Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.C([NH:19][C@H:20]([C:22](O)=[O:23])[CH3:21])(OCC1C=CC=CC=1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[NH2:45][C@H:46]([C:52]([OH:54])=[O:53])[CH2:47][CH2:48][C:49](=[O:51])[NH2:50].[OH-].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl>CCOCC.C(#N)C>[NH2:19][C@H:20]([C:22]([NH:45][C@H:46]([C:52]([OH:54])=[O:53])[CH2:47][CH2:48][C:49](=[O:51])[NH2:50])=[O:23])[CH3:21]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Reaction time: 1 h
Yield: 45 %

Procedure:
Dissolve 30 mmol of hexachloroethane with 10 ml of acetonitrile, drop it into a mixed system composed of 10 mmol of carbobenzoxy alanine (Z-Ala), 20 ml of triphenylphosphine and 10 ml of acetonitrile. After reacting at 5° C. for 1.0 h., drop it into 20 ml of water containing 10 mmol of glutamine. While reacting, regulate pH to 10 with 20 mmol of sodium hydroxide and then potassium carbonate successively, the reaction temperature is 5° C., and the reaction time after dropping is 2 hours. And then acidify it to regulate pH to 3.0 with concentrated hydrochloric acid. The aqueous phase, after concentrated, reacts with trifluoroacetic acid at room temperature for 40 hours. After the reaction is finished, add in 50 ml of ether, solids deposit, the product L-Ala-L-Gln is obtained with a yield of 45% by recrystallizing the solids with 1,4-dioxane-water.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH:26]=O>>[CH3:20][N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: Cn1cccc1C=O
Product: Cn1cccc1CN1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1-methylpyrrole-2-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(1-methylpyrrol-2-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Br[C:2]1[C:3]([N:25]2[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]2)=[N:4][CH:5]=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=1)=[O:8].O1CCCCC1[N:37]1[C:41](B2OC(C)(C)C(C)(C)O2)=[CH:40][CH:39]=[N:38]1>>[OH:30][C@@H:27]1[CH2:28][CH2:29][N:25]([C:3]2[C:2]([C:39]3[NH:38][N:37]=[CH:41][CH:40]=3)=[CH:24][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:23])([F:22])[C:18]([F:20])([F:19])[F:21])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:26]1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)C(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 8 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(perfluoroethoxy)phenyl)nicotinamide (Stage 19.1) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to afford an off-white solid. HPLC (Condition 4) tR=4.86 min, UPLC-MS (Condition 3) tR=0.97 min, m/z=484.4 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.62-1.92 (m, 2H) 2.94 (d, J=1.00 Hz, 1H) 3.18-3.34 (m, 2H) 3.37-3.51 (m, 1H) 4.13-4.22 (m, 1H) 4.70-4.91 (m, 1H) 6.37 (br. s, 1H) 7.31 (d, J=8.99 Hz, 2H) 7.86 (m, J=9.00 Hz, 3H) 8.01 (br. s, 1H) 8.65-8.83 (m, 1H) 10.17 (s, 1H) 12.84-13.11 (m, 1H).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[C:8]([CH:21]=1)[C:9]([O:11]CC1C=CC(OC)=CC=1)=[O:10]>O.C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[C:8]([CH:21]=1)[C:9]([OH:11])=[O:10]
Reactant: COc1ccc(COC(=O)c2cc(Br)ccc2OCc2ccc(OC)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(Br)cc2C(=O)O)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of lithium hydroxide (367 mg, 8.75 mmol) in water (20 ml) was added dropwise to a stirred solution of [4-(methyloxy)phenyl]methyl 5-bromo-2-({[4-(methyloxy)phenyl]methyl}oxy)benzoate (may be prepared as described in Description 17; 400 mg, 0.875 mmol) in THF over 1 min. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was evaporated and the aqueous phase (20 ml) was extracted with ethyl acetate (20 ml). The aqueous phase (20 ml) was adjusted to pH 2 with 2M hydrochloric acid (1 ml) and was extracted with ethyl acetate (3×20 ml). The organic phase was evaporated in vacuo to yield the title compound as a light yellow solid. 200 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc(N)cc1

