Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([NH2:7])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:34])[C:15]2[O:21][C:20]3[C:22]([Cl:30])=[CH:23][C:24]([NH:26][CH2:27][CH2:28]Cl)=[CH:25][C:19]=3[CH2:18][S:17](=[O:32])(=[O:31])[C:16]=2[CH:33]=1)=[O:11].O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:34])[C:15]2[O:21][C:20]3[C:22]([Cl:30])=[CH:23][C:24]([NH:26][CH2:27][CH2:28][NH:7][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:25][C:19]=3[CH2:18][S:17](=[O:31])(=[O:32])[C:16]=2[CH:33]=1)=[O:11]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Reactant: NN1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCNN3CCOCC3)cc(Cl)c1O2
Temperature: 120 °C
Reaction time: 5.5 h

Procedure:
Morpholin-4-ylamine (0.1 mL, 1.16 mmol) and tetrabutylammonium iodide (0.075 g, 0.2 mmol) were sequentially added with stirring to a solution of the carboxylic acid of Example 56k (0.250 g, 0.59 mmol) in dry DMF (4 mL). The reaction mixture was then stirred at 120° C. for 5.5 h in an atmosphere of nitrogen. It was treated with cold water and the solid that precipitated was filtered, washed with water, and dried. The solid was treated with a methanolic HCl solution and refluxed at 70° C. for 3 h. The solution was concentrated and treated with an aqueous sodium bicarbonate solution. The solid that precipitated was filtered, washed with water, dried and purified using flash chromatography (silica gel, 2% methanol/chloroform) to obtain the title compound. Yield: 0.105 g, (36.45%). 1H NMR (DMSO-d6): δ 2.50-2.60 (m, 4H, 2CH2), 2.70 (s, 3H, CH3), 2.80 (t, 2H, CH2), 2.80 (t, 2H, CH2), 3.62-3.70 (m, 4H, 2CH2), 3.90 (s, 3H, OCH3), 5.20 (s, 2H, CH2), 6.20 (t, 1H, NH), 6.85 (s, 2H, 2Ar), 8.15 (s, 1H, Ar), 8.25 (s, 1H, Ar); MS: m/e (CI+) 496 (M+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:13]([O:15]C(OCC)=O)=O)[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8].[NH3:21]>C(#N)C>[S:1]1[CH:5]=[CH:4][S:3][C:2]1=[C:6]([C:13](=[O:15])[NH2:21])[C:7]([O:9][CH:10]([CH3:12])[CH3:11])=[O:8]
Reactant: CCOC(=O)OC(=O)C(C(=O)OC(C)C)=C1SC=CS1
Reactant: N
Solvent: CC#N
Product: CC(C)OC(=O)C(C(N)=O)=C1SC=CS1
Temperature: 25 °C

Procedure:
Isopropyl 2-(1,3-dithiol-2-ylidene)-2-(ethoxycarbonyloxy-carbonyl)acetate (20.65 g) was added to a solution of ammonia in acetonitrile (150 ml) and the mixture was stirred at room temperature for an hour. The reaction mixture was evaporated to dryness and the residue was recrystallized from methylene chloride to obtain the pure product. (12.0 g, 77%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[C:11]([NH:20][CH2:21][CH2:22][OH:23])=[N:10][C:9]=2[C:24]#[N:25])[CH:5]=[CH:6][CH:7]=1.[O:26]1[CH2:31]CO[CH2:28][CH:27]1CN>>[O:23]1[CH2:28][CH2:27][O:26][CH2:31][CH:22]1[CH2:21][NH:20][C:11]1[C:12]2[C:17](=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[C:9]([C:24]#[N:25])[N:10]=1
Reactant: NCC1COCCO1
Reactant: COc1ccc2c(NCCO)nc(C#N)c(-c3cccc(F)c3)c2c1
Product: COc1ccc2c(NCC3COCCO3)nc(C#N)c(-c3cccc(F)c3)c2c1

Procedure:
Following the procedure for 4-(3-fluorophenyl)-1-[(2-hydroxyethyl)amino]-6-methoxyisoquinoline-3-carbonitrile, using 1,4-dioxan-2-ylmethylamine in place of 2-aminoethanol, the title compound was synthesized.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)[CH:11]=[CH:10][C:5]=2[C:6]=1[C:7](Cl)=[O:8].[CH3:24][C:25]1[NH:29][N:28]=[C:27]([NH2:30])[CH:26]=1>>[CH3:24][C:25]1[NH:29][N:28]=[C:27]([NH:30][C:7]([C:6]2[C:5]3[CH:10]=[CH:11][C:12]([O:14][C:15]4[CH:20]=[CH:19][N:18]=[C:17]5[CH:21]=[CH:22][S:23][C:16]=45)=[CH:13][C:4]=3[O:3][C:2]=2[CH3:1])=[O:8])[CH:26]=1
Reactant: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)Cl
Reactant: Cc1cc(N)n[nH]1
Product: Cc1cc(NC(=O)c2c(C)oc3cc(Oc4ccnc5ccsc45)ccc23)n[nH]1

