Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[CH2:22]([NH:29][C:30](=[O:33])[NH:31][NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)C.C([O-])(=O)C.[Na+]>O>[CH2:22]([NH:29][C:30](=[O:33])[NH:31]/[N:32]=[C:10]1/[C:8](=[O:9])[N:7]([CH2:6][CH2:5][N:4]([CH:18]([CH3:20])[CH3:19])[CH:1]([CH3:3])[CH3:2])[C:17]2[C:12]/1=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NNC(=O)NCc1ccccc1
Reactant: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)C(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)N(CCN1C(=O)/C(=N/NC(=O)NCc2ccccc2)c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.5 %

Procedure:
To a suspension of 1.37 g of 1-(2-diisopropylaminoethyl)isatin and 1.20 g of 4-benzylsemicarbazide hydrochloride in 20 ml of a mixture of ethanol and water (2:1) was added 0.50 g of sodium acetate. The mixture was stirred for 18 hours at room temperature, and then concentrated under reduced pressure. An aqueous sodium bicarbonate solution was added to the residue. The precipitates were collected by filtration, washed with water, and recrystallized from aqueous ethanol to obtain 1.21 g of (E)-1-(2-diisopropylaminoethyl)isatin 3-(4-benzylsemicarbazone) having a melting point of 164°-165° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1.Br[CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH3:52].BrCC1OC(C(F)(F)F)=CC=1>>[CH3:52][O:51][CH2:50][CH2:49][O:48][CH2:47][CH2:46][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: COCCOCCBr
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COCCOCCN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 1-bromo-2-(2-methoxyethoxy)ethane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (65%) as a colorless solid: mp 90-91° C.; 1H NMR (300 MHz, CDCl3) δ7.32-7.20 (m, 1H), 7.14-7.09 (m, 1H), 7.05-6.97 (m, 2H), 6.46 (s, 1H), 6.21 (s, 1H), 4.73 (ABq, 2H), 4.19-4.12 (m, 2H), 4.12-4.05 (m, 2H), 4.05-3.96 (m, 1H), 3.94-3.83 (m, 1H), 3.64-3.57 (m, 2H), 3.51-3.44 (m, 2H), 3.32 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.6, 155.2, 144.5, 142.5, 138.3, 132.3, 128.7, 123.7, 123.2, 121.2, 111.6, 109.2, 99.3, 80.0, 71.9, 70.4, 68.2, 64.5, 63.9, 59.0, 58.0, 402; MS (ES+) m/z 397.9 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][OH:41])[CH2:36][CH2:35]3)=[CH:27][CH:26]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20]C)=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl.[Cl-].[NH4+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](/[C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][CH2:33][N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][OH:41])[CH2:38][CH2:39]3)=[CH:29][CH:30]=2)=[CH:9]/[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(C#CCN3CCC(CO)CC3)cc2)cc1C
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OC/C=C(/c2ccc(Cl)cc2)c2ccc(C#CCN3CCC(CO)CC3)cc2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The above ester (210 mg, 0.37 mmol) was dissolved in a mixture of tetrahydrofuran (5 mL) and methanol (2 mL). A solution of lithium hydroxide monohydrate (36 mg, 0.73 mmol) in water (2 mL) was added and the mixture was stirred for 2 h at ambient temperature. The reaction mixture was diluted with water (15 mL) and acidified with 2 M hydrochloric acid to pH˜6. A saturated solution of ammonium chloride (5 mL) was added and the mixture was extracted with ethyl acetate (4×15 mL). The organic extracts were washed with 10% aqueous solution of ammonium chloride (2×20 mL) and brine (2×15 mL), dried with anhydrous magnesium sulfate and subsequently evaporated in vacuo. The residue was triturated with hexanes (2×10 mL) yielding the title compound as amorphous solid.
Reaction SMILES: N(OCC(C)C)=O.[Cl:8][C:9]1[CH:39]=[CH:38][C:12]([CH2:13][CH2:14][NH:15][C:16]([C:18]2[CH:36]=[CH:35][C:21]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:25][C:24]=3[Cl:34])=[C:20](N)[CH:19]=2)=[O:17])=[CH:11][CH:10]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH2:14][NH:15][C:16]([C:18]2[CH:36]=[CH:35][C:21]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:25][C:24]=3[Cl:34])=[CH:20][CH:19]=2)=[O:17])=[CH:38][CH:39]=1
Reactant: COC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2N)c(Cl)c1
Agent: CC(C)CON=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Cl)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
Isobutyl nitrite (0.0751 ml, 0.634 mmol) was diluted with DMF (1 mL), placed under nitrogen and heated to 60° C. Methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)-2-aminophenoxy)-3-chlorophenyl)acetate (100 mg, 0.211 mmol) in DMF (1 mL) was added dropwise and the reaction was stirred for 1 hour. The reaction was cooled, diluted with ethyl acetate and washed with 2N HCl, saturated sodium bicarbonate and brine. The organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a biotage 12i column, eluting with DCM:MeOH (99:1) to yield methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-chlorophenyl)acetate (70 mg, 72.3% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1.[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([NH:20][C:21]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCCNc1cnccn1
Reactant: O=C(N=C=S)c1ccccc1
Product: O=C(NC(=S)NCCCNc1cnccn1)c1ccccc1

