Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([N:15](CC)CC)C.[NH2:20][CH:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22]O>O1CCOCC1.C(OCC)(=O)C>[CH2:24]([C:21]1[N:20]=[C:2]2[C:11]([NH2:15])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]2[CH:22]=1)[CH:25]([CH3:27])[CH3:26]
Reactant: CCN(CC)CC
Reactant: CC(C)CC(N)CO
Reactant: Clc1nc2ccccc2nc1Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)Cc1cn2c(n1)c(N)nc1ccccc12
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
To a solution of 2,3-dichloroquinoxaline (2.0 g, 10.0 mmol) in 10 mL of 1,4-dioxane was added triethyl amine (1.81 g, 18 mmol) and followed by 2-amino-4-methylpentan-1-ol (1.4 g, 12 mmol). The reaction mixture was separated into 2 microwave tubes. And then the mixture was stirred in microwave for 10 minutes at 130° C. The combined reaction mixture was diluted with 150 mL of ethyl acetate and then was washed with water (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography eluted with ethyl acetate and hexanes to give the titled compound (2.3 g, 69%)
Reaction SMILES: [CH2:1]([C@H:8]([NH:39]C(=O)OC(C)(C)C)[CH2:9][C@H:10]([OH:38])[C@@H:11]([NH:25][C:26](=[O:37])[C@@H:27]([NH:32][C:33]([O:35][CH3:36])=[O:34])[C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:39][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][C@H:10]([OH:38])[C@@H:11]([NH:25][C:26]([C@@H:27]([NH:32][C:33](=[O:34])[O:35][CH3:36])[C:28]([CH3:30])([CH3:31])[CH3:29])=[O:37])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution containing the product from Example 23R (0.34 g, 0.54 mmol) in dichloromethane (5 mL) was treated with trifluoroacetic acid (5 mL), stirred at 25° C. for 1 hour, and concentrated. The residue was partitioned between dichloromethane and saturated NaHCO3 solution. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The crude product (0.251 g) was used without further purification.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]=[O:13])=[CH:6][CH:5]=1)[CH2:2][CH3:3].C[C@H](NC([C@H]1N(C([C@@H](NC([C@@H](N)CC2C=CC(O)=CC=2)=O)CC(O)=O)=O)CCC1)=O)C(N1[C@H](C(N2[C@H](C(N3[C@H](C(N4[C@H](C(N5[C@H](C(N6[C@H](C(O)=O)CCC6)=O)CCC5)=O)CCC4)=O)CCC3)=O)CCC2)=O)CCC1)=O>Cl.CO>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH:12]=[O:13])[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(CCC=O)cc1
Agent: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CC(=O)O)NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Solvent: CO
Product: CCCC1CCC(CCC=O)CC1
Temperature: 0 °C
Yield: 75.7 %

