Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31]>>[OH:32][CH:29]([CH2:30][OH:31])[CH2:28][NH:27][C:21]([C:14]1[C:15](=[O:20])[N:16]([CH3:19])[C:17]2[C:12]([C:13]=1[OH:26])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:18]=2)=[O:22]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Reactant: NCC(O)CO
Product: Cn1c(=O)c(C(=O)NCC(O)CO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 89 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (10 mg, 0.028 mmol) described in example 92 and 3-amino-1,2-propanediol (36 mg, 0.393 mmol), was prepared N-(2,3-dihydroxypropyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (10 mg, 91% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.49 (br s, 1 H), 8.56 (s, 1 H), 7.39 (s, 1 H), 7.17-7.13 (m, 2 H), 7.04-6.99 (m, 2 H), 4.13 (s, 2 H), 3.92 (m, 1 H), 3.67-3.54 (m, 4 H), 3.57 (s, 3 H).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([C:14]1[C:15]([F:35])=[C:16]([N:22](S(CCC)(=O)=O)[S:23]([CH2:26][CH2:27][CH3:28])(=[O:25])=[O:24])[CH:17]=[C:18]([F:21])[C:19]=1[F:20])=[O:13])=[CH:7][CH:6]=2.[C-:36]#[N:37].[Na+]>CN(C=O)C.O>[C:36]([C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([C:14]1[C:15]([F:35])=[C:16]([NH:22][S:23]([CH2:26][CH2:27][CH3:28])(=[O:24])=[O:25])[CH:17]=[C:18]([F:21])[C:19]=1[F:20])=[O:13])=[CH:7][CH:6]=2)#[N:37]
Reactant: [C-]#N
Reactant: CCCS(=O)(=O)N(c1cc(F)c(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F)S(=O)(=O)CCC
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1cc(F)c(F)c(C(=O)c2ccc3ncc(C#N)nc3c2)c1F
Temperature: 100 °C

Procedure:
A mixture of N-(3-(3-chloroquinoxaline-6-carbonyl)-2,4,5-trifluorophenyl)-N-(propylsulfonyl)propane-1-sulfonamide (50 mg, 0.1 mmol, 1.0 eq.) and NaCN (9.8 mg, 0.002 mol, 2.0 eq.) in DMF (10 mL) was heated at 100° C. for 10 h under N2 protection. The mixture was cooled, diluted with water and extracted with EA (20 mL×3). The combined organic layers were washed with water, saline and dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=4/1, v/v) to afford N-(3-(3-cyanoquinoxaline-6-carbonyl)-2,4,5-trifluorophenyl)propane-1-sulfonamide. LRMS (MAT) m/z calculated 435.1, found 435.0. 1H NMR (DMSO-d6, 400 MHz) δ 10.11 (brs, 1 H), 9.52 (s, 1 H), 8.75 (s, 1 H), 8.52 (d, 1 H), 8.41 (d, 1 H), 7.79 (m, 1 H), 3.22 (t, 2 H), 1.72 (m, 2 H), 0.95 (t, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34].Cl.CCOCC>C(Cl)Cl.CCOCC>[ClH:1].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([N:10]1[CH2:11][CH2:12][C:7]2[NH:6][C:5]3[N:13]=[CH:14][C:2]([Cl:1])=[CH:3][C:4]=3[C:8]=2[CH2:9]1)=[O:34]
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: COc1ccccc1N=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1NC(=O)N1CCc2[nH]c3ncc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol), and DIEA (0.04 mL, 0.24 mmol) were dissolved in DCM (2 mL). 2-Methoxyphenyl isocyanate (0.03 mL, 0.24 mmol) was added dropwise, and the reaction solution was stirred overnight at room temperature. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. Additional ether was added to drive precipitate formation. The resulting precipitate was filtered and dried under vacuum to provide 31 (32 mg, 33% yield) as a yellow solid. LC-MS (M+H=357, obsd.=357).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([O:7][CH2:8][C@@H:9]([CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[O:10][C:11]([O:13][CH3:14])=[O:12])=[O:6].[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[Cl-:1].[CH3:14][O:13][C:11]([O:10][C@H:9]([CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:8][O:7][C:5]([NH:4][CH2:3][CH2:2][N+:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:6])=[O:12]
Reactant: c1ccncc1
Reactant: CCCCCCCCCCCCCCCCCCOC[C@H](COC(=O)NCCCl)OC(=O)OC
Product: CCCCCCCCCCCCCCCCCCOC[C@H](COC(=O)NCC[n+]1ccccc1)OC(=O)OC
Product: [Cl-]

