Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Cl:5])(Cl)(Cl)Cl.[CH2:6]([O:13][C:14]([NH:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27]CO)=[C:19]([N+:30]([O-:32])=[O:31])[CH:18]=1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH2:6]([O:13][C:14]([NH:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27][CH2:1][Cl:5])=[C:19]([N+:30]([O-:32])=[O:31])[CH:18]=1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C(Nc1cc([N+](=O)[O-])c(CCO)c2ccccc12)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1cc([N+](=O)[O-])c(CCCl)c2ccccc12)OCc1ccccc1
Reaction time: 3 h
Yield: 96.2 %

Procedure:
CCl4 (0.2 mL, 2.18 mmol) was added to a solution of 2-[4-(N-benzyloxycarbonylamino)-2-nitronaphthalen-1-yl]ethanol (0.1 g, 0.27 mmol) and Ph3P (0.29 g, 1.09 mmol) in CH2Cl2 (5 mL) under N2 atmosphere and stirred for 3 h. Flash chromatography (10% AcOEt-Petroleum ether) afforded of 2-[4-(N-benzyloxycarbonylamino)-2-nitronaphthalen-1-yl]ethyl chloride (0.1 g, 96%) as an orange solid. M.p. 122-124° C.; 1H NMR (CDCl3, 500 MHz) δ 8.18 (d, 8.5, 1H), 7.89 (d, 8.5, 1H), 7.70 (t, 7.0, 1H), 7.62 (t, 7.0, 1H), 7.45 (d, 7.0, 2H), 7.41 (t, 7.5, 2H), 7.35 (t, 7.5, 1H), 6.95 (s, 1H), 4.93 (brs, 1H), 4.51 (d, 5.0, 2H), 3.86 (t, 8.0, 2H), 3.56 (t, 8.5, 2H); IR (neat) 3087, 3033, 2927, 2856, 1594, 1519, 1439, 1342, 1124, 752, 699 cm−1. FABMS (NBA) m/z 340 (M−CO2+), ESMS m/z 341 (M−CO2+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[CH2:7][NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:22]([S:25][CH2:26][CH:27]([CH3:31])[C:28](Cl)=[O:29])(=[O:24])[CH3:23]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:14])[CH2:7][N:8]([C:28](=[O:29])[CH:27]([CH3:31])[CH2:26][S:25][C:22](=[O:24])[CH3:23])[CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNC1CCCC1
Reactant: CC(=O)SCC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a solution containing 60 g (0.30 mol) of N-cyclopentylglycine t- butyl ester and 75 ml (0.54 mol) of triethylamine in 200 ml of methylene chloride at 0° C. was added dropwise a solution of 54 g (0.30 mol) of 3-acetylthio-2-methylpropanoyl chloride in 250 ml of methylene chloride. After the reaction mixture was stirred at room temperature overnight, it was filtered and concentrated in vacuo. The residue was taken up in ethyl acetate and wasned once with saturated aqueous NaHCO3, once with brine, three times with 5% aqueous HCl, once with brine, and five times with saturated aqueous NaHCO3. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to yield 80.1 g (78%) of N-(3-acetylthio-2-methylpropanoyl)-N-cyclopentylglycine t-butyl ester as an oil which crystallized on standing.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([OH:13])=[C:7]([C:14](=[O:16])[CH3:15])[C:6]=1[CH3:17])(=[O:3])[CH3:2].[C:18]1(=O)[CH2:21][CH2:20][CH2:19]1>N1CCCCC1.C(OCC)(=O)C>[C:1]([O:4][C:5]1[C:6]([CH3:17])=[C:7]2[C:8](=[C:9]([CH3:12])[C:10]=1[CH3:11])[O:13][C:18]1([CH2:21][CH2:20][CH2:19]1)[CH2:15][C:14]2=[O:16])(=[O:3])[CH3:2]
Reactant: O=C1CCC1
Reactant: CC(=O)Oc1c(C)c(C)c(O)c(C(C)=O)c1C
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC1(CCC1)O2
Temperature: 180 °C
Reaction time: 0.33 h