Procedure:
A reaction flask was charged with 3-(4-propyl-phenyl)-propionaldehyde (240 g, prepared as above), methanol (200 mL), and TMOF (150 g). The reaction mass was cooled to 0° C. and hydrochloric acid (37%, 1 g) was added in one portion. The reaction was exothermic and the temperature rose to 23° C. The reaction mass was quenched with sodium methoxide in methanol (25%, 10 g) and the solvent was removed by evaporation. The crude intermediate product 3-(4-propyl-phenyl)-propionaldehyde dimethylacetal (300 g), 2-propanol (100 mL), and rutheniium on alumina (3 g) were then charged to a 1 L zipper autoclave. The autoclave was purged with nitrogen followed by hydrogen. The autoclave was pressurized with 500 psi hygrogen and heated to 150° C. for 6 hours. The autoclave vessel was then cooled to an ambient temperature, depressurized, and purged with nitrogen. The reaction mass was filtered through celite to remove the catalyst and further hydrolyzed in the presence of water (2 L) containing hydrochloric acid (37%, 2 g) at 90° C. for 5 hours. The organic layer was separated and washed with saturated sodium carbonate solution (500 mL). Subsequent fractional distillation afforded 4-propyl cyclohexanepropanal (188 g), which had a boiling point of 107° C. at a pressure of 7 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:29][CH:30]=O)[CH2:10][N:11]2[C:17](=[O:18])[C:16]3[C:19]4[C:24]([CH:25]=[C:26]([C:27]#[N:28])[C:15]=3[S:14][CH2:13][CH2:12]2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:33][O:34][NH2:35]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:29][CH2:30][NH:35][O:34][CH3:33])[CH2:10][N:11]2[C:17](=[O:18])[C:16]3[C:19]4[C:24]([CH:25]=[C:26]([C:27]#[N:28])[C:15]=3[S:14][CH2:13][CH2:12]2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: N#Cc1cc2ccccc2c2c1SCCN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C2=O
Reactant: CON
Agent: Cl
Product: CONCC[C@H](CN1CCSc2c(C#N)cc3ccccc3c2C1=O)c1ccc(Cl)c(Cl)c1
Yield: 65.8 %

Procedure:
By the method described in Example 79, Intermediate 78a (40 mg, 0.085 mmol) and methoxyamine hydrochloride (13 mg, 0.154 mmol) were converted to 28 mg of the title compound.
Reaction SMILES: [CH2:1](OCC)C.FB(F)F.[CH:10]1[C:23]2[CH:22]=[CH:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[NH:13][S:12](=[O:25])(=[O:24])[N:11]=1.C[Li]>C1COCC1>[CH3:1][CH:10]1[C:23]2[CH:22]=[CH:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[NH:13][S:12](=[O:25])(=[O:24])[NH:11]1
Reactant: O=S1(=O)N=Cc2ccc3cccnc3c2N1
Reactant: CCOCC
Agent: FB(F)F
Agent: [Li]C
Solvent: C1CCOC1
Product: CC1NS(=O)(=O)Nc2c1ccc1cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.8 %

Procedure:
Ethoxyethane—trifluoroborane (1:1; 32.3 μl, 0.26 mmol) was added dropwise to a solution of 4H-3-thia-2,4,5-triaza-phenanthrene 3,3-dioxide 406 (60 mg, 0.26 mmol) in dry THF (3 ml) under an atmosphere of N2. The mixture was stirred at room temperature for 1 h and then cooled to −78° C. Methyllithium (1.6M in Et2O; 1.61 ml, 2.57 mmol) was added dropwise and the mixture was stirred −78° C. for 1 h. The reaction was quenched with sat NH4Cl (2 ml) at -78° C. and the mixture was warmed to room temperature. The mixture was extracted with EtOAc and the residue was purified by preparative HPLC (acidic conditions 1) to give the title compound (18 mg, 28%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:12]([OH:14])=O)=[CH:5][N:6]=[CH:7]2.CC[N:17](C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:12]([NH2:17])=[O:14])=[CH:5][N:6]=[CH:7]2
Reactant: O=C(O)c1cncc2cccc(Br)c12
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: NC(=O)c1cncc2cccc(Br)c12
Reaction time: 8 h
Yield: 60 %

Procedure:
To a stirred solution of 5-bromoisoquinoline-4-carboxylic acid (Intermediate-17) (1 equiv, 2.0 mmol) in dry THF (10.0 ml) were added, DIPEA (3 equiv), HOBT (1.5 equiv), EDC.HCl (1.5 equiv) at RT and the mixture was stirred for 10 min. To this, corresponding amine (1.2 equiv) was added and the reaction mixture was stirred overnight. After completion (TLC), it was concentrated under reduced pressure and the crude product was purified by flash column chromatography to furnish the corresponding amide derivative (60-80%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH3:23][NH:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:15]=[CH:16][C:17]([C:20]([N:24]([CH3:23])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:21])=[CH:18][CH:19]=1
Reactant: CNCCc1ccccc1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)N(C)CCc4ccccc4)cc3)c2)o1