Procedure:
A solution of 0.07 g of (R)-1-O-[(2-chloroethyl) carbamoyl]-2-O-(methoxycarbonyl)-3-O-octadecylglycerine in 10 ml of pyridine is heated at 80° C. for 3 days. The solution is evaporated and the residue is recrystallized from acetone-n-hexane. There is obtained 1-[2-[1-[(R)-2-[(methoxycarbonyl)oxy]-3-(octadecyloxy)propoxy]formamido]-ethyl]pyridinium chloride of melting point 83° C. (dec.).
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][C:5]1[C:14]([Cl:15])=[C:13]([Cl:16])[CH:12]=[C:11]2[C:6]=1[N:7]=[C:8](Cl)[C:9](Cl)=[N:10]2.[CH3:19][OH:20]>>[NH2:4][C:5]1[C:14]([Cl:15])=[C:13]([Cl:16])[CH:12]=[C:11]2[C:6]=1[N:7]=[C:8]([O:20][CH3:19])[C:9]([O:2][CH3:1])=[N:10]2
Reactant: CO
Reactant: Nc1c(Cl)c(Cl)cc2nc(Cl)c(Cl)nc12
Reactant: C[O-]
Agent: [Na+]
Product: COc1nc2cc(Cl)c(Cl)c(N)c2nc1OC
Yield: 79 %

Procedure:
A solution of sodium methoxide (25% solution in methanol, 274 ml, 1.28 mol) was added to a suspension of 5-amino-2,3,6,7-tetrachloroquinoxaline (72.4 g, 0.256 mol) in dry methanol (1 l) and the resulting mixture was heated at reflux for 30 minutes. The mixture was cooled, concentrated under reduced pressure, and the residue partitioned between water and ethyl acetate (total of 8 l). The organic solution was dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by trituration with methanol, followed by dissolution in dichloromethane (2 l) and filtration. The filtrate was concentrated under reduced pressure to give 5-amino-6,7-dichloro-2,3-dimethoxy-quinoxaline as a yellow solid (55.0 g, 79%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]2[C:11](=[O:16])[NH:12][NH:13][C:14]=2[CH3:15])[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[C:23](OC(=O)C)(=[O:25])[CH3:24].C(O)(=O)C>CN(C)C=O.O>[C:23]([N:13]1[C:14]([CH3:15])=[C:10]([CH2:9][C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([F:1])[CH:3]=2)[C:11](=[O:16])[NH:12]1)(=[O:25])[CH3:24]
Reactant: Cc1ccc(Cc2c(C)[nH][nH]c2=O)cc1F
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)n1[nH]c(=O)c(Cc2ccc(C)c(F)c2)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
4-[(3-Fluoro-4-methylphenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one (1.00 g) was suspended in N,N-dimethyl-formamide (5 mL) at room temperature. Potassium carbonate (0.376 g) was added to the suspension, and the mixture was stirred for 30 minutes. Acetic anhydride (0.486 g) was added to the reaction mixture in a dropwise manner at room temperature. The mixture was stirred at room temperature overnight and at 50° C. for 2 hours. The mixture was cooled to room temperature under stirring, the mixed solution of glacial acetic acid (0.164 g) and water (5.0 g) was added to the mixture. After confirming the precipitation of the crystals, water (25 g) was added to the mixture. The obtained crystals were collected by filtration and washed with water. The obtained wet crystals were dried under reduced pressure to give a yellowish-white solid of 1-acetyl-4-[(3-fluoro-4-methylphenyl)methyl]-1,2-dihydro-5-methyl-3H-pyrazol-3-one (0.502 g).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]=O)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[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].[CH3:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34]([CH3:47])=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:54]6[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[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: CN1CCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(C=O)c3)c2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCN(C)CC4)c3)c2C)c1