Procedure:
A solution of 4.18 g (0.02 mole) of ethyl p-nitrophenylacetate in 200 mL of ethanol is subjected to catalytic hydrogenation. The mixture is filtered to remove the catalyst and the filtrate is concentrated to obtain quantitative yield of ethyl 4-aminophenylacetate. To an agitated solution of the ethyl 4-aminophenylacetate and 2.02 g (0.02 mole) of triethylamine in 50 ml of dimethylformamide is added dropwise a solution of 7.58 g (0.020 mole) of 1-(3-chloropropyl)-α,α-bis(4-fluorophenyl)-4-piperidinemethanol in 20 ml of dimethylformamide. After stirring at ambient temperature for 4 hr the reaction mixture is heated at 70° C. for 4 hr. The reaction mixture is concentrated and the crude product partitioned between methylene chloride and water. The methylene chloride solution is washed with water, dried over anhydrous magnesium sulfate, and concentrated to yield the title compound.
Reaction SMILES: [CH:1]([S:4]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14]/[C:15](=[C:22]2\[C:23](=[O:31])[NH:24][C:25]3[C:30]\2=[CH:29][CH:28]=[CH:27][CH:26]=3)/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].Cl[CH2:33][CH2:34][N:35]([CH3:37])[CH3:36].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[CH3:36][N:35]([CH3:37])[CH2:34][CH2:33][N:7]([C:8]1[CH:9]=[CH:10][C:11]([NH:14]/[C:15](=[C:22]2\[C:23](=[O:31])[NH:24][C:25]3[C:30]\2=[CH:29][CH:28]=[CH:27][CH:26]=3)/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[S:4]([CH:1]([CH3:3])[CH3:2])(=[O:5])=[O:6]
Reactant: CC(C)S(=O)(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)S(=O)(=O)N(CCN(C)C)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 36 from (Z)-3-{1-[4-(isopropylsulphonylamino)-phenylamino]-1-phenyl-methylidene}-2-indolinone, 1-chloro-2-dimethylamino-ethane, potassium carbonate and sodium iodide in acetone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)=[CH:11][C:10]([C:21]([OH:23])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:48]3[CH2:52][C:51](=[O:53])[NH:50][CH2:49]3)=O)=N2)C=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)=[CH:11][C:10]([C:21]([N:48]3[CH2:52][C:51](=[O:53])[NH:50][CH2:49]3)=[O:23])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Reactant: O=C(O)c1cc(-c2ccc(F)c(Cl)c2)n(-c2cccc(Br)c2)n1
Product: O=C1CN(C(=O)c2cc(-c3ccc(F)c(Cl)c3)n(-c3cccc(Br)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 99A in analogy to the synthesis of the compound of Example 23. 186 mg (79% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.Cl[C:18]1[C:19]2[S:26][C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:24][C:20]=2[N:21]=[CH:22][N:23]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:18]3[C:19]4[S:26][C:25]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Clc1ncnc2cc(-c3ccccc3)sc12
Reactant: COc1cccc(Nc2ccc(N)cc2)c1
Product: COc1cccc(Nc2ccc(Nc3ncnc4cc(-c5ccccc5)sc34)cc2)c1
Yield: 17 %

Procedure:
Utilizing a procedure analogous to that described in Example 61, the title compound was prepared in 17% yield from added N-(3-methoxy-phenyl)-benzene-1,4-diamine (100 mg, 0.405 mmol) and 4-chloro-6-phenyl-thieno[3,2-d]pyrimidine (100 mg, 0.405 mmol). RP18-HPLC RT: 6.833 minutes; API MS: 425.53 (M+1); MP: 189-191° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=O)=[CH:19][CH:18]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([NH:40][C:23]([C:20]3[CH:21]=[CH:22][C:17]([C:3]4[CH:4]=[C:5]([NH:8][C:9]([CH:11]5[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]5)=[O:10])[CH:6]=[CH:7][C:2]=4[Cl:1])=[CH:18][CH:19]=3)=[O:25])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1
Reactant: O=C(O)c1ccc(-c2cc(NC(=O)C3CCCCC3)ccc2Cl)cc1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(NC(=O)C5CCCCC5)ccc4Cl)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.6 %