Procedure:
This material was prepared from 2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carbonyl chloride 101 and (5-methyl-1H-pyrazol-3-yl)amine in a similar manner as that described for example 108. 1H NMR (DMSO-d6) δ 12.09 (1H, bs), 10.45 (1H, s), 8.50 (1H, d, J=5.6 Hz), 8.14 (1H, d, J=5.6 Hz), 7.77 (1H, d, J=8.6 Hz), 7.65 (1H, d, J=2.3 Hz), 7.59 (1H, d, J=5.3 Hz), 7.24 (1H, dd, J=8.3, 2.0 Hz), 6.64 (1H, d, J=5.6 Hz), 6.39 (1H, bs), 2.64 (3H, s), 2.23 (3H, s).
Reaction SMILES: [C:1]1([NH:7]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>>[CH:4]1[CH:5]=[CH:6][C:1]([NH:7][C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][CH:12]=2)=[CH:2][CH:3]=1
Reactant: ONc1ccccc1
Reactant: Nc1ccccc1
Agent: Cl
Product: Nc1ccc(Nc2ccccc2)cc1

Procedure:
It is disclosed that phenylhydroxylamine and aniline in the presence of concentrated HCl, HZSM-5, HY zeolites, Nafion, filtrol (acid clay), NaHSO4/SiO4, or montmorillonite yield p-aminodiphenylamine. In each case, the predominant isomer of aminodiphenylamine was the para isomer.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:13]=[C:12]([C:14]#[N:15])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1N.N([O-])=O.[Na+].[BrH:22]>O.[Cu]Br>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:13]=[C:12]([C:14]#[N:15])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[Br:22]
Reactant: COC(=O)c1cc(C#N)c(C(=O)OC)cc1N
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(C#N)c(C(=O)OC)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 7 %

Procedure:
To a suspension of 2-amino-5-cyano-terephthalic acid dimethyl ester (11.6 g, 49.5 mmol) in hydrobromic acid (20 ml, 48%) at 0° C. was added an aqueous solution of sodium nitrite (55 mmol, 11 ml, 5M). The reaction mixture was stirred at 0° C. for 30 minutes. Copper (I) bromide (7.1 g, 49.5 mmol) was added as a solution in hydrobromic acid (10 ml, 48%) and the reaction mixture stirred at 0° C. for 10 min before heating at 65° C. for 1 hour. The reaction mixture was cooled to room temperature, diluted with water (50 ml) and the resultant mixture extracted with ethyl acetate (3×20 mL). The aqueous fraction was filtered to recover un-reacted 2-amino-5-cyano-terephthalic acid dimethyl ester (7.1 g). The combined organic fractions were washed with brine (20 ml), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0-50% ethyl acetate in cyclohexane) to yield the title compound as a brown solid (1.0 g, 7%). 1H NMR (CDCl3, 400 MHz) 8.43 (1H, s), 8.19 (1H, s), 4.04 (3H, s), 4.00 (3H, s).
Reaction SMILES: [CH3:1][C@H:2]([O:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([O:27]C)[N:13]2[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[C:9]([NH2:29])[N:8]=1)[CH2:3][CH2:4][CH3:5].Cl.O1CCOCC1>CO>[NH2:29][C:9]1[N:8]=[C:7]([O:6][C@@H:2]([CH3:1])[CH2:3][CH2:4][CH3:5])[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:27])[N:13]2[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCNC3CCOCC3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCC[C@H](C)Oc1nc(N)c2[nH]c(=O)n(CCCCNC3CCOCC3)c2n1
Yield: 96.3 %