Procedure:
A mixture of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-2-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.000152 mol) in 1,2-dichloroethane (4 mL) with 1-methylpiperazine (26.6 mg., 0.00024 mol) and sodium triacetoxyborohydride (68 mg, 0.00032 mol) and AcOH (12 μL) was placed on an oscillating shaker overnight at room temperature. The reaction was quenched with sat. aq. NaHCO3, then extracted with 1,2-dichloroethane (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. Purification was carried out on Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of 1,2-dichloroethane and transferred to a vial and pumped down to afford the title compound as a pale brown colored solid [55.1 mg (49%). LC-MS m/z 743.9 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([O:22]CC)=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)#[N:2].[OH:25]O.Cl>O1CCCC1.CO.O.[OH-].[Na+]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([OH:22])=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)(=[O:25])[NH2:2]
Reactant: OO
Reactant: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)O
Temperature: 55 °C
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidine-5-carboxylate (C4, 800 mg) in tetrahydrofuran (25 mL) and methanol (25 mL), water (2 mL) and 4.0 mol/L aqueous sodium hydroxide (8 mL) were added at room temperature, and the mixture was stirred at 55° C. for 1 hour and 20 minutes. The reaction mixture was cooled to room temperature, and then 35% aqueous hydrogen peroxide (8 mL) was added to the mixture, and the mixture was stirred at the same temperature for 45 minutes. To the reaction mixture, 3.0 mol/L aqueous hydrochloric acid was added until the reaction mixture was neutralized. The solid matter was taken by filtration, and dried under reduced pressure to obtain 2-((4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxylic acid (C2, 500 mg) as white solid.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([Br:15])[C:9]([Br:14])=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[N:3]=1.[OH-].[Na+].I[CH2:19][CH3:20]>C(#N)C>[Br:1][C:2]1[N:6]([CH2:19][CH3:20])[C:5]2[CH:7]=[C:8]([Br:15])[C:9]([Br:14])=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[N:3]=1
Reactant: CCI
Reactant: O=[N+]([O-])c1c(Br)c(Br)cc2[nH]c(Br)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCn1c(Br)nc2c([N+](=O)[O-])c(Br)c(Br)cc21
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
2,5,6-tribromo-4-nitro-1H-1,3-benzodiazole (Method 2) (28 mmol, 10 g) was dissolved in acetonitrile (200 ml), and then NaOH (33.8 mmol, 1.35 g) was added. The resulting mixture was stirred at temperature for 0.5 h. Next 2-iodoethane (225 mmol, 35.16 g) was added, and the mixture was heated to 85° C. until the reaction was complete (20 h) by LC/MS. The mixture was allowed to cool to RT and concentrated in-vacuo. The product was taken up into ethyl acetate and washed with water. The organic extract was dried over MgSO4, filtered and concentrated. The product was purified on silica gel using EA/hex (1:1) to afford compound 2,5,6-tribromo-1-ethyl-4-nitro-1H-1,3-benzodiazole (mg). 1H NMR (600 MHz, DMSO) δ 8.58 (s, 1H), 4.36 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H); m/z 427.8; rt 3.5 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=1.ClC(N(C)C)=C(C)C.[NH2:25][C:26]1[CH:27]=[N:28][C:29]2[C:34]([C:35]=1[N:36]1[CH2:41][CH2:40][CH2:39][C@H:38]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:37]1)=[CH:33][CH:32]=[CH:31][CH:30]=2.N1C=CC=CC=1>C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([NH:25][C:26]2[CH:27]=[N:28][C:29]3[C:34]([C:35]=2[N:36]2[CH2:41][CH2:40][CH2:39][C@H:38]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:37]2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:16])[N:13]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3ccccc23)C1
Reactant: O=C(O)c1csc(-c2c(F)cccc2F)n1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3ccccc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a suspension of 2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (28.5 mg, 0.118 mmol) in DCM (0.5 mL), a solution of 1-chloro-N,N,2-trimethylpropenylamine (45.0 mg, 0.337 mmol) in DCM (1.0 mL) was added slowly. The mixture was stirred at room temperature for 2 h. A solution of tert-butyl [(3S)-1-(3-aminoquinolin-4-yl)piperidin-3-yl]carbamate (from step 2 in Example 1, 36.9 mg, 0.108 mmol) in DCM (2.0 mL) was added, followed by pyridine (93.2 mg, 1.18 mmol). The mixture was then stirred at room temperature for a further 2 h, and then concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to give the title compound as a pale yellow oil (57.4 mg, 94%). LCMS calc. for C29H30F2N5O3S (M+H)+: m/z=566.2. found 566.2.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:13])[C:4](=[S:12])[S:5][C:6]=1[C:7]([O:9]CC)=O.Cl.[C:15](N)(=[NH:17])[CH3:16].C[O-].[Na+]>C(O)C.CO>[CH3:13][N:3]1[C:2]2[N:1]=[C:15]([CH3:16])[NH:17][C:7](=[O:9])[C:6]=2[S:5][C:4]1=[S:12]
Reactant: CCOC(=O)c1sc(=S)n(C)c1N
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: Cc1nc2c(sc(=S)n2C)c(=O)[nH]1
Yield: 73.3 %