Procedure:
2′-Methyl-N-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(phenylethyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and N-methyl-N-(phenylethyl)amine using method M. NMR; δH [2H6]—DMSO 7.89,(1H, dd), 7.75,(1H, d), 7.54,(1H, d), 7.47-7.17,(8H, m), 6.99,(1H, d), 3.69,(1H, m), 3.43,(1H, m), 3.04,(1.5H, s), 2.92,(1H, m), 2.87,(1.5H, s), 2.80,(1H, m), 2.56,(3H, s), 2.31,(3H, s). LCMS; retention time 3.39 min, MH+ 412.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[C:4]([NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][C:19]=2[Cl:20])=[O:14])[CH:3]=1.[OH-].[Na+]>CC(N(C)C)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][C:19]=2[Cl:20])=[O:14])[CH:3]=1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)c1sccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: O=C(O)c1ccc(Cl)cc1NC(=O)c1sccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
Methyl 4-chloro-2-(3-chlorothiophene-2-carboxamido)benzoate (90 mg, 0.27 mmol) was dissolved in 4 mL of dimethylacetamide. 1 M NaOH (1 mL) was added and the reaction was stirred at room temperature overnight. The product was precipitated by the addition of 1 M HCl to the reaction mixture. The product was filtered and dried under vacuum to give 69 mg of white solid. 1H NMR (400 MHz, d6-DMSO): 12.08 (s, 1H), 8.68 (d, 1H), 8.05 (d, 1H), 8.03 (d, 1H), 7.32 (dd, 1H), 7.28 (d, 1H); MS (EI) for C12H7Cl2NO3S: 316 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]O)=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[ClH:28].[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:9][C:10]([C:21]4[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=4)=[C:11]([C:13]([NH:15][C:16]4[S:17][CH:18]=[CH:19][N:20]=4)=[O:14])[N:12]=3)=[CH:4][CH:3]=2)=[CH:31][CH:30]=1
Reactant: OCc1ccc(Cl)cc1
Reactant: Cc1ccc(-c2[nH]c(-c3ccc(O)cc3)nc2C(=O)Nc2nccs2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2[nH]c(-c3ccc(OCc4ccc(Cl)cc4)cc3)nc2C(=O)Nc2nccs2)cc1
Product: Cl
Reaction time: 40 h
Yield: 23.1 %

Procedure:
2-(4-Hydroxyphenyl)-5-(4-methylphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (0.38 g) obtained in Example 23, 4-chlorobenzyl alcohol (0.14 g) and triphenylphosphine (0.26 g) were dissolved in tetrahydrofuran (25 ml) and diethyl azodicarboxylate (0.16 ml) was added. The mixture was stirred for 40 hr. Water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried. The solvent was evaporated and the obtained residue was purified by silica gel chromatography (hexane:ethyl acetate=7:3). The obtained residue was converted to hydrochloride to give 2-(4-(4-chlorophenylmethyloxy)-phenyl)-5-(4-methylphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide hydrochloride (61 mg), melting point 203-205° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15](C(N)=O)[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.C[O:23][CH:24]([O:28][CH3:29])N(C)C>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:24]([O:28][CH3:29])=[O:23])[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Solvent: CO
Product: COC(=O)c1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a suspension of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxamide prepared as set forth in Example A-223 (2.9 g, 0.01 mol) in 50 mL of methanol was added N,N-dimethylformamide dimethyl acetal (3.67 g, 0.03 mol) dropwise. The reaction mixture was stirred at room temperature overnight and heated at reflux for 4hours. After cooling, the precipitate was collected by filtration and air-dried to give 2.0 g of methyl 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxylate as a white solid (69% yield), mp: 239-241° C. Anal. Calc'd for C16H12FN3O2: C, 64.64; H, 4.07; N, 14.13. Found: C, 64.36; H, 4.10; N, 14.27.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:34])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:22]=[C:21]([C:23]([NH:25][CH:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29]C)=[O:28])=[O:24])[O:20][N:19]=2)=[CH:14][CH:13]=1.[OH-].[Li+]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:34])[NH:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[N:22]=[C:21]([C:23]([NH:25][CH:26]([CH:31]([CH3:32])[CH3:33])[C:27]([OH:29])=[O:28])=[O:24])[O:20][N:19]=2)=[CH:16][CH:17]=1
Reactant: COC(=O)C(NC(=O)c1nc(-c2ccc(NC(=O)Nc3ccc(F)cc3F)cc2)no1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)C(NC(=O)c1nc(-c2ccc(NC(=O)Nc3ccc(F)cc3F)cc2)no1)C(=O)O
Temperature: 25 °C
Yield: 81.89 %