Procedure:
2-{[(1S)-1-Methylbutyl]oxy}-8-(methyloxy)-9-[4-(tetrahydro-2H-pyran-4-ylamino)butyl]-9H-purin-6-amine (30.35 mg, 0.075 mmol) was dissolved in methanol (2.0 ml) and treated with 4M HCl in 1,4 dioxane (0.467 ml, 1.866 mmol) and stirred in a capped vial over the weekend. The solvent was evaporated under nitrogen and the residue was dissolved in methanol and passed down an aminopropyl SPE cartridge (2 g, pre-conditioned with 2 column volumes of methanol) and washed through with 1 column volume of methanol. The eluant was evaporated under nitrogen in a blowdown unit to give the title compound as an off-white solid (28.34 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:42][CH3:43])=[C:10]([CH2:19][NH:20][C:21](=[O:41])[CH2:22][C:23]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]=O)[CH:34]=4)[CH:30]=[CH:31][CH:32]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:42][CH3:43])=[C:10]([CH2:19][NH:20][C:21](=[O:41])[CH2:22][C:23]([NH:25][CH2:26][C:27]3[CH:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][N:44]5[CH2:49][CH2:48][O:47][CH2:46][CH2:45]5)[CH:34]=4)[CH:30]=[CH:31][CH:32]=3)=[O:24])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C1COCCN1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1cccc(-c2cccc(C=O)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)CC(=O)NCc1cccc(-c2cccc(CN3CCOCC3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
To N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-3-biphenylyl)methyl]propanediamide (30 mg, 0.051 mmol) was added morpholine (4.49 mg, 0.051 mmol) followed by NaB(OAc)3H (36.4 mg, 0.172 mmol) and AcOH (4.91 μL, 0.086 mmol) in dimethyl sulfoxide (DMSO) (0.5 mL). The mixture was stirred overnight at room temperature. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc (3×1 mL). Combined organic layers were washed with saturated NaCl, dried (Na2SO4) and concentrated. The crude products were redissolved in MeOH/DMSO (1/1) and purified using a Gilson HPLC (acidic conditions) and basified with an amine cartridge to afford 11.9 mg (34%) of the title compound. LC-MS m/z 654 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11]([S:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])[CH:15]=1)=[O:12])=[O:5])C.[OH-].[Na+]>CO.O>[CH3:27][C:26]1[O:25][C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:23][C:22]=1[CH2:21][O:20][C:16]1[CH:15]=[C:14]([S:13][C:11]([N:7]2[CH2:8][CH2:9][CH2:10][C@@H:6]2[C:4]([OH:5])=[O:3])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)[C@H]1CCCN1C(=O)Sc1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(SC(=O)N2CCC[C@@H]2C(=O)O)c1
Reaction time: 4 h

Procedure:
To a stirred solution of the title D compound, (R)-1-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenylsulfanylcarbonyl]-pyrrolidine-2-carboxylic acid ethyl ester (1.5 g, 3.22 mmol) in methanol (15 mL) is added sodium hydroxide (0.26 g, 6.44 mmol) in water (10 mL) at RT. The reaction mixture is stirred for 4 h. The reaction mixture is concentrated at reduced pressure, poured into water, the aqueous layer is separated, washed with ethyl acetate twice, acidified with concentrated HCl and extracted three times with ethyl acetate. The combined ethyl acetate extract is concentrated and triturated with 1:1 methyl-t-butyl ether and hexane to give (R)-1-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenylsulfanylcarbonyl]-pyrrolidine-2-carboxylic acid as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[C@H:18]2[N:13]([C:14]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][C:15]=3[O:16][CH2:17]2)[C:12](=[O:27])[O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].IC.[CH3:32]C(=O)OCC>C1COCC1>[Si:1]([O:8][CH2:9][C@H:10]1[C@H:18]2[N:13]([C:14]3[CH:22]=[CH:21][C:20]([N:23]([CH3:32])[C:24](=[O:26])[CH3:25])=[CH:19][C:15]=3[O:16][CH2:17]2)[C:12](=[O:27])[O:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CC(=O)Nc1ccc2c(c1)OC[C@H]1[C@H](CO[Si](C)(C)C(C)(C)C)OC(=O)N21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(=O)N(C)c1ccc2c(c1)OC[C@H]1[C@H](CO[Si](C)(C)C(C)(C)C)OC(=O)N21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.11 %

