate (5.4 g, 0.03 mol) in DMF (25 mL) was added. The reaction mixture was stirred for 0.5 hours, then was cooled in an ice bath and N-(2-chloroethyl)morpholine hydrochloride (5.6 g, 0.03 mol) was added. The reaction mixture was at room temperature overnight, then was heated on a steam bath for four hours. The solvent was stripped, the residue was partitioned between cold water and ether, the organic layer was separated, and the aqueous layer was extracted with ether. The organic layers were combined, dried over MgSO4, filtered and stripped to afford crude product which was purified by column chromatography on silica gel eluting with ethyl acetate to afford 4.64 g of ethyl 3-[2-(4-morpholinyl)ethoxy]phenylacetate.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl.[N:30]1([CH2:37][CH2:38][C:39]2[CH:47]=[CH:46][C:42]([C:43](O)=O)=[CH:41][CH:40]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[N:30]1([CH2:37][CH2:38][C:39]2[CH:47]=[CH:46][C:42]([CH2:43][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=3[CH:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:41][CH:40]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CCNc1ccc(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(O)c1ccc(CCN2CCCCCC2)cc1
Agent: Cl
Product: COc1ccc(NCCCc2ccc(CCN3CCCCCC3)cc2)c(C2CCc3cc(O)ccc3C2)c1
Yield: 59.5 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-5-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (50 mg) and 4-(2-azepan-1-ylethyl)benzoic acid hydrochloride (100 mg) according to an analogous synthetic method to Example 152, the title compound (40 mg) was obtained.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C@@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[CH:21][C:22]4[N:27]=[C:26]5[C:28]([Cl:32])=[C:29]([Cl:31])[S:30][C:25]5=[CH:24][CH:23]=4)[CH:15]=3)[OH:13])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.CCN(CC)CC.[CH3:40][S:41](Cl)(=[O:43])=[O:42].C([O-])(O)=O.[Na+]>>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C@@H:12]([C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]4[N:27]=[C:26]5[C:28]([Cl:32])=[C:29]([Cl:31])[S:30][C:25]5=[CH:24][CH:23]=4)[CH:17]=[CH:18][CH:19]=3)[O:13][S:41]([CH3:40])(=[O:43])=[O:42])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: O[C@@H](CCc1ccc(C2CC2)cc1)c1cccc(C=Cc2ccc3sc(Cl)c(Cl)c3n2)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H](CCc1ccc(C2CC2)cc1)c1cccc(C=Cc2ccc3sc(Cl)c(Cl)c3n2)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of the alcohol (Step 5) (230 mg, 0.47 mmol) in CHCl2 (2.5 mL) was added at -40° C. Et3N (100 μL, 0.717 mmol) and MsCl (45.0 μL, 0.574 mmo.). The resulting mixture was then warmed to 0° C. After a period of 10 min, a saturated solution of NaHCO3 was added. The mesylate was extracted with CH2C12, dried over Na2SO4, evaporated and co-distilled two times with toluene and used as such for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)=[C:4]([C:16]#[C:17][CH2:18][OH:19])[CH:3]=1.[H][H]>O1CCCC1.[Ni]>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[N:9]2)=[C:4]([CH2:16][CH2:17][CH2:18][OH:19])[CH:3]=1
Reactant: [H][H]
Reactant: COc1nc2cc(Cl)cc(C#CCO)c2nc1OC
Agent: [Ni]
Solvent: C1CCOC1
Product: COc1nc2cc(Cl)cc(CCCO)c2nc1OC
Yield: 98 %

Procedure:
2.05 g (7.36 mmol) of 3-(7-chloro-2,3-dimethoxy-quinoxalin-5-yl)-prop-2-yn-1-ol are hydrogenated at normal pressure in 20 ml of tetrahydrofuran with approximately 0.4 g of Raney nickel until twice the molar amount of hydrogen has been absorbed. The hydrogenated mixture is filtered with suction over a glass fiber filter and the filtrate is concentrated. 2.04 g (98%) of 3-(7-chloro-2,3-dimethoxy-quinoxalin-5-yl)-propan-1-ol are obtained in the form of beige crystals having a melting point of 104-105° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:62]1[CH:67]=[CH:66][C:65]([F:68])=[CH:64][C:63]=1[F:69]>C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[F:68][C:65]1[CH:64]=[C:63]([F:69])[CH:62]=[CH:67][C:66]=1[NH:3][CH2:4][CH2:5][CH2:6][CH2:7][NH2:8]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: NCCCCN
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CCOCC
Product: NCCCCNc1ccc(F)cc1F
Temperature: 110 °C
Reaction time: 8 h

