Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([C:23]#[C:24][C:25]3[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[CH:26]=3)=[CH:9][N:10]([C@H:11]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]3)[C:6]=2[CH:5]=[CH:4][N:3]=1.CC(C)([O-])C.[Na+].C(=[NH:54])(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:54][C:2]1[C:7]2[C:8]([C:23]#[C:24][C:25]3[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[C:27]([O:33][CH3:34])[CH:26]=3)=[CH:9][N:10]([C@H:11]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12]3)[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: COc1cc(C#Cc2cn([C@H]3CCN(C(=O)OC(C)(C)C)C3)c3ccnc(Cl)c23)cc(OC)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc(C#Cc2cn([C@H]3CCN(C(=O)OC(C)(C)C)C3)c3ccnc(N)c23)cc(OC)c1
Temperature: 115 °C
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere, the (S)-tert-butyl 3-(4-chloro-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)pyrrolidine-1-carboxylate (120 mg) obtained in Step 3,2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP) (26 mg), sodium tert-butoxide (72 mg), benzophenone imine (92 mg), and tris(dibenzylideneacetone)dipalladium (36 mg) were suspended in toluene (10 ml), and the result was stirred at 115° C. for 90 minutes. After dilution with ethyl acetate, celite filtration was performed. The solvent was distilled off under reduced pressure. Hydroxyaminehydrochloride (366 mg), sodium bicarbonate (442 mg), methanol (16 ml), and water (4 ml) were added to the resulting residue, and the resulting mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure. Thereafter, ethyl acetate and a saturated sodium chloride solution were added to separate the organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless, amorphous substance (35 mg). Physical properties: m/z [M+H]+ 463.4
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+:10]1C=CC=C[CH:11]=1.[NH+]1C=CC=CC=1.[Cl:22][C:23]1[S:48][C:26]2[NH:27][C:28]([C:30]([NH:32][CH:33]3[CH2:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]([CH2:43][CH2:44][CH2:45][OH:46])[C:34]3=[O:47])=[O:31])=[CH:29][C:25]=2[CH:24]=1>CN(C=O)C>[Cl:22][C:23]1[S:48][C:26]2[NH:27][C:28]([C:30]([NH:32][CH:33]3[CH2:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]([CH2:43][CH2:44][C:45]([NH:10][CH3:11])=[O:46])[C:34]3=[O:47])=[O:31])=[CH:29][C:25]=2[CH:24]=1
Reactant: O=C(NC1Cc2ccccc2N(CCCO)C1=O)c1cc2cc(Cl)sc2[nH]1
Reactant: c1cc[nH+]cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Solvent: CN(C)C=O
Product: CNC(=O)CCN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reaction time: 24 h
Yield: 60.8 %

Procedure:
Pyridinium dichromate (329 mg, 0.88 mmol) was added to 2-chloro-N-[1-(3-hydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 43; 100 mg, 0.248 mmol) in DMF (3 mL) and the reaction was stirred for 24 hours. The reaction was diluted with EtOAC (20 mL) and filtered through celite. The filtrate was washed with 1M HCl (aq.) and the organic layer was dried (MgSO4), filtered and evaporated to afford the crude acid which was used without purification. Standard amide bond formation analogous to Method 3 except using methylamine (2.0 M in THF) as amine gave the title compound (65 mg, 61% over 2 steps) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[CH2:5][N:6]([CH3:8])[CH3:7])[CH3:2].Br[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1>>[CH3:7][N:6]([CH2:5][CH:4]1[CH2:14][CH:15]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[C:16]2[C:1](=[CH:2][CH:13]=[CH:12][CH:11]=2)[O:3]1)[CH3:8]
Reactant: COc1ccc(Br)cc1
Reactant: CCOC(=O)CN(C)C
Product: COc1ccc(C2CC(CN(C)C)Oc3ccccc32)cc1