Procedure:
Methyl 2-(3-(4-(3-(2,4-difluorophenyl) ureido)phenyl)-1,2,4-oxadiazole-5-carboxamido)-3-methylbutanoate was added to THF and to this 1N lithium hydroxide was added and stirred at room temperature. After completion of the reaction the solvent was evaporated and the crude product so obtained was dissolved in ethyl acetate and washed with water, brine, dried by sodium sulphate and concentrated to give a solid. The solid was then purified by column chromatography. Yield 81.89%; 1H NMR (DMSO-d6) δ: 0.96 (d, 6H, C(CH3)2), 2.20 (m, 1H, CHMe2), 4.231 (m, 1H, NHCH), 7.07 (m, 1H), 7.35 (m, 1H), 7.67 (d, 2H), 8.011 (d, 2H), 8.10 (m, 1H), 8.61 (s, 1H, NH), 9.372 (s, 1H, NH), 9.39 (s, 1H, NH), 13.025 (s, 1H, COOH); MS (m/z) 458 (M+−1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16](Cl)[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([S:28]([O-:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na+].CN(C)C=O>O>[C:22]1([S:28]([CH:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[C:17]([O:19][CH3:20])=[O:18])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)C(Cl)Cc1ccc(OCc2ccccc2)cc1
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1)S(=O)(=O)c1ccccc1
Temperature: 80 °C

Procedure:
A mixture of methyl 3-(4-benzyloxyphenyl)-2-chloropropanoate (International Patent Appl., Publication No. WO 9101337) (0.50 g), sodium benzenesulphinate (0.29 g) and dry N,N-dimethylformamide (25 mL) was heated at 80° C. for 24 hrs. The mixture was cooled and diluted with water (500 mL), then extracted with dichloromethane (2×250 mL). The combined organic solutions were washed with water (2×250 mL) and brine (250 mL), dried (MgSO4) and evaporated. The residue was chromatographed on silica gel with dichloromethane as eluent to afford the title compound.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[N:10]=[C:9]([S:11][CH3:12])[N:8]=[C:7]2[N:13]([C:18]3[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=3)C=[N:15][C:16](=[O:17])[C:6]=12>C(O)(=O)C>[CH3:12][S:11][C:9]1[N:8]=[C:7]([NH:13][C:18]2[CH:19]=[CH:20][C:21]([S:24][CH3:25])=[CH:22][CH:23]=2)[C:6]2[C:16](=[O:17])[NH:15][CH:3]=[CH:4][C:5]=2[N:10]=1
Reactant: CSc1ccc(-n2cnc(=O)c3c(/C=C/N(C)C)nc(SC)nc32)cc1
Solvent: CC(=O)O
Product: CSc1ccc(Nc2nc(SC)nc3cc[nH]c(=O)c23)cc1
Yield: 75 %

