Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([OH:12])=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:25]1([C@@H:31]([NH:33][CH2:34][C:35]([C:37]2([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:39][CH2:38]2)=[O:36])[CH3:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>O1CCCC1.C(OCC)(=O)C>[CH2:7]([O:6][P:4]([CH2:9][C:10]([N:33]([CH2:34][C:35]([C:37]1([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:38][CH2:39]1)=[O:36])[C@H:31]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:32])=[O:12])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(CC(=O)O)OCC
Reactant: CCOC(=O)C1(C(=O)CN[C@@H](C)c2ccccc2)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)CN(C(=O)CP(=O)(OCC)OCC)[C@@H](C)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
Diethylphosphonoacetic acid (15.1 g, 76.8 mmol) was dissolved in anhydrous tetrahydrofuran (120 ml), and after adding 1,1′-carbonyldiimidazole (13.7 g, 84.5 mmol) while cooling with ice, it was stirred at room temperature for 1 hour. After adding an anhydrous tetrahydrofuran (30 ml) solution of ethyl 1-[2-[N-[1-(S)-phenylethyl]amino]acetyl]cyclopropanecarboxylate (17.6 g, 64.0 mmol) to the reaction solution while cooling with ice, it was stirred at room temperature for 1 hour. After adding 1 mol/l hydrochloric acid (100 ml) and ethyl acetate (100 ml) to the reaction solution and performing an extraction operation, the organic layer was separated. The aqueous layer was then subjected to extraction with ethyl acetate (100 ml) and the combined organic layer was washed with saturated sodium bicarbonate water (100 ml) and saturated saline solution (100 ml) in that order, and then dried over anhydrous sodium sulfate. After filtering and then concentrating the filtrate under a reduced pressure, 28.7 g (99%) of the title compound was obtained as a yellow syrup.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:4].O[Li].O.O>CO>[C:17]([O:16][C:14]([NH:13][CH2:12][C:5]1([C:3]([OH:4])=[O:2])[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)C1(CNC(=O)OC(C)(C)C)CC12CCCC2
Agent: [Li]O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCC1(C(=O)O)CC12CCCC2
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To a solution of 1-(tert-butoxycarbonylaminomethyl)-spiro[2.4]heptane-1-carboxylic acid methyl ester (16.5 g, 58.2 mmol) in methanol (100 mL) was added LiOH—H2O (4.9 g, 116 mmol) and water (15 mL). After 3 hours, additional methanol (50 mL) and water (15 mL) was added and reflux was continued for 6 hours total. The solvent was removed under reduced pressure. The residue was dissolved in water (200 mL) and washed with ether (200 mL). The aqueous solution was cooled in an ice bath and methylene chloride (200 mL) was added. With stirring, 4N HCl was added dropwise until pH=2-3. The layers were separated and the aqueous layer was extracted with methylene chloride (2×300 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. The residue was dissolved in hexane and evaporated to give 12.6 g (80%) of 1-(tert-butoxycarbonylaminomethyl)-spiro[2.4]heptane-1-carboxylic acid as a white foamy solid: 1H NMR (300 MHz, CDCl3) δ 1.08 (d, J=5.0 Hz, 1H), 1.44 (s, 9H), 1.45 (m, 2H), 1.55-1.8 (m, 6H), 1.92 (m, 1H), 3.35 (dd, J=6.0, 14.0 Hz, 1H), 3.44 (dd, J=6.0, 14.0 Hz, 1H), 5.28 (br t, 1H); MS (APCI) m/z=170 [M+H-100(Boc)]+.
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:9][C:7]=1[NH2:8].O.O.[Sn](Cl)Cl>O.Cl>[Cl:5][C:6]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:9][C:7]=1[NH:8][NH2:1]
Reactant: CC(C)Oc1cc(N)c(Cl)cc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1cc(NN)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
A solution of 15.8 g (0.23 mole) of sodium nitrite in 100 mL of water was added to a stirred solution of 50.0 g (0.23 mole) of 2,4-dichloro-5-(1-methylethoxy)aniline in 250 mL of concentrated hydrochloric acid at 0° C. over 30 minutes. After complete addition, the mixture was stirred at 0° C. for 30 minutes. A solution of 114.0 g (0.506 mole) of tin (II) chloride dihydrate in 125 mL of concentrated hydrochloric acid was added dropwise to the reaction mixture. After complete addition, the mixture was stirred for one hour. The resultant white slurry was filtered. The filter cake was added to a 20% aqueous sodium hydroxide solution and stirred for 30 minutes. The basic mixture was filtered, and the filter cake recrystallized from methanol and water to yield 37.0 g of 2,4-dichloro-5-(1-methylethoxy)phenylhydrazine.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([CH2:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10](=[O:18])[CH:9]=1)[C:4]([OH:6])=[O:5].[H][H]>O.[C].[Pd]>[ClH:1].[NH2:2][CH:3]([CH2:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10](=[O:18])[CH2:9]1)[C:4]([OH:6])=[O:5]
Reactant: NC(Cc1cc(=O)[nH]c2ccccc12)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Product: NC(CC1CC(=O)Nc2ccccc21)C(=O)O