Procedure:
A mixture of 2′-Chloro-5′-(cyclohexanecarbonyl-amino)-biphenyl-4-carboxylic acid (103 mg), 4-(4-methyl-piperazin-1-ylmethyl)-phenylamine (59 mg) and HBTU (148 mg) in dry DMF (10 ml) containing triethylamine (362 μl) was stirred at room temp for 18 h. Most of the DMF was evaporated and the residue diluted with water. The resulting solid was collected by filtration. This material was then purified by reverse phase Prep HPLC giving the title compound as a yellow solid (51 mg)
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:51])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@@H:16]([CH2:47][C:48](O)=[O:49])[CH2:15]2)=[CH:10][CH:9]=1.ClC(N(C)C)=C(C)C.[C:60]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])(=[O:63])[NH:61][NH2:62].CCN(CC)CC>C(Cl)Cl>[C:65]([O:64][C:60]([NH:61][NH:62][C:48](=[O:49])[CH2:47][C@H:16]1[CH2:15][C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][O:6][CH2:5][C@@H:4]([CH3:51])[CH2:3][O:2][CH3:1])=[CH:9][CH:10]=2)[C@@H:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:18][N:17]1[S:37]([C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)(=[O:39])=[O:38])=[O:63])([CH3:68])([CH3:67])[CH3:66]
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reactant: CC(C)(C)OC(=O)NN
Agent: CC(C)=C(Cl)N(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(=O)NNC(=O)OC(C)(C)C)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 1 mmol of [(2R,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-acetic acid (example 1g) in 5 ml of CH2Cl2 is treated at RT with 1.5 mmol of 1-chloro-N,N,2-trimethylpropenylamine, and stirred at RT for 2.5 h. This solution is added slowly, at 0° C., to a solution of 5 mmol of tert-butyl carbazate [870-46-2] and 5 mmol of Et3N in 1 ml of CH2Cl2. The reaction mixture is stirred at 4° C. for 16.5 h, then quenched with H2O. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic extracts are washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a yellow oil. Rf=0.34 (EtOAc/Heptane 2:1); Rt=5.28 (gradient I).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[N:15]=[C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:17][C:18]=1[CH3:19])[CH:5]=[CH:6][CH:7]=O.[O:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][CH2:7][CH:30]2[O:26][C:27](=[O:32])[NH:28][C:29]2=[O:31])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[N:15]=[C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:17][C:18]=1[CH3:19]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(C=CC=O)cc1F
Reactant: O=C1COC(=O)N1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCCC2OC(=O)NC2=O)cc1F

Procedure:
In substantially the same manner as in Working Example 11, 3-fluoro-4-(5-methyl-2-phenyl-4-oxazolyl methoxy)cinnamaldehyde was condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic reduction to yield 5-[3-[3-fluoro-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-2,4-oxazolidinedione, which was recrystallized from dichloromethane-methanol to give colorless prisms, m.p.180-181° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:45]=[CH:44][C:20]([C:21]([NH:23][C:24]3[CH:25]=[C:26]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:27]=[CH:28][C:29]=3[NH:30]C(=O)OC(C)(C)C)=[O:22])=[CH:19][CH:18]=2)[CH2:13]1)(C(C)(C)C)(C)C>C(O)(C(F)(F)F)=O.O.CCOC(C)=O>[NH2:30][C:29]1[CH:28]=[CH:27][C:26]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[CH:25][C:24]=1[NH:23][C:21](=[O:22])[C:20]1[CH:44]=[CH:45][C:17]([N:14]2[CH2:15][CH2:16][C@H:12]([NH:11][CH2:10][CH2:9][OH:8])[CH2:13]2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(N2CC[C@H](NCCO[Si](C)(C)C(C)(C)C)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(N2CC[C@H](NCCO)C2)cc1
Yield: 81.6 %

Procedure:
A solution of 443 (0.13 g, 0.206 mmol) in TFA (0.392 mL) and water (0.021 mL) was stirred for 2 h at room temperature. The solvent was evaporated and the residue obtained was dissolved in EtOAc, washed with sat NaHCO3 and sat NaCl. The organic layer was dried with MgSO4, filtered and concentrated to a brown solid. Trituration in Et2O generated the title compound 444 as a beige powder (70 mg, 82% yield).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[C:9]([OH:18])=[C:10]([C:15](=[O:17])[CH3:16])[CH:11]=[CH:12][C:13]=1[OH:14].[Br:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Br)=[CH:23][CH:22]=1.Cl>CC(C)=O.CCOC(C)=O>[Br:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:14][C:13]2[CH:12]=[CH:11][C:10]([C:15](=[O:17])[CH3:16])=[C:9]([OH:18])[C:8]=2[Cl:7])=[CH:23][CH:22]=1
Reactant: BrCc1ccc(CBr)cc1
Reactant: CC(=O)c1ccc(O)c(Cl)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCc2ccc(CBr)cc2)c(Cl)c1O