Procedure:
Reacting 2-(3-aminopropylamino)pyrazine with benzoyl isothiocyanate by the procedure of Example 46 gives N-benzoyl-N'-[3-(2-pyrazinylamino)propyl]thiourea. Removing the benzoyl group by the procedure of Example 46 gives N-[3-(2-pyrazinylamino)propyl]thiourea.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH:21]1([CH2:26][C:27](Cl)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]1>O1CCCC1>[CH:21]1([CH2:26][C:27]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(Cl)CC1CCCC1
Reactant: COC(=O)c1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=O)CC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl 4-aminobenzoate (0.25 g, 1.654 mmol) in tetrahydrofuran (8.27 ml) was treated with diisopropylethylamine (0.433 ml, 2.481 mmol) and 2-cyclopentylacetyl chloride (0.279 g, 1.902 mmol) and the reaction mixture was stirred at ambient temperature for 2 hours. Concentration and normal phase chromatography provided the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)(=O)=O.[Cl-].[Li+].C([Sn](CCCC)(CCCC)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)CCC.[F-].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[N:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:7]1[N:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)C(F)(F)F)nc23)CC1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CN1CCC(c2c[nH]c3ccc(-c4ccccn4)nc23)CC1
Temperature: 105 °C
Reaction time: 0.08 h
Yield: 25.8 %

Procedure:
O-Trifluoromethanesulfonyl-3-(1-methylpiperidin-4-yl)-5-hydroxy-4-aza-1H-indole (150 mg, 0.413 mmol), palladium(II)acetate (9.2 mg, 0.041 mmol), 1,1′-bis(diphenylphosphino)ferrocene (45 mg, 0.083), lithium chloride (105 mg, 2.48 mmol), and 15 mL of 1,4-dioxane were combined and stirred for 5 minutes. 2-Tributylstannylpyridine (197 μL, 0.537 mmol) was added and the mixture was heated to reflux (about 105° C.) and stirred for about 18 hours. 50 mL of 8M aqueous potassium fluoride solution was added and the solution was extracted with 3:1 chloroform:isopropanol and brine and concentrated in vacuo. The residue was purified by silica gel flash chromatography (0-20% methanol:dichloromethane) to give 31.1 mg of the title compound. (26%). MS(FD) m/e 293.1 (M+).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:5]=2[O:4][CH:3]=1.[H][H]>[Pd].CO>[CH3:1][CH:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: [H][H]
Reactant: COC(=O)c1ccc2c(C)coc2c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)OCC2C
Yield: 95.1 %

Procedure:
Methyl 3-methylbenzofuran-6-carboxylate (400 mg, 2.1 mmol), palladium on carbon (50 mg, 0.56 mmol), in methanol (10 mL) was charged with hydrogen (0.4 MPa) at room temperature for 12 hours. Then filtered, and the organic layer was concentrated to dryness and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=10:1) to give the product methyl 3-methyl-2,3-dihydrobenzofuran-6-carboxylate (384 mg, 95%) as white solid. LRMS (M+H+) m/z: calcd 192.21. found 192. 1H NMR (300 MHz, CDCl3) δ 7.54-7.51 (m, 1H), 7.27-7.22 (m, 2H), 4.72-4.66 (m, 1H), 4.10-4.06 (m, 1H), 3.56-3.53 (m, 1H), 1.32 (m, 3H).
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7]([CH2:11][C:12]3[C:20]([Br:21])=[CH:19][C:15]4[O:16][CH2:17][O:18][C:14]=4[CH:13]=3)=[N:8]2)=[C:4]([NH2:22])[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].S(C1C=CC(C)=CC=1)(O[CH2:33][CH2:34][CH2:35][C:36]#[CH:37])(=O)=O>CN(C=O)C>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][C:12]3[C:20]([Br:21])=[CH:19][C:15]4[O:16][CH2:17][O:18][C:14]=4[CH:13]=3)[N:8]2[CH2:37][CH2:36][CH2:35][C:34]#[CH:33])=[C:4]([NH2:22])[N:3]=1
Reactant: Nc1nc(F)nc2nc(Cc3cc4c(cc3Br)OCO4)[nH]c12
Reactant: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CCCCn1c(Cc2cc3c(cc2Br)OCO3)nc2c(N)nc(F)nc21