Procedure:
1,4-Diaminobutane dihydrochloride (0.97 g; 6 mmol), sodium t-butoxide (1.87 g, 19.5 mmol), rac-BINAP (61.0 mg, 0.09 mmol), and Pd(dba)2 (35.0 mg, 0.06 mmol) are charged to a flame dried screw-cap vial. The vial is vacuumed and back filled with nitrogen. Then anhydrous toluene (15 mL) is added, followed by the addition of 1-bromo-2,4-difluorobenzene (0.34 mL, 3.00 mmol). The mixture is stirred under nitrogen at 110° C. overnight. The reaction mixture is diluted with 80 mL of diethyl ether and filtered through a pad of celite 545. The filtrate is extracted with 6N aqueous HCl (10 mL×3). The combined aqueous layers are washed twice with diethyl ether and adjusted with 1M aqueous NaOH to pH>12. The aqueous layer was extracted with diethyl ether three times. The combined ether phase is dried over anhydrous Na2SO4, filtered, and concentrated to obtain N′-(2,4-difluorophenyl)butane-1,4-diamine as a brown oil: 1H NMR (CDCl3) δ 1.55 (m, 2H), 1.66 (m, 2H), 2.74 (t, 2H), 3.12 (t, 2H), 6.55 (m, 1H), 6.73 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][C:11]([C:17]4[N:18]=[C:19]([CH2:27][CH:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[N:20]5[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]=45)=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[CH3:43][S:44]([N:31]1[CH2:32][CH2:33][CH:28]([CH2:27][C:19]2[N:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]3=[C:17]([C:11]3[CH:10]=[C:9]4[C:14]([CH:15]=[CH:16][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[N:8]4)=[CH:13][CH:12]=3)[N:18]=2)[CH2:29][CH2:30]1)(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1nccn2c(CC3CCNCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Cc2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1
Reaction time: 0.17 h

Procedure:
1-(2-phenylquinolin-7-yl)-3-(piperidin-4-ylmethyl)-imidazo-[1,5-a]-pyrazin-8-amine (110.00 mg, 0.25 mmol) in a dried 15 mL round-bottom flask was dissolved in 2.00 mL of CH2Cl2 and charged with PS-DIEA (150.00 mg, 0.46 mmol). Methanesulfonyl chloride (10 μL, 0.47 equiv) was added in one portion. After 10 min., another 5 μL of methanesulfonyl chloride (0.24 equiv) was added. After another 10 min., another 2.1 μL of methanesulfonyl chloride (0.1 equiv) was added. The reaction was filtered through a fritted funnel, and the resins were rinsed multiple times with CH2Cl2. The crude product was purified by 5 g Jones silica gel (wetted with 100% CH2Cl2, dry loaded with silica, and eluted with 2% (7N NH3) in MeOH/CH2Cl2→5% (7N NH3) in MeOH/CH2Cl2) and afforded the desired product; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.41 (1H, d, J=0.85), 8.29 (1H, d, J=8.86), 8.20 (2H, dd, J=1.51, J=1.12), 7.97 (2H, m), 7.86 (1H, dd, J=1.72, J=1.72), 7.53 (4H, m), 7.24 (1H, d, J=5.26), 7.08 (1H, d, J=6.75), 3.85 (2H, d, J=11.88), 2.98 (2H, d, J=7.08), 2.68 (2H, t), 2.20 (1H, m), 1.94 (2H, d, J=10.92), 1.50 (2H, m); MS (ES+): m/z 513.02/514.03 (80/70) [MH+]; HPLC: tR=2.17 min (OpenLynx, polar—5 min).
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:11][S:12]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Br[CH2:26][CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1>CN(C=O)C>[NH:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28]([CH2:27][CH2:26][N:11]([CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[S:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:29]1
Reactant: O=S(=O)(NCCc1ccccc1)c1cccc2ccccc12
Reactant: BrCCc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1cccc2ccccc12)N(CCc1ccccc1)CCc1c[nH]c2ccccc12
Reaction time: 2.5 h
Yield: 83.6 %