Procedure:
A solution of the crude 3-acetyl-4-hydroxy-2,5,6-trimethyl-phenyl acetate prepared as in Step 1 (1.0 g), cyclobutanone (415 mg) and piperidine (10 drops) in xylenes (2 mL) was heated at 180° C. for 5 min and then 230° C. for 20 min using a microwave. The solution was diluted with ethyl acetate, washed with water and brine, dried, evaporated, and chromatographed (silica gel, hexane-ethyl acetate 3% to 8%) to give 354 mg of 5,7,8-trimethyl-4-oxo-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-yl acetate.
Reaction SMILES: FC(F)(F)C1C=C(C=CC=1)OC([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)C#N.C(NCCO)(=O)C.Cl.Cl.[F:31][C:32]([F:59])([F:58])[C:33]1[CH:34]=[C:35]([CH:55]=[CH:56][CH:57]=1)[O:36][C:37](=NC1C=CC(Cl)=CC=1)[C:38]([O:40][CH2:41][CH2:42][NH:43][C:44](=[O:46])[CH3:45])=[O:39]>CN(C)C=O.O.C(Cl)Cl>[F:59][C:32]([F:31])([F:58])[C:33]1[CH:34]=[C:35]([CH:55]=[CH:56][CH:57]=1)[O:36][CH:37]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:38]([O:40][CH2:41][CH2:42][NH:43][C:44](=[O:46])[CH3:45])=[O:39]
Reactant: CC(=O)NCCOC(=O)C(=Nc1ccc(Cl)cc1)Oc1cccc(C(F)(F)F)c1
Reactant: N#CC(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Agent: CC(=O)NCCO
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)NCCOC(=O)C(Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Reaction time: 5 h
Yield: 25 %

Procedure:
(3-Trifluoromethylphenoxy)(4-chlorophenyl)acetonitrile is added to a solution of 2-acetamidoethanol (20.6 g., 0.2 mole) in anhydrous dimethylformamide (25 ml.). The reaction mixture is cooled to -10°C. and saturated with hydrogen chloride (50 g., 1.37 mole) and stirred for 5 hours at -10° to 0°C. To this reaction mixture containing 2-acetamidoethyl (3-trifluoromethylphenoxy)(4-chlorophenyl)iminoacetate hydrochloride is added methylene chloride (200 ml.) and then water (100 ml.). The organic layer is collected, washed with water (2 × 100 ml.) and then dried over magnesium sulfate. The dried solution is decolorized with carbon, filtered and then slowly diluted with hexane (1 liter) to afford 10.7 g. (25% yield) of 2-acetamidoethyl (3-trifluoromethylphenoxy)(4-chlorophenyl)acetate, m.p. 93°-95°C.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1.[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][NH:15]1.FC(F)(F)S([O-])(=O)=O.[Ca+2].FC(F)(F)S([O-])(=O)=O>C(#N)C>[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][N:15]1[CH2:3][CH:2]([CH:4]1[CH2:13][CH2:12][C:7]2([O:11][CH2:10][CH2:9][O:8]2)[CH2:6][CH2:5]1)[OH:1]
Reactant: C1COC2(CCC(C3CO3)CC2)O1
Reactant: c1ccc2c(c1)CNC2
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Ca+2]
Solvent: CC#N
Product: OC(CN1Cc2ccccc2C1)C1CCC2(CC1)OCCO2

Procedure:
A solution of 8-oxiranyl-1,4-dioxaspiro[4.5]decane (1.41 g, 7.66 mmol), isoindoline (1.00 g, 8.43 mmol) and calcium trifluoromethanesulfonate (1.29 g, 3.8 mmol) in anhydrous acetonitrile (60 ml) was stirred at room temperature overnight. The solvent was then concentrated in vacuo. The residue was taken up in ethyl acetate (50 ml) and the solution was washed with 25% potassium carbonate solution (3×50 ml). The aqueous phase was extracted with ethyl acetate (3×40 ml) and the combined organic phases were dried with sodium sulfate and concentrated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]([CH3:11])[S:6][C:7]=1[C:8]([OH:10])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[F:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C=O.CN(C)C(=O)C>[CH:40]1([C:38]([NH:37][C:35]2[N:36]=[C:31]3[CH:30]=[CH:29][C:28]([O:27][C:26]4[CH:43]=[CH:44][C:45]([F:46])=[C:24]([NH:23][C:8]([C:7]5[S:6][C:5]([CH3:11])=[N:4][C:3]=5[O:2][CH3:1])=[O:10])[CH:25]=4)=[N:33][N:32]3[CH:34]=2)=[O:39])[CH2:41][CH2:42]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: COc1nc(C)sc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: COc1nc(C)sc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 40.1 %