Procedure:
5 Grams of 2-amino-3-(2-quinolon-4-yl)propionic acid hydrochloride was dissolved in 150 ml of water. To this solution was added 1 g of 10%-palladium carbon, then hydrogen gas was adsorbed thereto at 70° C. under a normal pressure. The catalyst was removed from the reaction mixture by filtration, then the filtrate was concentrated under a reduced pressure. The residue thus obtained was crystallized by adding acetone, then recrystallized from ethanol-ether to obtain 3.6 g of 2-amino-3-(3,4-dihydroquinolin-2-on-4-yl)propionic acid hydrochloride in the form of white powdery product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:8][C:6]1[N:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH:17][CH2:16][C:15]2[CH:18]=[CH:19][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: COc1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CNc2cc(Cl)nc(C)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A mixture of 4,6-dichloro-2-methylpyrimidine (Aldrich) (1.45 g, 8.90 mmol), 4-methoxybenzylamine (Alfa Aesar) (1.278 mL, 9.78 mmol), and triethylamine (1.488 mL, 10.67 mmol) in DMF (10.0 mL) was stirred at 25° C. for 18 h. The resulting mixture was partitioned between EtOAc (300 mL) and half-saturated aqueous NaHCO3 (80 mL). The organic layer was separated, sequentially washed with water (2×80 mL) and brine (80 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (ISCO, 120 g, 0 to 100% EtOAc/Hexanes) furnished 6-chloro-N-(4-methoxybenzyl)-2-methylpyrimidin-4-amine (2.30 g, 8.72 mmol, 98% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.23 (d, J=8.41 Hz, 2H); 6.89 (d, J=8.61 Hz, 2H); 6.18 (s, 1H); 4.42 (br. s., 2H); 3.81 (s, 3H); 2.50 (s, 3H). m/z (ESI, +ve ion) 264.1 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([N+:19]([O-])=O)=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]2)[CH:8]=1)=[O:2].[H][H]>[Pd].CCOC(C)=O>[NH2:19][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:8][C:7]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]1
Reactant: COC(=O)C1CCN(c2cc(C=O)ccc2[N+](=O)[O-])CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(c2cc(C=O)ccc2N)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 5.5 %

Procedure:
To methyl 1-(5-formyl-2-nitrophenyl)piperidine-4-carboxylate 64 (0.881 g, 3.0 mmol) was added EtOAc (20 mL) and palladium (0.482 mg, 0.45 mmol). The nitrogen atmosphere was replaced by hydrogen from a double balloon and the reaction mixture was stirred at room temperature for 3 h, filtered, and concentrated in vacuo. Purification by flash column chromatography on silica gel (eluted with 50% to 100% EtOAc in hexanes) gave methyl 1-(2-amino-5-formylphenyl)piperidine-4-carboxylate 65 (0.043 g, 5.4% yield) as a yellow oil. Mass spectrum: calculated for C14H18N2O3 262.1. found 263.2 (M++1). In addition, methyl 1-(2-amino-5-(hydroxymethyl)phenyl)piperidine-4-carboxylate 66 (0.534 g, 67% yield) was isolated as a yellow solid. Mass spectrum: calculated for C14H20N2O3 264.2. found 265.2 (M++1).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.C(O)(C(F)(F)F)=O.[N+:22]([O-])([OH:24])=[O:23]>>[N+:22]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[CH2:1][CH:2]([N:10]1[CH2:11][CH2:12][CH2:13][CH2:14]1)[CH2:3]2)([O-:24])=[O:23]
Reactant: c1ccc2c(c1)CC(N1CCCC1)C2
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc2c(c1)CC(N1CCCC1)C2
Temperature: 7.5 °C
Reaction time: 5 h