Procedure:
The process of example 4 was repeated using N,N-dimethylglycine ethyl ester in place of N,N-dimethylalanine ethyl ester in part (a), and using p-bromoanisole in place of 4-bromochlorobenzene in part (c) to yield the title compound which was isolated as the hydrobromide salt.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:22]=[C:21]([C:23]2[C:32]3[C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[S:35][C:31]=3[C:30]([Br:40])=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[CH:28]3)[CH:20]=[C:19]([Br:41])[C:5]=1[O:6][C@H:7]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([O:10]C)=[O:9].CO>C1COCC1>[Br:3][C:4]1[CH:22]=[C:21]([C:23]2[C:32]3[C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[S:35][C:31]=3[C:30]([Br:40])=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[CH:28]3)[CH:20]=[C:19]([Br:41])[C:5]=1[O:6][C@H:7]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:8]([OH:10])=[O:9]
Reactant: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc4ccccc4c23)cc1Br
Yield: 67 %

Procedure:
Aqueous potassium hydroxide (1 N, 6.37 mL, 6.37 mmol) was added to a stirred solution of (R)-2-[2,6-dibromo-4-(6-bromo-benzo[b]naphtho[2,3-d]thiophen-11 -yl)-phenoxy]-3-phenyl-propionic acid, methyl ester (2.31 g, 3.19 mmol) in THF (22 mL)/methanol (15 mL). After 2 h the solution was concentrated, diluted with water (100 mL) and acidified with 10% aqueous HCl. The solid was filtered, washed with water and triturated with petroleum ether. It was then recrystalyzed from methanol to provide the title compound as a white solid (1.52 g, 67%): mp 140-142° C.: [a]D25=+25.66 (10.52 mg/mL CHCl3); NMR (DMSO-d6);δ13.26 (broad s, 1 H), 8.29 (d, J=8 Hz, 1 H), 8.07 (d, J=8 Hz, 1 H), 7.80 (m, 1 H), 7.79 (dd, J=7, 3 Hz, 2 H), 7.63 (ddd, J=8, 7, 1 Hz, 1 H), 7.55 (d, J=8 Hz, 1 H), 7.51 (ddd, J=8, 7, 1 Hz, 1 H), 7.41 (d, J=7 Hz, 2 H), 7.38-7.32 (m, 3 H), 7.31-7.22 (m, 3 H), 6.64 (d, J=8 Hz, 1 H), 5.32 (t, J =7 Hz, 1 H), 3.41 (d, J=7 Hz, 2 H); MS (EI): [M+], 3 bromine isotope pattern, 708 (35%), 710 (90%) 712 (100%) 714 (40%); Anal. Calc. for C31H19Br3O3S: C, 52.35, H, 2.69, N, 0.00. Found: C, 52.46, H, 2.59, N, 0.10. Chiral analytical HPLC determined that this compound had approx. 100% EE [column:Chirobiotic V, 5 micron (4.6 ×250 mm); isocratic, 1:1 ethanol:hexane; flow rate =0.80 mL/min; injection volume =0.3 μL; sample conc. =0.25 mg/mL; retention time, R-enantiomer =21 min; retention time, S-enantiomer =16 min⟧
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH:2]=[CH2:3].[C:11]1([N:17]=[C:18]=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH:2]=[CH2:3].[C:11]1([NH:17][C:18]([O:10][CH2:5][CH3:4])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C=Nc1ccccc1
Agent: C=CCc1ccccc1O
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccccc1

Procedure:
A mixture of 13.5 g. of 2-allyl-phenol, 13.1 g. of phenylisocyanate and 0.5 g. of pyridine is kept at 100° C. for five minutes. Petroleum ether is added whereupon the precipitated crystals are filtered off with suction and washed with petroleum ether to give 2-allyl-phenol-phenylurethane, melting at 108° C. to 109° C.
Reaction SMILES: CS[C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[Cl:10][C:11]1[CH:37]=[CH:36][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C@@H:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[CH2:24][NH2:25])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1>CC(O)C>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C@@H:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=4)[CH2:24][NH:25][C:3]3=[CH:4][N+:5]([O-:7])=[O:6])=[CH:18][CH:17]=2)=[CH:36][CH:37]=1
Reactant: NC[C@@H](Nc1ccc(Oc2ccc(Cl)cc2)cc1)c1cccc(C(F)(F)F)c1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CC(C)O
Product: O=[N+]([O-])C=C1NC[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 80 °C