Procedure:
Under inert atmosphere, to a stirred solution of NaH (0.016 g, 0.36 mmol) in 0.20 ml anhydrous DMF at 0° C., was added a solution of compound of Example 2 (0.108 g, 0.35 mmol) in 0.60 ml anhydrous DMF. The temperature was maintained during 1.5 h. After this time, a solution of 3-(2-Bromoethyl)indole (0.088 g, 0.39 mmol) in 0.6 anhydrous DMF was added dropwise to the reaction mixture of step at 0° C., and was stirred during 2.5 h. Once the solvent was evaporated, the crude mixture was chromatographically purified over SiO2 using Hexane/AcOEt (70:30) as the eluant, furnishing 133 mg of the desired product in 84% yield (purity ≧80%, expressed in % HPLC area).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:14][C:13](=[O:15])[CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[CH3:16][Mg]Cl>C1COCC1>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:12][C:13]([CH3:16])([OH:15])[CH2:14]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: C[Mg]Cl
Reactant: O=C1CC(c2ncc3c(Cl)nccn23)C1
Solvent: C1CCOC1
Product: CC1(O)CC(c2ncc3c(Cl)nccn23)C1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
3-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutanone (1.95 g, 8.80 mmol) in anhydrous THF (77.78 mL) at −78° C. under an atmosphere of nitrogen was treated slowly with a 3.0 M solution of methylmagnesium chloride in THF (5.9 mL). The solution stirred for 3 hr at −78° C. then quenched with 40 mL of semi-saturated aqueous NH4Cl (NH4Cl dilution in 1:1 mixture with water) at −78° C. and allowed to warm up to rt. The mixture was then extracted with EtOAc (3×40 mL) and the combined extracts washed with brine (30 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude solid was purified by chromatography over silica gel eluting with 1:1 EtOAc/DCM to 4% MeOH in (1:1) EtOAc/DCM to afford desired product. 1H-NMR (400 MHz, CDCl3) δ ppm 1.54 (s, 3 H), 2.74-2.60 (m, 4 H), 3.75-3.39 (m, 1 H), 7.35 (d, J=5.04 Hz, 1 H), 7.71 (d, J=5.00 Hz, 1 H) and 7.86 (s, 1 H). MS (ES+): m/z 238.15 and 240.17 [MH+].
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([CH:11]([O:13][CH2:14][C:15]2([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH3:12])[C:8]2[C:4](=[CH:5][N:6]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:7]=2)[CH:3]=1.[CH3:43]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:15]2([CH2:14][O:13][CH:11]([C:9]3[C:8]4[C:4](=[CH:5][N:6]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:7]=4)[CH:3]=[C:2]([CH3:43])[CH:10]=3)[CH3:12])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[CH:29][CH:30]=1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Br)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: CB1OB(C)OB(C)O1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C(=O)OC(C)(C)C)CC2)c2nn(COCC[Si](C)(C)C)cc2c1
Temperature: 110 °C

Procedure:
(±)-tert-Butyl 4-((1-(5-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (150 mg, 0.226 mmol), trimethylboroxine (0.063 mL, 0.453 mmol), and tetrakis(triphenylphosphine) palladium(0) (13.1 mg, 0.011 mmol) were combined in dry tetrahydrofuran (1. 1 mL) and 4 M sodium carbonate (0.17 mL ) in a microwave tube and sealed. After flushing the mixture with nitrogen, the mixture was heated at 110° C. for 2 h via microwave. After cooling to room temperature, the reaction mixture was concentrated, dissolved in diethyl ether and washed with water and brine, concentrated and purified by flash chromatography on silica gel (20-25% EtOAc/Hex) to afford 49 mg (36.2%) as an oil. 1H-NMR (CDCl3, 500 MHz) δ 7.93 (s, 1H), 7.32 (m, 2H), 7.24 (s, 1H), 7.02 (m, 2H), 6.66 (s, 1H), 5.65 (s, 2H), 4.96 (d, J=5 Hz, 1H), 3.33-3.75 (m, 6H), 3.0-3.15 (m, 2H), 2.29 (s, 3H), 1.85-2.2 (m, 4H), 1.43 (m, 12H), 0.89 (m, 2H), −0.06 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 161.4 (d, J=974 Hz), 155.1, 146.2, 139.2, 133.3, 131.7, 129.1, 129.0, 124.0, 122.8, 121.8, 117.1, 115.1, 114.9, 81.7, 79.4, 77.6, 74.1, 67.3, 65.9, 41.3, 28.6, 23.1, 21.9, 17.9, 15.4, −1.4; Mass spec.: 598.45(MH)+.
Reaction SMILES: CNC.C1COCC1.[CH3:9][N:10]([CH:12]=O)[CH3:11].ClC[C:16](=[NH:49])[NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:48])[C:28](=[C:39]2[NH:43][C:42]3[CH:44]=[CH:45][CH:46]=[CH:47][C:41]=3[NH:40]2)[C:29]([C:31]2[CH:36]=[C:35]([F:37])[CH:34]=[C:33]([F:38])[CH:32]=2)=[O:30])[CH:22]=1)(=[O:20])=[O:19]>O>[F:37][C:35]1[CH:36]=[C:31]([C:29](=[O:30])[C:28](=[C:39]2[NH:40][C:41]3[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=3[NH:43]2)[C:27]([C:23]2[CH:22]=[C:21]([S:18]([NH:17][C:16](=[NH:49])[CH2:12][N:10]([CH3:9])[CH3:11])(=[O:19])=[O:20])[CH:26]=[CH:25][CH:24]=2)=[O:48])[CH:32]=[C:33]([F:38])[CH:34]=1
Reactant: N=C(CCl)NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Reactant: CN(C)C=O
Agent: CNC
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CC(=N)NS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 M dimethylamine/THF solution (0.85 mL) was added to a DMF (5 mL) solution of 2-chloro-N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)ethanimidamide (181 mg), followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=50/1), and recrystallized from ethyl acetate/n-hexane to obtain N-({3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]phenyl}sulfonyl)-2-(dimethylamino)ethanimidamide (76 mg).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][C:9]=1[CH3:10])=[O:4].[C:17]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)#[N:18].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH3:10][C:9]1[O:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][C:5]=1[C:3](=[O:4])[CH2:2][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]#[N:18])=[CH:20][CH:21]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: Cc1oc(-c2ccccc2)nc1C(=O)COc1ccc(C#N)cc1
Yield: 79.2 %