Procedure:
To a solution of Example 55A (8.38 g, 44.7 mmol) in TFA (320 ml, 4154 mmol) was added concentrated nitric acid (2.86 ml, 44.7 mmol) dropwise at 0° C. The mixture was stirred at 0-15° C. for 5 hours. The mixture was next concentrated then dissolved in 200 mL of ethyl acetate and the organic solution was poured into a separatory funnel and washed with saturated aqueous sodium bicarbonate (2×150 mL) and saturated aqueous brine (1×100 mL), dried over magnesium sulfate, filtered and concentrated. The crude was recrystallized in ethyl acetate/hexane mixture to give the title compound. MS (ESI) m/z 233.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[N:9]([NH2:17])[CH:8]=1)([CH3:6])[CH3:5].[CH3:19][C:20]1[C:25]([C:26](O)=[O:27])=[CH:24][N:23]=[C:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[N:21]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:18])[C:4]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[N:9]([NH:17][C:26]([C:25]2[C:20]([CH3:19])=[N:21][C:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[N:23][CH:24]=2)=[O:27])[CH:8]=1)([CH3:6])[CH3:5]
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Reactant: COC(=O)C(C)(C)c1cn(N)c2ccc(F)cc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)c1cn(NC(=O)c2cnc(-c3ccccn3)nc2C)c2ccc(F)cc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 2-(1-amino-5-fluoro-1H-indol-3-yl)-2-methyl-propionic acid methyl ester (0.85 mmol) and 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (201 mg, 0.935 mmol) in DMF (8.5 mL) is stirred at 40° C. for 0.5 h. The mixture is treated with DMTMM (246 mg, 0.89 mmol) and stirred at 60° C. for 1 h. The mixture is concentrated in vacuo, diluted with saturated aqueous Na2CO3 (20 mL), and extracted with EtOAc (3×20 mL). The combined organic layer is dried (Na2SO4), filtered and concentrated in vacuo to afford 2-{5-fluoro-1-[(4-methyl-2-pyridin-2-yl-pyrimidine-5-carbonyl)-amino]-1H-indol-3-yl}-2-methyl-propionic acid methyl ester, which is used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1)#[N:2].[NH2:13][CH2:14][CH2:15][C:16]([NH:18][C@H:19]([C:28]([NH:30][C@H:31]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:29])[CH2:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:17]>>[C:42]([O:41][C:39](=[O:40])[C@H:31]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[NH:30][C:28](=[O:29])[C@H:19]([CH2:20][C:21]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:27])[NH:18][C:16](=[O:17])[CH2:15][CH2:14][NH:13][C:10](=[O:12])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)([CH3:43])([CH3:44])[CH3:45]
Reactant: N#Cc1ccc(CC(=O)O)cc1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)CCN)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)CCNC(=O)Cc1ccc(C#N)cc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Yield: 51.5 %

Procedure:
142 mg of 4-cyanophenylacetic acid were coupled with 371 mg of H-β-Ala-Asp(O-tBu)-Phe-O-tBu (Example 1b) in the manner described in Example 1a), yielding 250 mg of N-[N-[N-(p-cyanophenylacetyl)-β-alanyl]-3-t-butoxycarbonyl-L-alanyl]-3-phenyl-L-alanine t-butyl ester, m.p. 93°-94° C., after chromatography on silica gel using ethyl acetate/methanol.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Li+:13].[Cl-:14].[CH3:15][C:16]1([CH3:24])[O:23][CH2:22][CH:21]2[CH:19]([O:20]2)[CH2:18][O:17]1>C(O)(C)C>[OH:20][CH:21]1[CH2:22][O:23][C:16]([CH3:24])([CH3:15])[O:17][CH2:18][CH:19]1[N:1]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Li+:13].[Cl-:14]
Reactant: C1CNCCNCCNCCN1
Reactant: CC1(C)OCC2OC2CO1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(C)O
Product: CC1(C)OCC(O)C(N2CCNCCNCCNCC2)CO1
Temperature: 0 °C