Procedure:
In the same manner as in Example 259 and using 4-methoxy-2-methyl-1,3-thiazole-5-carboxylic acid (100 mg, 0.60 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (61 μL, 0.72 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (89 mg, 40%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[N:26]=2)[N:4]=1)[CH3:2].[Si:32]([O:39][C@H:40]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C@H:41]1[CH2:52]O)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Si:32]([O:39][C@H:40]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C@H:41]1[CH2:52][O:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][N:5]2[C:6]3[C:11](=[C:10]([NH:12][C:13]([C:15]4[N:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:18]5=[N:17][CH:16]=4)=[O:14])[CH:9]=[CH:8][CH:7]=3)[C:3]([CH2:1][CH3:2])=[N:4]2)[N:26]=1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CCc1nn(Cc2cccc(O)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1nn(Cc2cccc(OC[C@H]3[C@@H](O[Si](C)(C)C(C)(C)C)CCN3C(=O)OC(C)(C)C)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Reaction time: 16 h

Procedure:
To a suspension of N-(3-ethyl-1-((6-hydroxypyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (26 mg, 0.0630 mmol; prepared as in Example 17, Step A) in THF (5 mL) was added (2S,3S)-tert-butyl 3-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (62.7 mg, 0.189 mmol), triphenylphosphine (54.6 mg, 0.208 mmol) and diethyl azodicarboxylate (81.9 μL, 0.208 mmol). The suspension became a clear solution, which was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure and silica gel chromatography (DCM/MeOH 10:1) provided the product mixed with triphenyl phosphine oxide (65.6 mg).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[Br:8][C:9]1[N:14]=[C:13]([CH:15]=O)[CH:12]=[CH:11][CH:10]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[Br:8][C:9]1[N:14]=[C:13]([CH2:15][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])[CH:12]=[CH:11][CH:10]=1
Reactant: CCCNCCC
Reactant: O=Cc1cccc(Br)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1cccc(Br)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
Dipropylamine (7.4 mL, 54 mmol) and 6-bromopyridine-2-carbaldehyde (5.0 g, 27 mmol) were dissolved in 1,2-dichloroethane (50 mL). 2 drops of glacial acetic acid was added followed by sodium triacetoxyborohydride (11.4 g, 54 mmol). The reaction was stirred at 50° C. for 1 h. The reaction was cooled and quenched with water. The solution was diluted with saturated sodium bicarbonate and extracted with ethyl acetate (3 times). The organic layers were dried over magnesium sulfate, filtered and concentrated. Flash chromatography gave 5.34 g (73% yield) of product.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH:17]1([CH2:23][O:24][C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[ClH:1].[CH:17]1([CH2:23][O:24][C:25]2[CH:31]=[CH:30][C:28]([NH:29][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:27][CH:26]=2)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CCOC(=O)c1ccc2nccc(Cl)c2c1
Reactant: Nc1ccc(OCC2CCCCC2)cc1
Product: CCOC(=O)c1ccc2nccc(Nc3ccc(OCC4CCCCC4)cc3)c2c1
Product: Cl