Procedure:
Compound N-((3R,3aS)-3-(((t-butyldimethylsilyl)oxy)methyl)-1-oxo-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-7-yl)-acetamide (0.685 g, 1.747 mmol) was dissolved in 20 ml of THF and cooled on ice-salt bath. 60% NaH (0.14 g, 3.495 mmol) was added. The ice bath was removed, and the reaction mixture was stirred at room temperature for 30 min, and then cooled on ice-salt bath. Iodomethane (0.496 g, 3.495 mmol) was added slowly in dropwise. The ice bath was removed, and the reaction mixture was stirred at room temperature for 3 h. TLC (PE/EA=1/1) was employed to monitor the reaction. After the reaction completed, the reaction was quenched by adding 10 ml of water and then extracted with EA (10 ml×3). The organic phase was combined, dried over anhydrous sodium sulfate, and the solvent was evaporated. Column chromatography (PE/EA=3/1) afforded white solid 0.618 g, yield: 87.11%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][C@@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:14][S:13]1.[CH:21]1([CH2:24]Br)[CH2:23][CH2:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([CH2:24][CH:21]2[CH2:23][CH2:22]2)[C@@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:14][S:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](CC(C)C)CS1
Reactant: BrCC1CC1
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC[C@H](CC(C)C)N1CC1CC1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with cyclopropylmethyl bromide according to Method D2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-4-isobutyl-3-(cyclopropylmethyl)-1,3-thiazolidine.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1.[CH2:29]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH3:30]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([N:34]4[CH2:35][CH2:36][N:31]([CH2:29][CH3:30])[CH2:32][CH2:33]4)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:4]=2[N:3]=1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(=O)Cl)cc3C)cc12
Reactant: CCN1CCNCC1
Product: CCN1CCN(C(=O)c2ccc(CCc3cnc4c(N)nc5cc(C)ccc5c4c3)c(C)c2)CC1

Procedure:
(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenyl)(4-ethylpiperazin-1-yl)methanone was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116/Step 2) and 1-ethylpiperazine following the procedures described for Example 117. 1H NMR (Methanol-d4): δ 8.59 (s, 1H), 8.37 (s, 1H), 8.06 (d, 1H), 7.32 (s, 1H), 7.00-7.12 (m, 4H), 3.67 (br, 2H), 3.06-3.13 (m, 4H), 2.45 (br, 4H), 2.37 (q, 2H), 2.41 (s, 3H), 2.26 (s, 3H), 2.19 (br, 2H), 1.04 (t, 3H), LRMS [M+H]=468.3
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:17][CH2:18][CH3:19])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([CH2:20][CH2:21][C:22]([OH:24])=O)[C:7]2=[O:25])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][NH:27][CH3:28].C(N(CC)CC)C>CN(C=O)C>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:17][CH2:18][CH3:19])[N:14]=[C:15]([CH3:16])[C:10]=3[CH:9]=[C:8]([CH2:20][CH2:21][C:22]([N:27]([CH3:28])[CH3:26])=[O:24])[C:7]2=[O:25])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCNc1nc(C)c2cc(CCC(=O)O)c(=O)n(C3CCCC3)c2n1
Reactant: CNC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNc1nc(C)c2cc(CCC(=O)N(C)C)c(=O)n(C3CCCC3)c2n1
Temperature: 50 °C
Yield: 54.8 %

Procedure:
3-(8-cyclopentyl-2-(ethylamino)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)propanoic acid (94 mg, 0.27 mmole), dimethylamine (1.09 mmole, 0.55 ml of 2.0 M solution in THF), triethylamine (27.6 mg, 0.27 mmole), O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (HATU, 104 mg, 0.27 mmole) and DMF (3.0 ml) were added to a reaction vial equipped with a stir bar. The reaction mixture was heated at 50° C. for 26 h. The reaction was quenched with water (2 ml), and the volatiles were removed under reduced pressure to a residue. Ethyl acetate (70 ml) and water (30 ml) were added and shaken well. The organic layer was separated, washed with water (2×30 ml), brine (30 ml), and dried over sodium sulfate. The solvent was removed under reduced pressure to a residue, which was purified using silica (100% petroleum ether to 100% ethyl acetate). The fractions were combined, and the volatiles were removed to a colorless oil as the title compound (55 mg, 54% yield).
Reaction SMILES: [C:1]([O:4][CH:5]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[C:17]([F:25])[CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)=O)(=O)[CH3:2].C([O-])(=O)C.[NH4+:30]>C(O)(=O)C>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:30]=[C:1]([CH3:2])[O:4][C:5]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[C:17]([F:25])[CH:16]=2)=[CH:9][CH:10]=1
Reactant: CC(=O)OC(C(=O)c1ccc(Br)cc1)c1ccc(S(C)(=O)=O)c(F)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1nc(-c2ccc(Br)cc2)c(-c2ccc(S(C)(=O)=O)c(F)c2)o1
Temperature: 25 °C
Yield: 62.9 %