Procedure:
A round bottom flask was charged with 5-[(E)-2-(dimethylamino)ethenyl]-7-(methylthio)-1-[4-(methylthio)phenyl]pyrimido[4,5-d]pyrimidin-4(1H)-one (0.43 g, 1.30 mmol) and acetic acid (50 mL). The reaction was stirred at reflux for 18 h and acetic acid was removed under vacuum. Methylene chloride (20 mL) was added to the residue and the product was collected by filtration (0.27 g, 75% yield).
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>>[CH2:8]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=C1CCC(O)N1
Reactant: CCCCCCO
Product: CCCCCCOC1CCC(=O)N1
Temperature: 60 °C

Procedure:
A mixture of 0.4 g of 5-hydroxy-pyrrolidin-2-one, 10 cm3 of n-hexanol and 0.2 g of Amberlite IR 120H is heated to 60° C. for 3 hours. The solvent is distilled off at 25° C. under 0.3 mbar. The residue is chromatographed on silica (eluent: ethyl acetate); 0.5 g of the residue is crystallized from hexane, and the expected product is obtained, m.p. 35°-37° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[C:32]([C:36]1[CH:60]=[CH:59][C:39]([C:40]([NH:42][C@@H:43]([CH2:48][C:49]2[CH:54]=[CH:53][C:52](/[C:55](=[N:57]/O)/[NH2:56])=[CH:51][CH:50]=2)[C:44]([O:46][CH3:47])=[O:45])=[O:41])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>CN(C=O)C>[C:32]([C:36]1[CH:60]=[CH:59][C:39]([C:40]([NH:42][C@@H:43]([CH2:48][C:49]2[CH:50]=[CH:51][C:52]([C:55](=[NH:56])[NH:57][O:14][C:13](=[O:15])[C:12]3[CH:16]=[CH:17][C:9]([O:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:10][CH:11]=3)=[CH:53][CH:54]=2)[C:44]([O:46][CH3:47])=[O:45])=[O:41])=[CH:38][CH:37]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1
Reactant: COC(=O)[C@H](Cc1ccc(/C(N)=N/O)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCCCCCCOc1ccc(C(=O)ONC(=N)c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC)cc2)cc1
Reaction time: 2 h