Procedure:
In a manner similar to that described in Example 39, Part B., 2.0 g (8.48 mmol) of ethyl 4-chloroquinolin-6-carboxylate and 1.74 g (8.48 mmol) of 4-(cyclohexylmethyloxy)aniline were transformed into the title compound: yield 3.41 g (92%); m.p. 251°-253° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:24])[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=3)=[CH:16][C:10]=2[C:9]1=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[CH:28]=[C:29]([C:32](Cl)=[O:33])[S:30][CH:31]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:24])[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:32]([C:29]4[S:30][CH:31]=[C:27]([CH3:26])[CH:28]=4)=[O:33])[N:18]=3)=[CH:16][C:10]=2[C:9]1=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1csc(C(=O)Cl)c1
Reactant: Cn1c(-c2ccnc(N)n2)cc2c1CCN(C(=O)OC(C)(C)C)C2=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1csc(C(=O)Nc2nccc(-c3cc4c(n3C)CCN(C(=O)OC(C)(C)C)C4=O)n2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
2-(2-Amino-pyrimidin-4-yl)-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (prepared as described in Example 9) (300 mg, 0.873 mmol) was suspended in dry pyridine under nitrogen atmosphere and sonicated for 2 minutes. 4-Methyl-thiophene-2-carbonyl chloride (0.142 mL, 1.135 mmol, 1.3 eq) and DMAP (10 mg, 0.087 mmol, 0.1 eq) were added and the mixture was stirred at room temperature for 3 hours. Pyridine was then evaporated and the residue was taken up with saturated aqueous NaHCO3 (10 mL) and extracted with ethyl acetate (3×10 mL). Combined organic layers were washed with brine (3×10 mL), dried over Na2SO4 and evaporated to dryness. The crude product was purified by chromatography on silica gel (gradient n-hexane/ethyl acetate 1:1 to pure ethyl acetate) to obtain 394 mg of 1-methyl-2-{2-[(4-methyl-thiophene-2-carbonyl)-amino]-pyrimidin-4-yl}-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (85%).
Reaction SMILES: [CH3:1][N:2](C(OC(C)(C)C)=O)[C:3](N1C=CC=N1)=[N:4]C(OC(C)(C)C)=O.C(N(C(C)C)C(C)C)C.[ClH:33].Cl.[NH2:35][CH2:36][CH2:37][N:38]1[C:46]2[C:45]([NH:47][C:48]3[CH:53]=[CH:52][C:51]([O:54][C:55]4[CH:60]=[CH:59][CH:58]=[C:57]([C:61]([F:64])([F:63])[F:62])[CH:56]=4)=[C:50]([Cl:65])[CH:49]=3)=[N:44][CH:43]=[N:42][C:41]=2[CH:40]=[CH:39]1.O>C(#N)C>[ClH:65].[ClH:33].[Cl:65][C:50]1[CH:49]=[C:48]([NH:47][C:45]2[C:46]3[N:38]([CH2:37][CH2:36][NH:35][C:3]([NH:2][CH3:1])=[NH:4])[CH:39]=[CH:40][C:41]=3[N:42]=[CH:43][N:44]=2)[CH:53]=[CH:52][C:51]=1[O:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([C:61]([F:64])([F:63])[F:62])[CH:56]=1
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Reactant: CN(C(=O)OC(C)(C)C)C(=NC(=O)OC(C)(C)C)n1cccn1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=N)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 96 h
Yield: 88.5 %

Procedure:
To a solution of N-methyl-N,N′-bis(tert-butoxy carbonyl)-1H-pyrazole-1-carboxamidine (138 mg) and ethyldiisopropylamine (0.16 mL) in acetonitrile (4 mL) was added 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (200 mg), and the mixture was stirred at room temperature for 4 days. Under ice-cooling, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane=80:20→100:0). The obtained product was dissolved in ethyl acetate, 4N hydrochloric acid/ethyl acetate was added, and the mixture was stirred at room temperature for 22 hrs. The precipitate was collected by filtration, and washed with ethyl acetate and diisopropyl ether to give the title compound (98 mg) as a powder.
Reaction SMILES: [C:1]([S:4][CH2:5]/[C:6](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)/[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>>[O:9]=[C:7]([NH:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])/[C:6](/[CH2:5][S:4][C:1](=[O:3])[CH3:2])=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1
Reactant: CC(=O)SC/C(=C\c1ccc(C(F)(F)F)cc1)C(=O)O
Reactant: NCCC(=O)OCc1ccccc1
Product: CC(=O)SC/C(=C\c1ccc(C(F)(F)F)cc1)C(=O)NCCC(=O)OCc1ccccc1