Procedure:
The mixture of 2-acetoxy-1-(4-bromophenyl)-2-[3-fluoro-4-(methylsulfonyl)phenyl]-1-ethanone (743.7 mg, 1.733 mmol) and ammonium acetate (333.9 mg, 4.333 mmol) in acetic acid (15 mL) was heated at reflux temperature for 2.5 hours, and cooled down to room temperature. The mixture was evaporated, diluted with ethyl acetate (100 mL), washed with saturated NaHCO3 solution (100 mL×2), water (50 mL), brine (50 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (1/2) to provide the subtitle compound (447.1 mg, 63% yield) as a solid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:16]=[N:17][NH:18][CH:19]=4)[C:11]=3[CH:20]=2)=[N:5][N:6]=1.I[CH2:22][CH3:23]>>[CH2:22]([N:18]1[CH:19]=[C:15]([C:12]2[C:11]3[CH:20]=[C:7]([C:4]4[O:3][C:2]([CH3:1])=[N:6][N:5]=4)[CH:8]=[CH:9][C:10]=3[O:14][CH:13]=2)[CH:16]=[N:17]1)[CH3:23]
Reactant: CCI
Reactant: Cc1nnc(-c2ccc3occ(-c4cn[nH]c4)c3c2)o1
Product: CCn1cc(-c2coc3ccc(-c4nnc(C)o4)cc23)cn1
Yield: 80 %

Procedure:
In the same manner as in Example 1 and using 2-methyl-5-[3-(1H-pyrazol-4-yl)-1-benzofuran-5-yl]-1,3,4-oxadiazole instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and using iodoethane instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 80%) was obtained as colorless crystals.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:21]=[CH:20][C:7]([N:8]([CH3:19])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[C:6]([N+:22]([O-:24])=[O:23])[CH:5]=1.[CH3:25][CH2:26][CH2:27]Br.O>CN(C=O)C>[CH3:19][N:8]([S:9]([C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:10])=[O:11])[C:7]1[CH:20]=[CH:21][C:4]([O:3][CH2:25][CH2:26][CH3:27])=[CH:5][C:6]=1[N+:22]([O-:24])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)N(C)c2ccc(O)cc2[N+](=O)[O-])cc1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1ccc(N(C)S(=O)(=O)c2ccc(C)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 41.6 %

Procedure:
To a suspension of sodium hydride (60%, 0.05 g (1.25 mmol)) in 1.0 ml of DMF, 4′-hydroxy-N-methyl-2′-nitro-p-toluenesulfonanilide (0.32 g (0.99 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, n-propyl bromide (0.20 g (2.20 mmol)) was added dropwise and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. Diisopropyl ether was added to the residue and crystals separated were filtered and washed to give 0.15 g (42%) of the title compound as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH:15]=[CH:16][CH2:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:31]O>>[CH2:1]([O:8][C:9]1[C:10]([CH:15]=[CH:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:31])=[O:23])=[CH:25][CH:26]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(CC=Cc2ncccc2OCc2ccccc2)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(CC=Cc2ncccc2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 49 %

Procedure:
4-[3-(3-Benzyloxy-2-pyridyl)prop-2-enyl)benzoic acid (0.1 g, 0.29 mmol) was dissolved in methanol (5 ml) and cooled to 0° C. To the solution was added thionyl chloride (0.086 g, 0.73 mmol). The reaction was allowed to warm to ambient temperature and stirred at ambient temperature for 18 hours. The reaction mixture was then evaporated, the residue partitioned between ethyl acetate and water and the organic phase dried (MgSO4) and evaporated. The residue was purified by chromatography (SiO2 EtOAc/CH2Cl2) to give methyl 4-[3-(3-benzyloxy-2-pyridyl)prop-2-enyl]benzoate as an oil (0.05 g, 49%).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[C:10]([C:17]([OH:19])=O)[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][CH2:21][C:22]([OH:24])=[O:23]>>[O:14]=[C:12]1[C:11]2[C:10](=[CH:9][C:8]([S:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:16][CH:15]=2)[C:17](=[O:19])[N:20]1[CH2:21][C:22]([OH:24])=[O:23]
Reactant: O=C(O)c1ccc(Sc2ccccc2)cc1C(=O)O
Reactant: NCC(=O)O
Product: O=C(O)CN1C(=O)c2ccc(Sc3ccccc3)cc2C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.1 %

Procedure:
5.62 g of 4-phenylsulfanyl-phthalic acid (20.5 mmol) and 1.55 g of glycine (20.5 mmol) were ground thoroughly together in a mortar. Then the mixture was heated to 210° C. to 220° C. in an oil bath. The molten mass was stirred with a spatula at this temperature for 15 min before it was allowed to cool to ambient temperature in vacuo. 6.30 g of the title compound were obtained; MS-(−)-ion: M−1=311.8; 1H NMR (DMSO-d6): δ=7.82 (d, 1H), 7.46 to 7.62 (m, 7 H), 4.26 (s, 2H).