Procedure:
Add K2CO3 (1.48 g, 10.7 mmol) to a solution of 1-(3-chloro-2,4-dihydroxy-phenyl)ethanone (2.00 g, 10.7 mmol) and 1,4-bis(bromomethyl)benzene (2.83 g, 10.7 mmol) in acetone (100 mL). Cool and work up with a 10% HCl solution and EtOAc. Triturate in acetone to remove insoluble material. Dry, filter, and concentrate. Purify the residue by flash chromatography on silica gel (731 mg, 18%): MS (esi negative) m/z 368.9 (rel intensity) (M−H, 55%), 367.0 (45%).
Reaction SMILES: C(OC([NH:8][CH2:9][C@@H:10]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.[ClH:21]>CO.C(O)(C)C>[ClH:21].[ClH:21].[NH2:8][CH2:9][C@H:10]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@@H](CNC(=O)OC(C)(C)C)N1CCCCC1
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: COC(=O)[C@H](CN)N1CCCCC1
Temperature: 40 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
3.7 g (12.9 mmol) of methyl (R)-3-tert-butoxycarbonylamino-2-piperidin-1-ylpropanoate are placed in a mixture of 25 ml of methanol and 15 ml of hydrochloric acid in solution in isopropanol having a concentration of 5-6N. The reaction medium is stirred at 40° C. for 18 h and then concentrated under vacuum. 3.5 g (100%) of methyl(S)-3-amino-2-piperidin-1-ylpropanoate dihydrochloride are obtained in the form of a beige solid.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][C:8](Cl)=[O:9])(=[O:4])=[O:3].[C:11]([O:15][C:16](=[O:47])[NH:17][C:18]([C:20]1[S:21][C:22]([S:45][CH3:46])=[C:23]([S:25]([C:28]2[CH:29]=[C:30]([C:34]3[C:39]([NH2:40])=[CH:38][C:37]([N+:41]([O-])=O)=[CH:36][C:35]=3[CH3:44])[CH:31]=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH:24]=1)=[NH:19])([CH3:14])([CH3:13])[CH3:12].CCN(CC)CC>C(Cl)Cl>[C:11]([O:15][C:16](=[O:47])[NH:17][C:18]([C:20]1[S:21][C:22]([S:45][CH3:46])=[C:23]([S:25]([C:28]2[CH:29]=[C:30]([C:34]3[C:39]([NH:40][C:8](=[O:9])[CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:38][C:37]([NH2:41])=[CH:36][C:35]=3[CH3:44])[CH:31]=[CH:32][CH:33]=2)(=[O:26])=[O:27])[CH:24]=1)=[NH:19])([CH3:14])([CH3:13])[CH3:12]
Reactant: CS(=O)(=O)CCCC(=O)Cl
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc([N+](=O)[O-])cc2N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(N)cc2NC(=O)CCCS(C)(=O)=O)c1
Reaction time: 1 h

Procedure:
The procedure in Example 261: step b was followed using 4-methanesulfonyl-butyryl chloride (Example 209: step a (53 mg, 0.29)), {[4-(6′-amino-2′-methyl-4′-nitro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 295: step h) 130 mg, 0.23 mmol), and Et3N (192 μL, 1.38 mmol) in DCM (5 mL). After stirring for 1 h, starting material remained and an additional 20 mg of acid chloride was added. The solution was partitioned between EtOAc (70 mL) and aq NH4Cl (30 mL) and the layers were separated. The organic layer was washed with NaHCO3 (20 mL) and brine (30 mL) and was dried over sodium sulfate. The solution was concentrated and the residue was purified by SiO2 flash column chromatography to yield 126 mg of the amide product. The residue dissolved in EtOH (5 mL). Saturated aqueous NH4Cl (1.5 mL) was added followed by iron powder (110 mg, 2 mmol). The mixture was vigorously stirred at 80° C. for 30 min. The solution was filtered through a 0.22 μm filter and was then partitioned between EtOAc (70 mL) and water (20 mL). The layers were separated, the organic solution was dried over sodium sulfate, and the solution was concentrated to give the crude title compound which was used without further purification. 1HMR (CDCl3): δ 7.99 (s, 1H), 7.96 (m, 2H), 7.77 (s, 1H), 7.57 (t, 1H, J=7.9 Hz), 7.43 (dt, 1H, J=1.3, 7.7 Hz), 7.10 (br s, 1H), 7.04 (br s, 1H), 6.43 (br s, 1H), 3.85 (br s, 2H), 2.92 (m, 2H), 2.88 (s, 3H), 2.56 (s, 3H), 2.20 (t, 2H, J=6.7 Hz), 1.98 (m, 2H), 1.90 (s, 3H), 1.50 (s, 9H).
Reaction SMILES: O=[C:2]([NH:12][NH:13][C:14](=O)[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1COCC1>[C:15]([C:14]1[S:29][C:2]([CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[N:12][N:13]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)NNC(=O)C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1nnc(C(C)(C)C)s1
Yield: 92.6 %