Procedure:
A solution of 2-Fluoro-8-(6-bromo-benzo[1,3]dioxol-5-ylmethyl)adenine (20 mg, 55 mol), Cs2CO3 (18 mg, 55 mol) and pent-4-ynyl tosylate (17 mg, 72 mol) in anhydrous DMF (138 L) was stirred at 60° C. for 2 h. Following solvent removal, the product (13 mg, 54.7%) was collected through silica gel column purification (EtOAc:hexanes:CHC13:i˜PrOH at 10:20:20:1). 1H NMR (400 MHz, CDC13) 7.05 (s, 1H), 6.60 (s, 1H), 6.15 (bs, 2H), 5.96 (s, 2H), 4.28 (s, 2H), 4.13 (t, J=7.5 Hz, 2H), 2.25-2.21 (m, 2H), 2.00 (t, J=2.6 Hz, 1H), 1.98-1.92 (m, 2H); 13C NMR (100 MHz, CDC13) 157.6, 156.0, 152.6, 150.2, 147.5, 127.6, 116.4, 114.1, 112.5, 109.5, 101.6, 81.9, 69.5, 41.9, 33.7, 27.8, 15.5; MS m/z 432.0 (M+H)+. HPLC: (a) 99.0% (60% water-40% acetonitrile); (b) 98.5% (35% to 55% acetonitrile).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH2:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][C@@H:28]1[CH3:33])[CH3:26]>>[CH2:25]([N:27]1[CH2:32][CH2:31][N:30]([C:19]([C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)=[O:20])[CH2:29][C@@H:28]1[CH3:33])[CH3:26]
Reactant: CCN1CCNC[C@@H]1C
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)C[C@@H]1C

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1-ethyl-2-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.87-1.19 (m, 6 H) 2.42 (s, 3 H) 2.47 (br. s., 1 H) 2.52-2.59 (m, 1 H) 2.62-2.76 (m, 1 H) 2.77-2.98 (m, 2 H) 3.06 (d, J=10.61 Hz, 1 H) 3.35 (br. s., 1 H) 3.46-3.75 (m, 1 H) 4.05 (br. s., 1 H) 7.60 (dd, J=7.96, 1.64 Hz, 1 H) 7.66 (d, J=1.26 Hz, 1 H) 7.90 (d, J=8.34 Hz, 1 H) 8.01 (dd, J=8.72, 2.15 Hz, 1H) 8.06 (s, 1 H) 8.43 (d, J=8.59 Hz, 1 H) 8.51 (d, J=1.77 Hz, 1 H) 11.83-12.92 (m, 1 H); ESI-MS m/z [M+H]+ 431.3.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH2:13])=[S:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14](OC(OCC)CBr)[CH3:15]>C(O)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[S:12][CH:14]=[CH:15][N:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(CBr)OCC
Reactant: NC(=S)Nc1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(Nc2nccs2)cc1
Temperature: 100 °C
Yield: 48.9 %