Procedure:
1,1-Bis(methylthio)-2-nitroethylene (13.1 mg, 0.079 mmol) and (S)—N1-(4-(4-chlorophenoxy)phenyl)-1-(3-(trifluoromethyl)phenyl)ethane-1,2-diamine prepared from Example 173 Step A (16.1 mg, 0.040 mmol) are dissolved in iPrOH (0.4 mL) and heated at 80° C. for 2 h. The solvent is removed and the residue is purified by preparatory LC/MS to provide the title compound; HPLC-MS calculated for C23H17ClF3N3O3 (M+H+) 476.1, found 476.1.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:2]1>[OH-].[Na+].[Rh]>[O:1]1[CH2:5][CH2:4][CH:3]([O:6][CH:7]2[CH2:8][CH2:9][CH:10]([OH:13])[CH2:11][CH2:12]2)[CH2:2]1
Reactant: Oc1ccc(OC2CCOC2)cc1
Agent: [Rh]
Agent: [Na+]
Agent: [OH-]
Product: OC1CCC(OC2CCOC2)CC1
Reaction time: 3 h
Yield: 85.9 %

Procedure:
4-(Tetrahydro-furan-3-yloxy)-phenol (900 mg, 5.00 mmol) was dissolved in 25 ml 0.4N NaOH and stirred with 500 mg Rh/C 5% under hydrogen atmosphere at 60° C. and 4 bar pressure for 3 hours. The catalyst was filtered off and the clear solution acidified with conc. H2SO4 to pH 1. The aqueous layer was saturated with NaCl and extracted two times with dichloromethane. The organic extracts were dried with sodium sulfate, filtered and evaporated. The crude product (800 mg, 86%) was obtained as a light brown liquid and used without any further purification for the next step.
Reaction SMILES: [CH2:1](/[C:3](=[CH:11]\[CH3:12])/[CH:4]=[CH:5]/[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+].Cl>CO.O>[CH2:11](/[C:3](=[CH:1]\[CH3:2])/[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7])[CH3:12]
Reactant: C/C=C(/C=C/C(=O)OCC)CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C/C=C(/C=C/C(=O)O)CC
Yield: 97.1 %

Procedure:
To a solution of 20.0 kg (119 mol) of ethyl (E,E)-4-ethyl-2,4-hexadienoate in 15 l of methanol is added a solution of 6.0 kg (150 mol) of sodium hydroxide in 60 l of water. The mixture is heated at 50°-55° C. for 1 hour and then cooled to 20°~25° C., poured into a 8%-hydrochloric acid solution at same temperature. The precipitate formed is collected by filtration, washed with 200 l of water and dried in vacuo overnight to give 16.2 kg of (E,E)-4-ethyl-2,4-hexadienoic acid (Yield 97.4%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:15])[N:3]=1.[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>N1C=CC=CC=1>[C:16]([NH:20][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:15])[N:3]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1nc(Cl)c2cccc([N+](=O)[O-])c2n1
Reactant: CC(C)(C)N
Solvent: c1ccncc1
Product: Cc1nc(NC(C)(C)C)c2cccc([N+](=O)[O-])c2n1
Yield: 57.3 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-55, step-1 using 4-chloro-2-methyl-8-nitroquinazoline (Intermediate-27, step-2, 300 mg, 1.34 mmol), and tert-butylamine (196 mg, 2.68 mmol) in pyridine (5 mL) to afford 200 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.62-8.59 (d, J=8.1 Hz, 1H), 8.16-8.13 (d, J=7.5 Hz, 1H), 7.61 (s, 1H), 7.51 (t, J=7.8 Hz, 1H), 2.45 (s, 3H), 1.55 (s, 9H); MS (m/z): 261.20 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:6]=[C:5]([NH:15][C@@H:16]2[CH2:21][CH2:20][C@H:19]([C:22](O)=[O:23])[CH2:18][CH2:17]2)[N:4]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:6]=[C:5]([NH:15][C@@H:16]2[CH2:17][CH2:18][C@H:19]([C:22]([NH:30][CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[C:26]([F:35])([F:36])[F:25])=[O:23])[CH2:20][CH2:21]2)[N:4]=1
Reactant: CNc1nc(N[C@H]2CC[C@@H](C(=O)O)CC2)nc(N2CCCCC2)n1
Reactant: NCc1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CNc1nc(N[C@H]2CC[C@@H](C(=O)NCc3ccccc3C(F)(F)F)CC2)nc(N2CCCCC2)n1
Yield: 70.8 %