Procedure:
To a solution of 15-1 (100 mg, 0.37 mmol) in THF (10 mL) was added lawesson's reagent (153 mg, 0.38 mmol) and it was refluxed for 3 h. The reaction mixture was concentrated and purified by gradient elution on silica gel (0 to 50% EtOAc in petroleum) to afford the title compound (93 mg, 92%). LRMS (ES) calculated M+H for C12H21N3O2S:272.4. Found: 272.2.
Reaction SMILES: [CH:1]([C:3]1[O:7][CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=1)=[O:2].P(OCC)(OCC)(O[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O.C(C1OC(C=O)=CC=1)C1C=CC=CC=1>CC#N.C(O)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:20]([C:5]1[CH:4]=[C:3]([CH:1]=[O:2])[O:7][CH:6]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1(C)OB(c2coc(C=O)c2)OC1(C)C
Reactant: CCOP(=O)(OCC)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=Cc1ccc(Cc2ccccc2)o1
Solvent: CC(C)O
Solvent: CC#N
Product: O=Cc1cc(Cc2ccccc2)co1
Yield: 40.8 %

Procedure:
The title compound was synthesized from 5-formylfuran-3-boronic acid pinacol ester (878 mg, 3.95 mmol), and benzyl diethyl phosphate (1.25 g, 5.14 mmol) using the same conditions used to synthesize 5-benzyl-furan-2-carbaldehyde, with the exception that TPP and Pd(OAc)2 were dissolved in 2:1 CH3CN/isopropyl alcohol. Purification by flash chromatography yielded 4-benzyl-furan-2-carbaldehyde as a white solid (300 mg, 41%). 1H NMR (400 MHz, CDCl3) δ ppm 9.56 (s, 1 H) 7.29-7.38 (m, 3 H) 7.24-7.28 (m, 2 H) 7.17 (d, J=3.5 Hz, 1 H) 6.19 (d, J=3.6 Hz, 1 H) 4.07 (s, 2 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[N:25]=[C:24](Cl)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:41][O:42][C:43]([C:45]1[CH:50]=[CH:49][C:48](B(O)O)=[CH:47][CH:46]=1)=[O:44]>O1CCOCC1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH3:33])[N:25]=[C:24]([C:48]4[CH:49]=[CH:50][C:45]([C:43]([O:42][CH3:41])=[O:44])=[CH:46][CH:47]=4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)c1c(C)nc(Cl)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)nc(-c2ccc(C(=O)OC)cc2)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 100 °C
Yield: 72.8 %

Procedure:
Ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-2-chloro-6-methylpyrimidine-5-carboxylate (0.8 g, 1.63 mmol), K2CO3 (0.56 g, 4 mmol), Pd(PPh3)4 (0.28 g, 0.24 mmol) were dissolved in dioxane/water (20:1), 4-(methoxycarbonyl)phenylboronic acid (0.38 g, 2.1 mmol) was added the mixture was heated to 100° C. for 3 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was concentrated and purified by column chromatography over silica gel using 30% EtOAc/hexanes as eluent to give the desired product (0.7 g). 1H NMR (400 MHz, DMSO-d6): δ 9.88 (s, 1H), 8.43 (d, J=8.0 Hz, 2H), 8.10 (d, J=8.0 Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 4.39 (q, J=6.8 Hz, 2H), 3.89 (s, 3H), 3.49 (s, 2H), 2.68 (m, 4H), 2.50 (s, 3H), 2.33 (m, 4H), 1.91 (t, J=6.8 Hz, 3H), 1.39 (s, 9H); MS m/z 590.2 (M+1).