Procedure:
To a suspension of 1-(4-nitrophenyl)-2-thiourea (5.00 g, 25.4 mmol) in acetic acid (40 mL) was added bromoacetaldehyde diethyl acetal (3.94 mL, 25.4 mmol) at RT. The resulting mixture was heated to 100° C. for 2 h. After cooling to RT, the solvent was removed in vacuo. The residue was diluted with 1M NaOH (100 mL) and EtOAc (100 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (2×100 mL). The combined organic extracts were dried over MgSO4 and concentrated. Purification by column chromatography (20-80% EtOAc in hexanes) afforded the product as a yellow solid (2.75 g, 49%). 1H-NMR (400 MHz, DMSO-d6) δ 11.02 (s, 8.231H), 8.23 (d, J=9.3 Hz, 2H), 7.85 (d, J=9.3 Hz, 2H), 7.41 (d, J=3.6 Hz, 1H), 7.15 (d, J=3.6 Hz, 1H). LC/MS (10-99%) M/Z: M+1 obs=222.1; tR=2.50 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](=[O:30])[N:12]([CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=2)[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:13]=1.[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:33]=1B(O)O.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:33]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](=[O:30])[N:12]([CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=2)[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:13]=1
Reactant: Cc1cccc(C)c1B(O)O
Reactant: CCOC(=O)COc1cccc(CCCn2cc(-c3ccccc3Br)ccc2=O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)COc1cccc(CCCn2cc(-c3ccccc3-c3c(C)cccc3C)ccc2=O)c1
Temperature: 100 °C
Reaction time: 40 h
Yield: 20.5 %

Procedure:
A mixture of ethyl (3-{3-[5-(2-bromophenyl)-2-oxopyridin-1(2H)-yl]propyl}phenoxy)acetate (255 mg), (2,6-dimethylphenyl)boronic acid (122 mg), 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (26 mg), tripotassium phosphate (345 mg) and palladium (II) acetate (4 mg) in toluene (10 mL) was stirred under N2 gas atmosphere at 100° C. for 40 hours and cooled to ambient temperature. To the mixture was added 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (26 mg), (2,6-dimethylphenyl)boronic acid (50 mg) and palladium (II) acetate (4 mg) and the mixture was stirred under N2 gas atmosphere at 100° C. for 60 hours and cooled to ambient temperature. The reaction mixture was acidified with 1M HCl aqueous solution and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was dissolved in EtOH (10 mL). To the solution was added concentrated H2SO4(1.5 mL) and the mixture was refluxed for 1.5 hours and cooled to ambient temperature. The reaction mixture was neutralized with saturated aqueous NaHCO3 solution and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=70:30) to give ethyl (3-{3-[5-(2′,6′-dimethylbiphenyl-2-yl)-2-oxopyridin-1(2H)-yl]propyl}phenoxy)acetate (55.1 mg) as a colorless oil.
Reaction SMILES: CN(C1CCCCC1)C.[C:10]([OH:15])(=[O:14])[CH:11]([CH3:13])[OH:12].Cl[CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19].S(=O)(=O)(O)O>>[CH3:17][Si:18]([CH2:21][O:14][C:10](=[O:15])[CH:11]([OH:12])[CH3:13])([CH3:20])[CH3:19]
Reactant: CC(O)C(=O)O
Reactant: C[Si](C)(C)CCl
Agent: O=S(=O)(O)O
Solvent: CN(C)C1CCCCC1
Product: CC(O)C(=O)OC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.1 %

Procedure:
400 g (3.15 moles) of N,N-dimethylcyclohexylamine were dropped into a mixture of 270 g (3 moles) of the S-enantiomer of the lactic acid and 736 g (6 moles) of chloromethyl-trimethyl silane within one hour, whilst stirring at room temperature without external cooling. The reaction mixture was heated to 95° C. with stirring and was kept at this temperature for 12 hours. Then the reaction mixture was cooled to room temperature and was poured into 1.2 liters of 10%-ic aqueous sulphuric acid. The organic phase was separated, washed twice with, in each case, 500 ml of water and was subjected to a fractionated distillation under reduced pressure. 430 g of a distillate were obtained thereby in a first fraction (boiling point: 50° C./20 mbar), which consisted of 15 g of an aqueous phase and of 415 g (3.38 moles) of chloromethyl-trimethylsilane. 371 g (2.10 moles) of the S-enantiomer of the 2-hydroxypropionic acid (trimethylsilyl)-methylester of a purity of 99.5% were obtained in a second fraction at a boiling point of b.p.=40° C./0.1 mbar. Based on chloromethyl-trimethyl-silane which had reacted, a yield of 85.1% of theory was calculated from this.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1.Cl[C:23]1[C:24]2[N:32]=[CH:31][CH:30]=[CH:29][C:25]=2[N:26]=[CH:27][N:28]=1.CCN(C(C)C)C(C)C>CC(O)C.CCOC(C)=O>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH:14][C:23]3[C:24]4[N:32]=[CH:31][CH:30]=[CH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH3:13])[N:9]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]=2[CH:21]=1
Reactant: Clc1ncnc2cccnc12
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2cccnc12)c1nc2ccc(F)cc2n1-c1ccccc1