Procedure:
A solution of cis-4-(4-(methylamino)-6-(piperidin-1-yl)-1,3,5-triazin-2-ylamino)cyclohexanecarboxylic acid (7.6 mg, 0.023 mmol, 1 equivalent), 2-trifluoromethyl benzylamine (4 μL, 0.03 mmol, 1.25 equivalents) and DMAP (0.6 mg, 0.2 equivalents) in dichloromethane (1.5 ml) was cooled with stirring in an ice bath. EDCl (6.6 mg, 0.034 mmol, 1.5 equivalents) was added. The reaction mixture was stirred at 0° C. for 30 min and at room temperature for 2-3 hours. The solution was diluted with dichloromethane (1 ml), which was further washed with saturated sodium bicarbonate and water. The organic layer was dried and purified by HPLC (Luna 5μ C8(2), 100×21 mm, 28-70% CH3CN/H2O, 0.1% TFA, 20 min) to afford the final product (8.0 mg, yield 71%). MS (ES+): m/e 492.30 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8](=[NH:20])[NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])N=1.[CH3:21]S(O)(=O)=O.C1(N)CCCCC1>>[NH2:20][C:8]([NH:4][CH:5]1[CH2:7][CH2:21][CH2:1][CH2:2][CH2:6]1)=[N:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)n2nc(C)cc2C)cc1
Reactant: CS(=O)(=O)O
Solvent: NC1CCCCC1
Product: Cc1ccc(S(=O)(=O)N=C(N)NC2CCCCC2)cc1

Procedure:
The compound of Example 4 was prepared according to the accompanying synthesis procedure from 0.5 ml of N-[(3,5-dimethylpyrazol-1-yl)-iminomethyl]-4-methylbenzene-sulfonamide solution (0.2 M, acetonitrile) with 19 mg of methanesulfonic acid and 0.5 ml of cyclohexylamine solution (1.0 M, acetonitrile) and filed in a substance databank. Calculated mol. wt. 295.40; found mol. wt. (M+H) 296.1; 591.5 (Dimer)
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:29]2[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=2)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]3)=[CH:16][CH:17]=1)([CH3:23])([CH3:24])[CH3:22]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Product: CC(C)(C)c1ccc(-c2ccc3c(c2)cc(C(=O)O)n3-c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared in accordance with Example 8(c) from 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester (see Example 1(a)) and 4-chlorophenylboronic acid, followed by ester hydrolysis in accordance with the procedure described in Example 35, Method 3, step (b).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:31]([O-:33])=[O:32])=[CH:4][C:5]([Cl:30])=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:18][O:19][C:20]=3[CH3:21])=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.[CH3:34][O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1.CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.N1CCCCC1>CN(C1C=CN=CC=1)C.ClCCCl>[Cl:30][C:5]1[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:18][O:19][C:20]=3[CH3:21])=[O:15])[CH2:10][CH2:9]2)=[CH:7][C:2]([NH:1][C:40](=[O:41])[C:39]2[CH:43]=[CH:44][C:36]([O:35][CH3:34])=[CH:37][CH:38]=2)=[C:3]([N+:31]([O-:33])=[O:32])[CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccccc1-c1noc(C)c1C(=O)N1CCN(c2cc(N)c([N+](=O)[O-])cc2Cl)CC1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Agent: CN(C)c1ccncc1
Solvent: C1CCNCC1
Solvent: ClCCCl
Product: COc1ccc(C(=O)Nc2cc(N3CCN(C(=O)c4c(-c5ccccc5OC)noc4C)CC3)c(Cl)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 73.5 %