Procedure:
10 g (58.08 mmol) of 1,4,7,10-tetraazacyclododecane, 4.85 g (116.16 mmol) of LiCl and 40.0 g (278.4 mmol) of 4,4-dimethyl-3,5,8-trioxabicyclo[5,1,0]octane are suspended in 40 ml of isopropanol and refluxed for 60 hours. Then, the reaction mixture is mixed with 30 ml of isopropanol and cooled slowly to 0° C. The crystals that are obtained are suctioned off, washed with 30 ml of methyl-tert-butyl ether and dried in a vacuum. 20.7 g (71% of theory) of 1,7-bis(6-hydroxy-2,2-dimethyl-1,3-dioxepan-5-yl)-1,4,7,10-tetraazacyclododecane LiCl complex is obtained as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH-:9].[O:10]=[C:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:24](O)=O)[C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2>C(O)(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]=[C:24]([C:19]3[C:18]4[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[C:11](=[O:10])[C:23]=4[CH:22]=[CH:21][CH:20]=3)[NH:1][C:2]=2[CH:7]=1
Reactant: [NH-]c1ccc(Cl)cc1N
Reactant: O=C(O)c1cccc2c1-c1ccccc1C2=O
Solvent: CC(=O)O
Product: O=C1c2ccccc2-c2c1cccc2-c1nc2ccc(Cl)cc2[nH]1

Procedure:
A mixture of 3.0 g of (2-amino-4-chlorophenyl)amide of 9-oxo-9H-fluorene-4-carboxylic acid in 120 ml of glacial acetic acid is refluxed for 2.5 hours. Allow the mixture to return to room temperature and evaporate the reaction medium to dryness under vacuum. The residue is taken up with 75 ml of dichloromethane, and the organic phase is washed with twice 50 ml of a saturated solution of sodium bicarbonate, and 50 ml of a saturated solution of sodium chloride. After drying over magnesium sulphate, the organic phase is evaporated to dryness under vacuum. In this way, we obtain 3.12 g of 4-(6-chloro-1H-benzimidazol-2-yl)-9H-fluoren-9-one in the form of a beige foam with the following characteristics:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C([N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23](Cl)=[O:24])=[CH:20][CH:21]=2)[C:16]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[N:15]1)(=O)C>N1C=CC=CC=1>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[C:19]([C:23]([NH:1][CH2:2][CH2:3][CH2:4][N:5]4[CH2:10][CH2:9][O:8][CH2:7][CH2:6]4)=[O:24])[CH:18]=3)[NH:14][N:15]=2)=[CH:31][CH:30]=1
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Reactant: NCCCN1CCOCC1
Solvent: c1ccncc1
Product: O=C(NCCCN1CCOCC1)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reaction time: 8 h
Yield: 13.5 %

Procedure:
To a flask containing a solution of 4-(3-Aminopropyl)-morpholine (117 μl, 0.79 mmol) in pyridine (1 mL) was added 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (230 mg, 0.72 mmol) dissolved in pyridine (5 mL). The reaction was allowed to stir under a nitrogen atmosphere overnight. The reaction was not complete so an additional equivalent of 4-(3-Aminopropyl)-morpholine (100 μl, 0.72 mmol) was added. The reaction was allowed to stir at room temperature overnight. LCMS showed the product formation. Solvent was removed by rotary evaporation. The reaction was treated with water and the product was extracted with ethyl acetate and dichloromethane. The organic layers were combined and washed with saturated aqueous sodium carbonate solution and brine. The organic layer was dried with magnesium sulfate, filtered and concentrated to yield the product. This was purified by semi-preparative HPLC. The product was washed with a sodium bicarbonate solution to remove the TFA salt to yield the title compound (37.3 mg, 13.5% yield). 1H NMR (DMSO-d6) δ 8.6 (m, 1H), 8.5 (m, 1H), 8.0 (m, 2H), 7.9 (m, 1H), 7.7 (m, 1H), 7.4 (m, 2H), 3.3 (m, 4H), 3.1 (m, 2H), 2.3 (m, 6H), 1.6 (m, 2H) ES-MS m/z 383 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22]>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: FC(F)(F)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)CCCn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 102.5 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (250 mg) in N,N-dimethylformamide (1.6 mL) was added cesium carbonate (675 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added 4-bromo-1,1,1-trifluorobutane (466 mg), and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×3). The organic layer was washed with saturated brine (20 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=9/1→0/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (440 mg) as a colorless transparent oil.
Reaction SMILES: Br[CH2:2]/[CH:3]=[C:4](\[CH3:12])/[CH:5](OCC)[O:6]CC.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[OH:21].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[O:21][CH2:2]/[CH:3]=[C:4](\[CH3:12])/[CH:5]=[O:6]
Reactant: CCOC(OCC)/C(C)=C/CBr
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C/C(C=O)=C\COc1ccc(Cl)cc1Cl
Reaction time: 5 h
Yield: 87.2 %