Procedure:
Ethyl 4-amino-3-methylthiazoline-2-thione-5-carboxylate (1.4g, 6.4 mmoles), prepared according to the procedure of Gewald, J. Prakt. Chem., 32, 26-30 (1966), was suspended in approximately 40ml of ethanol. Acetamidine hydrochloride (0.6g, 6.4 mmole) and 2.77g (12.8 mmole) of a 25% solution of sodium methoxide in methanol were added to the suspension and the resultant mixture refluxed for approximately 20 hours. The ethanol was removed in vacuo and the residue was suspended in water and neutralized with concentrated hydrochloric acid. The resultant precipitate was filtered and dried to provide 1 g of 3,5-dimethyl-6H-thiazolo[4,5-d]pyrimidin-7-one-2-thione. The structural assignment was confirmed by nuclear magnetic resonance spectral analysis.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6][C:5]2=[O:18].Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][Cl:26].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[ClH:26].[N:27]1([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:1][C:2]2[CH:11]=[CH:10][C:9]3[O:8][C:7]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:6][C:5](=[O:18])[C:4]=3[CH:3]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: ClCCCCCCBr
Reactant: C1COCCN1
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Product: Cl
Product: O=c1cc(-c2ccccc2)oc2ccc(OCCCCCCN3CCOCC3)cc12

Procedure:
The compound was prepared by a method similar to Example 3 from 6-hydroxyflavone, 1-bromo-6-chlorohexane and morpholine: mp 167°-170° C.
Reaction SMILES: [CH2:1]([Mg]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]1[O:20][C:13]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[O:12][CH2:11]1>C1COCC1>[CH2:1]([C:16]1([OH:19])[CH2:17][CH2:18][C:13]2([O:20][CH2:10][CH2:11][O:12]2)[CH2:14][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: OC1(Cc2ccccc2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
A 0° C. solution of 2M benzylmagnesium chloride in THF (20 mL) was treated with a solution of 1,4-cyclohexanedione mono-ethylene ketal (6.24 g, 40 mmol) in THF (50 mL), warmed to room temperature, stirred overnight, quenched with saturated NH4Cl (100 mL), and extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 6:1 hexanes/ethyl acetate to provide the desired product (8.08 g, 81%). MS (CI) m/e 231(M−18), 249 (M+H), 266.2 (M+18)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:43]=[CH:42][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[C:22]2[CH:41]=[CH:40][C:25]([O:26][C@H:27]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]([O:30]CC)=[O:29])=[CH:24][CH:23]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-].[K+].Cl>C1COCC1.CO>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][N:16]2[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]2[C:22]2[CH:23]=[CH:24][C:25]([O:26][C@H:27]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]([OH:30])=[O:29])=[CH:40][CH:41]=2)=[CH:42][CH:43]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1ccc(OCCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCc1ccc(OCCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a mixed solution of ethyl (2R)-2-(4-{l-[3-(4-heptylphenoxy)propyl]-5-methyl-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoate (480 mg, 0.825 mmol) in THF (15 ml) and methanol (15 ml) was added 1N aqueous potassium hydroxide solution (3 ml, 3 mmol) and the mixture was stirred for 1 hour at room temperature. The reaction solution was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate anhydride and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the object compound as an oily substance. 353 mg (yield: 77.3%)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[N:8]=[C:7]2N.N(OCCC(C)C)=O.CC(=O)OCC.C(Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[N:8]=[CH:7]2
Reactant: Nc1nc(Cl)nc2c(Br)cccc12
Agent: CC(C)CCON=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1ncc2cccc(Br)c2n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.4 %