Procedure:
A mixture of (4-(5-amino-2-chloro-4-nitrophenyl)piperazin-1-yl)(3-(2-methoxyphenyl)-5-methylisoxazol-4-yl)methanone (16 mg, 0.034 mmol, Preparation L), 4-methoxybenzoyl chloride (12 mg, 0.068 mmol), DMAP (6 mg, 0.034 mmol), and BEMP (19 mg, 0.068 mmol) in DCE (1 mL) was heated at 80° C. for 3 h. Cooled down to RT, the mixture was treated with piperidine (0.3 ml) for 1 h and concentrated in vacuo. HPLC purification gave the title compound (15.7 mg, 0.025 mmol, 74.9% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:9](F)=[N:8][CH:7]=2)#[N:2].[NH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>O1CCCC1>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])=[CH:10][C:9]([NH:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[N:8][CH:7]=2)#[N:2]
Reactant: NCCN1CCOCC1
Reactant: COC(=O)c1cccc(Nc2c(C#N)cnc3cnc(F)cc23)c1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(Nc2c(C#N)cnc3cnc(NCCN4CCOCC4)cc23)c1
Yield: 159.8 %

Procedure:
Following the procedure described above in Example 1, methyl 3-(3-cyano-6-fluoro-1,7-naphthyridin-4-ylamino)benzoate (0.25 g, 0.78 mmol, 1 eq) was reacted with 4-(2-aminoethyl)morpholine (1 mL, 7.62 mmol, 9.8 eq) in tetrahydrofuran (4 mL). Workup and flash column chromatography eluting with 2-5% methyl alcohol in dichloromethane yielded 539 mg product (54% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 2.40-2.46 (m, 4 H) 2.55 (t, J=6.44 Hz, 2 H) 3.34-3.39 (m, 2 H) 3.54-3.60 (m, 4 H) 3.87 (s, 3 H) 6.67 (t, J=5.18 Hz, 1 H) 7.01 (s, 1 H) 7.56 (dt, J=4.36, 1.23 Hz, 2 H) 7.79-7.83 (m, 2 H) 8.32 (s, 1 H) 8.87 (s, 1 H) 9.73 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1.[NH4+:17].[OH-]>O=S(Cl)Cl>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7]([NH2:17])=[O:8])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1
Reactant: [NH4+]
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OC
Temperature: 0 °C