Procedure:
(S)-1-(6-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (0.082 g, 0.25 mmol), 4-chloropyrido[3,2-d]pyrimidine (J. Med Chem, 1833, 1996) (0.035 g, 0.21 mmol) and DIPEA (0.174 mL, 1.0 mmol) in IPA (1 mL) was heated to 70° C. in a sealed tube under argon for 1 h. The reaction mixture was cooled, diluted with EtOAc (20 mL) and washed with water (2 mL). The aqueous was extracted with EtOAc (10 mL). The combined organic extracts were dried (Na2SO4), evaporated to dryness and purified by column chromatography (Si—PCC, gradient 0-8% (9:1 MeOH/0.880 NH3) in DCM). Product containing fractions were evaporated and freeze dried to give 317 as an off white solid, (15 mg, 18%). LCMS (Method C): RT 3.55 min [M+H]+ 385.05. 1H NMR δ (ppm) (DMSO-d6): 8.83 (1H, dd, J=4.24, 1.57 Hz), 8.63 (1H, d, J=7.55 Hz), 8.40 (1H, s), 8.11 (1H, dd, J=8.46, 1.57 Hz), 7.84 (1H, dd, J=8.47, 4.24 Hz), 7.74 (1H, dd, J=8.81, 4.85 Hz), 7.59 (2H, d, J=7.53 Hz), 7.50-7.50 (3H, m), 7.12 (1H, ddd, J=9.87, 8.81, 2.53 Hz), 6.86 (1H, dd, J=8.92, 2.51 Hz), 5.59 (1H, dq, J=7.09 Hz), 1.59 (3H, d, J=6.81 Hz)
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O.Cl>C1COCC1>[C:6]([C:7]1[CH:8]=[CH:9][C:10]([S:13]([NH2:16])(=[O:14])=[O:15])=[CH:11][CH:12]=1)#[CH:5]
Reactant: C[Si](C)(C)C#Cc1ccc(S(N)(=O)=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#Cc1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Yield: 62 %

Procedure:
To a solution of 4-[(trimethylsilyl)ethynyl]benzenesulfonamide prepared as in Step 1 (1.69 g, 3.13 mmole) in anhydrous THF under a N2 atmosphere was added TBAF (10 mL-1.0 M in THF, 10 mmole) and the resulting mixture was stirred at room temperature. When silica TLC (1:1 hexanes:EtOAc) indicated the reaction was complete, 10% HCl and EtOAc were added. The EtOAc layer was separated, washed twice with H2O, aqueous NH4Cl, dried over Na2SO4 and concentrated in vacuo to give 0.748 g (62% yield) of the product: ESHRMS m/z 199.0506 (M+NH4, C8H7NO2SNH4, Calc'd 199.0541).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][N:20]=[C:15]3[N:14]([CH:21]3[CH2:23][CH2:22]3)[C:13]2=[O:24])[CH2:9]1)(C)(C)C.[ClH:26].O1CCOCC1>CO>[ClH:26].[NH2:7][C@H:8]1[CH2:11][C@H:10]([N:12]2[C:16]3=[N:17][CH:18]=[CH:19][N:20]=[C:15]3[N:14]([CH:21]3[CH2:22][CH2:23]3)[C:13]2=[O:24])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3nccnc32)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3nccnc32)C1
Temperature: 25 °C
Yield: 65.6 %

Procedure:
To a round bottomed flask was added tert-butyl(trans-3-(3-cyclopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-1-yl)cyclobutyl)carbamate (1.905 g, 5.52 mmol) and hydrogen chloride, 4.0M solution in 1,4-dioxane (1.915 ml, 55.2 mmol) to stir at room temperature. The reaction was monitored by TLC until completion (10% MeOH/90% DCM). The reaction mixture was filtered and solids were washed with diethyl ether and dried in a vacuum oven to give the title compound (1.0201 g, 3.62 mmol, 65.6% yield). LCMS showed product peak at 0.997 min (m+1=246.1). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.94-1.06 (m, 4 H) 2.52-2.60 (m, 2 H) 2.90-2.99 (m, 1 H) 3.16 (ddd, J=14.52, 8.66, 7.34 Hz, 2 H) 3.96-4.08 (m, 1 H) 5.21-5.33 (m, 1 H) 7.92-8.01 (m, 2 H) 8.34 (br. s., 3 H).