Procedure:
To a stirred mixture of 8-bromo-2-chloroquinazolin-4-amine (12.93 g, 50 mmol) in THF (500 mL) was added isoamyl nitrite (23.43 g, 200 mmol) over 3 hours and 40 mins at 60° C. The mixture was stirred for another 5 hours. TLC (PE:EA, 1:1) showed reaction complete. After cooling to room temperature, the solvent was stripped and the residue was taken into DCM (300 mL). The organic layer was washed with brine (100 mL), water (100 mL), then dried over anhydrous Na2SO4 and purified by chromatography (DCM:PE, 1:1) to give the title compound as a yellow solid (8.21 g, 67%). 1HNMR (DMSO-d6, 400 MHz): δ 9.66 (s, 1H), 8.45 (dd, J=0.8, 7.6 Hz, 1H), 8.26 (dd, J=0.8, 8.0 Hz, 7.73 (dd, J=7.6, 8.0 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[OH-:11].[Cs+]>C(OCC)(=O)C.CCCCCCC>[OH:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9]
Reactant: [OH-]
Reactant: CC(=O)c1ccccc1Br
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(=O)c1ccccc1O
Yield: 83 %

Procedure:
Following general operating mode A, 2′-bromoacetophenone (199 mg, 1.0 mmol) was reacted with cesium hydroxide to give the expected product in the form of an oil with a yield of 83% (eluent: ethyl acetate/heptane 20:80).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([OH:12])=O)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[CH3:53][C:54]1[CH:59]=[CH:58][C:57]([CH3:60])=[CH:56][C:55]=1[NH:61][CH:62]1[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]1>CN(C=O)C.O>[C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:13])[CH2:9][C:10]([N:65]2[CH2:66][CH2:67][CH:62]([NH:61][C:55]3[CH:56]=[C:57]([CH3:60])[CH:58]=[CH:59][C:54]=3[CH3:53])[CH2:63][CH2:64]2)=[O:12])=[CH:5][CH:6]=1
Reactant: O=C(O)CC(=O)Nc1ccc(-c2ccccc2)cc1
Reactant: Cc1ccc(C)c(NC2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C)c(NC2CCN(C(=O)CC(=O)Nc3ccc(-c4ccccc4)cc3)CC2)c1
Reaction time: 8 h
Yield: 14.5 %

Procedure:
To a stirred solution of N-biphenyl-4-yl-malonamic acid (0.101 g, 0.00039 mole) in DMF (1 mL) was added DIPEA (0.233 g, 0.0018 mole), HOBt (0.053 g, 0.00039 mole) and EDCI.HCl (0.138 g, 0.00072 μmole). After 2 minutes (2,5-dimethyl-phenyl)-piperidin-4-yl-amine dihydrochloride (0.101 g, 0.00039 mole) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using silica gel 60-120 mesh (1% methanol in chloroform) afforded 0.025 g (16%) of N-biphenyl-4-yl-3-[4-(2,5-dimethyl-phenylamino)-piperidin-1-yl]-3-oxo-propionamide. LC-MS purity: 442.24 (M+1)+, 97.08%, 1H NMR (DMSO-d6): δ 10.1 (s, 1H), 7.7-7.5 (m, 6H), 7.4 (t, 2H), 7.35 (d, 1H), 6.9 (d, 1H), 6.5 (t, 2H), 4.5 (d, 1H), 4.0 (d, 1H), 3.7 (s, 1H), 3.5 (s, 2H), 3.4 (t, 2H), 3.1 (t, 1H), 2.3 (s, 3H), 2.2 (d, 2H), 2.1 (s, 3H), 1.5 (t, 2H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[CH:4]=[CH:3][C:2]=1[NH2:11].N1C=CC=CC=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21](Cl)=[O:22]>ClCCl.C(OCC)(=O)C>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([NH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:22]
Reactant: Nc1ccc2cccnc2n1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1ccc2cccnc2n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[1,8]-Naphthyridin-2-ylamine (85 mg, 0.59 mmol) was dissolved in dichloromethane (2 mL) and pyridine (0.10 mL, 1.2 mmol). 2,6-Difluorobenzoyl chloride (0.068 mL, 0.76 mmol) was then added and the reaction mixture was stirred at room temperature for 30 minutes. Next, the reaction mixture was diluted with ethyl acetate and washed with water followed by brine. The resulting organic solution was purified by column chromatography (EtOAc/hexanes) to give 2,6-difluoro-N-[1,8]naphthyridin-2-ylbenzamide. Yield 35 mg (21%). LCMS (ESI): calc. C15H9F2N3O=285; obs. M+H=286.