Procedure:
The (Z)-2-acetylthiomethyl-3-(4-trifluoromethylphenyl)propenoic acid obtained in step C is coupled with benzyl β-alaninate according to the experimental procedure described in Example 1 (step D).
Reaction SMILES: ClCCl.[Cl:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:6]=1[CH2:7][OH:8].[C:14](OC(=O)C)(=[O:16])[CH3:15]>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[Cl:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:6]=1[CH2:7][O:8][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1c(Cl)cccc1Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCc1c(Cl)cccc1Cl
Temperature: 5 °C
Reaction time: 2.5 h

Procedure:
Add 500 mL of dichloromethane to 100 g of 2,6-dichlorobenzyl alcohol followed by 117 mL of triethylamine. Cool the solution to 5° C. and add 65 mL of acetic anhydride. After 2.5 hr at room temperature, add another 10 mL of acetic anhydride, 20 mL of triethylamine and 0.5 g of 4-dimethylaminopyridine. Wash the organic layer with 1N HCl followed by saturated aqueous sodium bicarbonate and brine. Dry the organic layer (sodium sulfate) and evaporate to afford 131.5 g of the titled compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](I)[CH:3]=1.[C:12]1([Mg]Cl)[CH:17]=CC=C[CH:13]=1.C([Cu])#N.C(Br)C=C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH2:17][CH:12]=[CH2:13])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1I
Reactant: Cl[Mg]c1ccccc1
Agent: N#C[Cu]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To 4-fluoro-2-iodo-1-nitrobenzene (40.0 g, 150 mmol) in THF (200 mL) at −40° C. was added phenylmagnesium chloride (80.0 mL, 2M in THF, 161 mmol) dropwise. The reaction was stirred for 30 min followed by dropwise addition of CuCN.2LiCl (26.0 g, 150 mmol) in THF. The mixture was stirred an additional 30 min at which time allyl bromide (20.0 g, 161 mmol) was added. The reaction was stirred at −40° C. for 2 h followed by rt overnight. The reaction was quenched with saturated ammonium chloride and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4) and concentrated. Purification by flash chromatography provided the title compound of step B (11.0 g, 60.7 mmol, 42%). 1H NMR (400 MHz, CDCl3) δ ppm 3.70 (d, J=6.4 Hz, 2H), 5.08-5.71 (m, 2H), 6.87-6.02 (m, 1H), 7.01-7.11 (m, 2H), 7.95-8.05 (m, 1H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C@@H:14]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[NH2:15])[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11].[CH3:23][O:24][C:25]([C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)=[O:26].CCCP(=O)=O.CCOC(C)=O>O.CN(C=O)C>[F:2][C:3]1[CH:4]=[C:5]([C@H:14]([NH:15][C:31]([C:30]2[CH:34]=[CH:35][C:27]([C:25]([O:24][CH3:23])=[O:26])=[CH:28][CH:29]=2)=[O:32])[C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F
Agent: CCCP(=O)=O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-(3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methanamine hydrochloride (100 mg, 0.294 mmol, Intermediate 6), 4-(methoxycarbonyl)benzoic acid (52.9 mg, 0.294 mmol), and DMF (2 mL) were added TEA (0.123 mL, 0.881 mmol) and 50% propylphosphonic anhydride in EtOAc (0.175 mL, 0.587 mmol). The solution was stirred at room temperature. After 2 h, the reaction was diluted with water (30 mL), stirred for 30 min, and then filtered. The solids were washed with water and dried in the funnel to give the title compound as a white solid. MS (ESI pos. ion) m/z: 467.0 (M+H).
Reaction SMILES: [C:1]([O:5]C(OC(OC(C)(C)C)=O)=O)(C)(C)C.[CH2:16]([NH:19][C:20]1[N:21]=[C:22]([NH2:30])[C:23]2[S:28][CH:27]=[C:26]([CH3:29])[C:24]=2[N:25]=1)[CH:17]=[CH2:18].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.C(OCC)(=O)C.CCCCCC>C(#N)C>[CH2:16]([NH:19][C:20]1[N:21]=[C:22]([NH:30][C:1]([N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:5])[C:23]2[S:28][CH:27]=[C:26]([CH3:29])[C:24]=2[N:25]=1)[CH:17]=[CH2:18]
Reactant: C1CCNC1
Reactant: C=CCNc1nc(N)c2scc(C)c2n1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CCNc1nc(NC(=O)N2CCCC2)c2scc(C)c2n1
Reaction time: 0.33 h
Yield: 57 %