Procedure:
In 100 ml dimethylformamide there is combined 34.9 g (E)-4-bromo-1,1-diethoxy-2-methyl-2-butene, 24.0 g 2,4-dichlorophenol, 40.5 g potassium carbonate and 2.37 g potassium iodide and stirred under nitrogen for about five hours. The resulting solution is poured into 500 ml deionized water and the solution extracted with two 200 ml portions diethylether which are then combined and washed first with 300 ml 10% aqueous potassium carbonate solution and then with three 400 ml portions of deionized water. The ether solution is treated with magnesium sulfate and activated charcoal then filtered. The filtrate is evaporated to dryness and the yellow-brown oil is taken up in a mixture of 120 ml acetone and 20 ml water and stirred under nitrogen as 3.0 g p-toluenesulfonic acid is added. Thirty minutes after the addition, the solution is evaporated to dryness and the residue taken up in 200 ml diethylether and this solution washed with two 200 ml portions deionized water. The ether solution is treated with magnesium sulfate and activated carbon and then filtered. The filtrate is evaporated to dryness to yield 31.47 g purple oil which is purified by chromatography on a Waters Prep. 500 LC using a silica gel cartridge yielding 25.31 g of a yellow oil. The oil is recrystallized from diethylether-hexane yielding 18.22 g solid product, m.p. 58.5°-59.5° C. Elemental Analysis. Calculated: C,53.90; H,4.11; Cl,20.93. Found: C,53.86; H,4.00; Cl,28.78.
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[N:4][CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].P(Cl)(Cl)([Cl:15])=O.O>C(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:15])=[N:4][CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: Oc1ncnc(C(F)(F)F)c1Br
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1ncnc(Cl)c1Br
Temperature: 100 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
24.3 g (100.0 mmoles) of 5-bromo-4-hydroxy-6-trifluoromethylpyrimidine was suspended in 18.5 g (120.0 mmoles) of phosphorus oxychloride. The suspension was stirred at 100° C. for 2 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was gradually poured into water and extraction with chloroform was conducted. The resulting organic layer was washed with water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography to obtain 21.5 g (yield: 82.4%) of 5-bromo-4-chloro-6-trifluoromethylpyrimidine.
Reaction SMILES: [CH:1]([C:3]1[C:7](Br)=[CH:6][S:5][CH:4]=1)=[O:2].C(N(CC)CC)C.[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[CH:27])=[CH:22][CH:21]=1>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[C:27][C:7]2[C:3]([CH:1]=[O:2])=[CH:4][S:5][CH:6]=2)=[CH:22][CH:21]=1
Reactant: O=Cc1cscc1Br
Reactant: C#Cc1ccc(OCOC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCOc1ccc(C#Cc2cscc2C=O)cc1
Yield: 66.9 %

Procedure:
3-Formyl-4-bromothiophene (14.7 g) was dissolved in DMF (100 ml), followed by the addition of triethylamine (100 ml), CuI (0.25 g), Pd(PPh3)2Cl2 (0.5 g) and 4-methoxymethoxy-1-ethynylbenzene (11.4 g), and the mixture was reacted at 70° C. overnight. The reaction solution was filtered through Celite, poured into 1N hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate and brine, dried and evaporated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate system), to give 3-{[4-(methoxymethoxy)phenyl]ethynyl}-4-formylthiophene as a colorless oil (12.8 g, yield; 47%).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH:18]=1)[C:15](O)=[O:16].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:19][CH3:20])=[C:14]([CH:18]=1)[C:15]([NH:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1)=[O:16]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: Nc1ncc(Cl)s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1C(=O)Nc1ncc(Cl)s1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 2-amino-5-chlorothiazole hydrochloric acid (1.0 g, 5.9 mmol), 5-chloro-2-methoxybenzoic acid (1.3 g, 7.0 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (Chem-Impex International, 2.2 g, 12 mmol), 1-hydroxbenzotriazole (0.95 g, 7.0 mmol) and 4-dimethylaminopyridine (0.14 g, 1.2 mmol) in 6 mL of pyridine was allowed to stir at ambient temperature for 72 hours. The reaction mixture was concentrated under reduced pressure and 10 mL of H2O was added. The resulting solids were isolated by filtration, washed with 5 mL of H2O and twice with 5 mL of ethyl acetate, and dried to afford the title compound. MS (DCI/NH3) m/z 303 (M+H)+.