Procedure:
A suspension of 4,5-dimethoxy-2-nitrobenzoic acid 1 (2 g; 8.8 mmol) in SOCl2 (10 mL) was stirred under reflux for 50 minutes. After cooling, the reaction mixture was poured into a mixture of concentrated NH4OH (50 mL) and ice (30 g). The precipitate were collected by filtration, washed with water, and dried to give 1.85 g crude crystals. After recrystallization from DMF, 1.76 g pure product was obtained (88.5%). 1H NMR(DMSO-d6): δ 7.60(s, 2H, —NH2), 7.57(s, 1H , 6-H), 7.12(s, 1H , 3-H), 3.90, 3.87(s, s, 6H, —OCH3); IR(KBr) υmax: 3454, 2840, 1670, 1512, 1274, 1227 cm−1; GC/MS m/z 226(M+, 10.0), 178(98.5), 163(100.0), 135(51.0).
Reaction SMILES: [C:1]1([CH:7]2[N:12]([C:13]([N:15]3[CH2:24][CH2:23][C:22]4[CH:21]=[N:20][C:19]([NH:25][CH:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:18][C:17]=4[CH2:16]3)=[O:14])[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]1([CH:7]2[CH2:8][NH:9][CH2:10][CH2:11][N:12]2[C:13]([N:15]2[CH2:24][CH2:23][C:22]3[CH:21]=[N:20][C:19]([NH:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[N:18][C:17]=3[CH2:16]2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCc3cnc(NC4CCOCC4)nc3C2)C(c2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N1CCc2cnc(NC3CCOCC3)nc2C1)N1CCNCC1c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
tert-Butyl 3-phenyl-4-(2-(tetrahydro-2H-pyran-4-ylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carbonyl)piperazine-1-carboxylate (0.0446 g, 0.0853 mmol) was dissolved in 3:1 DCM/TFA at 0° C. and then stirred for 45 minutes at room temperature. The solution was concentrated, 0.1 mL of 7N NH3/MeOH was added and the solution was concentrated. DCM was added and the solids were removed by filtration. The mother liquor was concentrated to provide (2-phenylpiperazin-1-yl)(2-(tetrahydro-2H-pyran-4-ylamino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)methanone:MS m/z (APCI-pos) M+1=423.4.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:10]=3[O:9][C:8]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)=[CH:4][CH:3]=1.Br[CH2:36][CH2:37][CH2:38][O:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][O:41]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CC(=O)OCC.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:36][CH2:37][CH2:38][O:39][CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][O:41]4)[C:12](=[O:17])[N:11]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:10]=3[O:9][C:8]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=2)=[CH:33][CH:34]=1
Reactant: BrCCCOC1CCCCO1
Reactant: C[Si](C)(C)CCOCn1c(=O)[nH]c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(Cl)c3)oc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(Cl)c3)oc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 151.6 %

Procedure:
To a solution of 5-(4-chlorobenzyl)-6-(3-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)furo[2,3-d]pyrimidine-2,4(1H,3H)-dione (25.88 mg, 0.01 mmol) in DMF (3 mL) was added 2-(3-bromopropoxy)tetrahydro-2H-pyran (11.2 mg, 0.05 mmol) and K2CO3 (6.9 mg, 0.05 mmol). The reaction was stirred at 60° C. for 2 h, cooled to RT, then was diluted with EA (12 mL) and water (4 mL). The organic layer was washed with brine (3 mL), dried over Na2SO4, and concentrated to a residue which was purified by chromatography PE/EA (5:1) to give 5-(4-chlorobenzyl)-6-(3-chlorophenyl)-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1-((2-(trimethylsilyl)ethoxy)methyl) furo[2,3-d]pyrimidine-2,4(1H,3H)-dione (10 mg, 30.7% yield) as an oil. LCMS: (M++Na) 681 and TR=2.289 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][C@H:27]([N:31]([S:36]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH2:32][CH:33]([CH3:35])[CH3:34])[C:28]([OH:30])=[O:29])=S)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:46]#[C:47][NH2:48]>CO.[NH4+].[Cl-]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@H:12]([C:20]([NH:48][C:47]#[N:46])=[N:22][CH2:23][CH2:24][CH2:25][CH2:26][C@H:27]([N:31]([S:36]([C:39]2[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=2)(=[O:37])=[O:38])[CH2:32][CH:33]([CH3:34])[CH3:35])[C:28]([OH:30])=[O:29])[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: N#CN
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=S)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)NC#N)cc1
Reaction time: 0.08 h
Yield: 57 %

Procedure:
To a stirred solution of the thioamide, Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-[N′α-(4-methylbenzenesulfonyl)-L-thiophenylalanyl]-L-lysine, (227 mg, 0.33 mmol, example 72) in MeOH (3 mL) was added cyanamide (28 mg, 0.66 mmol). The mixture was stirred for 5 min, then mercuric acetate (209 mg, 0.66 mmol) was added. The reaction was stirred for 3 h then diluted with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with brine and concentrated then rediluted with THF/MeOH (2 mL/1 mL) and treated with 1N NaOH (0.8 mL). After stirring for 4 h, the reaction was acidified with 1N HCl and extracted with EtOAc. The organic layer was dried over MgSO4, concentrated and purified by column chromatography to give 128 mg (57%) of the final product.