Procedure:
122 mg (1.0 mmol) of N,N-dimethylaminopyridine was added to a solution of 306 mg (1.4 mmol) of di-t-butyldicarbonate in acetonitrile at room temperature, followed by stirring 20 minutes. After 220 mg (1.0 mmol) of 2-allylamino-4-amino-7-methylthieno[3,2-d]pyrimidine was added to the reaction solution, the mixture was stirred at room temperature for 2 hours. Further, 142 mg (2.0 mmol) of pyrrolidine was added thereto, followed by heating under reflux for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was purified by a silica gel chromatography (eluent: ethyl acetate-hexane=1/2] to give 181 mg (yield: 57.1%) of the title compound.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[C:14]1([CH3:21])[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:14]1([CH3:21])[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=1[O:20][C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1Oc1ccc(C#N)c(C#N)c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A mixture of 4-nitrophthalonitrile (10.6 g, 60.0 mmol), o-cresol (7.9 g, 72.0 mmol) and K2CO3 (16.6 g, 120.0 mmol) in DMF (70 mL) was heated to 60° C. under a nitrogen atmosphere for 3 hours. The crude reaction was then poured into H2O (300 mL). The resulting mixture was extracted twice with EtOAc. The combined organic layers were washed with sat'd NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. The residue was then dissolved in EtOH (60 mL). After storing for 5 hours at room temperature, the precipitate was collected by filtration and the filter cake was washed with cold EtOH to give the title compound in 8.9 g. MS: (+) m/z 235.46 (M+1).
Reaction SMILES: [C:1]([CH:4]([NH:35]C(OC(C)(C)C)=O)[CH2:5][CH2:6][CH2:7][C@@H:8]([C:27]([NH:29][C@@H:30]([C:32]([OH:34])=[O:33])[CH3:31])=[O:28])[NH:9][C:10]([NH:12][CH2:13][CH:14]([C:24]([OH:26])=[O:25])[NH:15][C:16](=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])([OH:3])=[O:2]>C(O)(C(F)(F)F)=O>[C:1]([CH:4]([NH2:35])[CH2:5][CH2:6][CH2:7][C@@H:8]([C:27]([NH:29][C@@H:30]([C:32]([OH:34])=[O:33])[CH3:31])=[O:28])[NH:9][C:10]([NH:12][CH2:13][CH:14]([C:24]([OH:26])=[O:25])[NH:15][C:16](=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])([OH:3])=[O:2]
Reactant: CCCCCCC(=O)NC(CNC(=O)N[C@@H](CCCC(NC(=O)OC(C)(C)C)C(=O)O)C(=O)N[C@H](C)C(=O)O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCC(=O)NC(CNC(=O)N[C@@H](CCCC(N)C(=O)O)C(=O)N[C@H](C)C(=O)O)C(=O)O

Procedure:
To 85.9 mg of 1b-5 under argon is treated with 500 μl of TFA according to Example 80. The volatiles are evaporated to a residue which is triturated with ether 3x and the ether is decanted. The residue is dried to give 77.9 mg of 1b-11 as a white solid. NMR(CD3OD) δ0.80(t,3H), 2.16(t,2H), 3.22 (br s, 5H), 3.58 (m, 2H), 3.85 (m, 1H), 4.15 (m, 1H), 4.30(d,1H), 4.40(m, 1H); MS(HR-FAB) m/z 526.2482 (M+H, calcd for C21H38N5O9 526.2489).