Procedure:
A mixture of 4-bromoacetyl-5-methyl-2-phenyloxazole (7.0 g), p-cyanophenol (3.0 g), potassium carbonate (6.9 g) and methyl ethyl ketone (100 ml) was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and water (100 ml)-ether (100 ml) was added to the residue. The mixture was stirred, and the crystals were collected by filtration. Recrystallization from chloroform-ethanol afforded 4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-oxoethoxy]benzonitrile (6.3 g, 78.8%), as brownish prisms, m.p. 202°-203° C.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[C:8]([Cl:20])=[N:9][C:10]([Cl:19])=[N:11][C:12]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)C.[Li+].[OH-]>C1COCC1.O>[Cl:19][C:10]1[N:9]=[C:8]([Cl:20])[C:7]([O:6][CH2:5][C:4]([OH:21])=[O:3])=[C:12]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:11]=1
Reactant: CCOC(=O)COc1c(Cl)nc(Cl)nc1N1CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)COc1c(Cl)nc(Cl)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.6 %

Procedure:
To a solution of (2,4-dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-acetic acid ethyl ester (581 mg, 1.73 mmol) in THF (10 mL) and water (2.5 mL) was added LiOH (951 μL, 1.90 mmol, 2M aqueous solution) and the resulting mixture stirred at RT for 2.5 hours. The reaction mixture was quenched with 1M HCl and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo affording (2,4-Dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-acetic acid as a white solid (515 mg, 97%). 1H NMR (400 MHz, CDCl3): δ 4.59 (2H, s), 3.93-3.87 (4H, m), 3.81-3.75 (4H, m).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][N:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17](Cl)=[O:18]>>[O:1]([C:8]1[CH:9]=[C:10]([O:14][C:17](=[O:18])[N:16]([CH3:15])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Oc2ccccc2)c1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1cccc(Oc2ccccc2)c1)c1ccccc1

Procedure:
The title product was prepared from 3-phenoxyphenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (79%, colourless oil).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:6][C:7]([Cl:10])=[CH:8][CH:9]=1)=[O:4].[C:11](#[N:15])[CH2:12][C:13]#[N:14].CC(C)([O-])C.[K+]>O1CCCC1>[Cl:10][C:7]1[S:6][C:5]([C:3]([CH2:2][CH:12]([C:11]#[N:15])[C:13]#[N:14])=[O:4])=[CH:9][CH:8]=1
Reactant: N#CCC#N
Reactant: O=C(CBr)c1ccc(Cl)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#CC(C#N)CC(=O)c1ccc(Cl)s1

Procedure:
A solution of 2-bromo-1-(5-chloro-2-thienyl)ethanone (11.50 g, 48 mmol) in tetrahydrofuran is added to a solution of malononitrile (3.17 g, 48 mmol) and potassium tert-butoxide (5.70 g, 51 mmol) in tetrahydrofuran at 0° C. The reaction mixture is stirred for several minutes, concentrated in vacuo, diluted with water and filtered to collect solids. Flash chromatography of the solids using silica gel and a (4:1) hexane/ethyl acetate solution gives the title compound as a yellow solid, mp 155°-158° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@@H:21]([NH:23]C(=O)OC(C)(C)C)[CH3:22])=[CH:17][C:16]=2[F:33])[CH:10]=3)[CH2:3][CH2:2]1.Cl.C(OCC)(=O)C>>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]3[C:13]([CH:14]=2)=[N:12][N:11]([C:15]2[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@@H:21]([NH2:23])[CH3:22])=[CH:17][C:16]=2[F:33])[CH:10]=3)[CH2:3][CH2:2]1
Reactant: C[C@@H](COc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)c(F)c1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@H](N)COc1ccc(-n2cc3ccc(OCC4CC4)cc3n2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A mixture of tert-butyl [(1S)-2-{4-[6-(cyclopropylmethoxy)-2H-indazol-2-yl]-3-fluorophenoxy}-1-methylethyl]carbamate (544 mg) and 4M hydrogen chloride/ethyl acetate (5 mL) was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, to the obtained residue was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as an orange oil (424 mg).