Procedure:
Prepared using General Procedure 5: To a solution of 4-(heptyloxy)benzoic acid (400.0 mg, 1.54 mmol) in anhydrous DMF (6 mL) were added HOBt (312.3 mg, 2.31 mmol) and EDC (442.75 mg, 2.31 mmol). After stirring for 2 h, (S,Z)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(N′-hydroxycarbamimidoyl)phenyl)-propanoate, INT-2 (673.3 mg, 1.69 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, partitioned between saturated aqueous NaHCO3 (15 mL) and EA (15 mL), and concentrated under reduced pressure to afford the intermediate (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(N-((4-(heptyloxy)benzoyl)oxy)carbamimidoyl)phenyl)propanoate. The intermediate was dissolved in DMF (10 mL) and heated to 100° C. for 18 h. The reaction mixture was cooled to room temperature and partitioned between EA (10 mL) and saturated aqueous NaHCO3 (50 mL). The organic layer was extracted with water (2×10 mL) and brine (10 mL). The organic layer was dried over MgSO4 and concentrated. The brown oil was purified by chromatography (EA/hexanes) to afford 710 mg (77%) of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)-1,2,4-oxadiazol-3-yl)phenyl)propanoate as a white solid. LCMS-ESI (m/z) calculated for C36H43N3O5: 597.3; no m/z observed, tR=12.80 min (Method 2). 1H NMR (400 MHz, DMSO) δ 8.84 (d, J=8.0 Hz, 1H), 8.08 (t, J=17.2 Hz, 2H), 7.97 (dd, J=18.2, 8.5 Hz, 2H), 7.74 (d, J=8.5 Hz, 2H), 7.50 (dd, J=18.6, 8.3 Hz, 4H), 7.18 (d, J=8.9 Hz, 2H), 4.85-4.63 (m, 1H), 4.09 (dd, J=13.8, 7.3 Hz, 2H), 3.67 (s, 3H), 3.24 (ddd, J=23.8, 15.7, 7.3 Hz, 4H), 2.08 (s, 4H), 1.74 (dd, J=14.1, 6.9 Hz, 2H), 1.42 (dd, J=13.6, 6.3 Hz, 2H), 1.30 (d, J=14.5 Hz, 9H), 0.88 (t, J=6.8 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 174.05, 170.87, 133.81, 165.14, 161.43, 153.21, 140.51, 129.70, 128.85, 128.78, 126.06, 125.84, 123.93, 123.39, 114.36, 114.25, 66.86, 52.66, 50.88, 34.32, 33.47, 30.06, 29.74, 27.33, 27.24, 24.23, 20.89, 12.80.
Reaction SMILES: [Br:1][C:2]1[C:10](N)=[C:9]2[C:5]([C:6]([S:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)(=[O:17])=[O:16])=[C:7]([C:12]([NH2:14])=[O:13])[NH:8]2)=[CH:4][CH:3]=1.[PH2](O)=O.N([O-])=O.[Na+]>O1CCCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:15]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)(=[O:16])=[O:17])=[C:7]([C:12]([NH2:14])=[O:13])[NH:8]2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1[nH]c2c(N)c(Br)ccc2c1S(=O)(=O)N1CCOCC1
Agent: O=N[O-]
Agent: O=[PH2]O
Agent: [Na+]
Solvent: C1CCOC1
Product: NC(=O)c1[nH]c2cc(Br)ccc2c1S(=O)(=O)N1CCOCC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
6-Bromo-7-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide (25 mg, 0.062 mmol, 1.0 equiv) was dissolved in 5 ml of tetrahydrofuran and cooled to 0° C. 1.3 mL of hypophosphorous acid (50% weight in water) was added, immediately followed by Cu2O (0.9 mg, 0.01 mmol, 0.1 equiv) and NaNO2 (21.4 mg, 0.31 mmol), and the reaction was stirred for 90 minutes. The reaction mixture was partitioned between dichloromethane and water and extracted four times with dichloromethane. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by preparative reversed phase HPLC provided the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 388.1 M+H]+.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[CH3:14])[C:2]([CH3:4])=[O:3].[H][H]>[Ni].CN(C)C=O>[NH:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[CH3:14])[C:2]([CH3:4])=[O:3]
Reactant: [H][H]
Reactant: CC(=O)Nc1ccc([N+](=O)[O-])cc1C
Agent: [Ni]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(N)cc1C

Procedure:
19.4g (0.1 mole) of 4-acetamino-3-methyl-nitrobenzene, 30g of dimethylformamide and 1g of fresh-developed Raney nickel were fed in an autoclave, 50kg/cm2 of hydrogen was then fed thereto, and, after the reaction was carried out at 60° to 120° C while stirring, the reaction mixture was removed immediately, the Raney nickel was removed while hot, and thereafter the product was poured into 100ml of methanol to separate the 4-acetamino-3-methylaniline produced.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]([CH3:15])([CH2:13][OH:14])[CH2:11][OH:12].[BH4-].[Na+].[OH-].[Na+]>CO.C(OCC)(=O)C>[CH2:1]([NH:9][C:10]([CH3:15])([CH2:13][OH:14])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(N)(CO)CO
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(CO)(CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzaldehyde (17.4 ml) was added dropwise to a solution of 2-amino-2-methyl-1,3-propanediol (20 g) in methanol (200 ml) at 0° C. and the whole was stirred at room temperature for 2 hours. Sodium borohydride (11.5 g) was added thereto in portions at 0° C. and the mixture was stirred for 10 minutes. 1N Sodium hydroxide solution and ethyl acetate were added and the organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo to give 2-benzylamino-2-methyl-1,3-propanediol (28.54 g).