Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[C:10]([NH2:22])([N:19]([CH3:21])[CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1>N1C=CC=CC=1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[C:10]([NH:22][S:29]([C:27]2[S:28][C:24]([Br:23])=[CH:25][CH:26]=2)(=[O:31])=[O:30])([N:19]([CH3:20])[CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: CN(C)C1(N)CN(C(=O)OC(C)(C)C)CCc2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C1(NS(=O)(=O)c2ccc(Br)s2)CN(C(=O)OC(C)(C)C)CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
To an ice bath cooled solution of the intermediate D3 (2.0 g, 0.0065 moles) in dry pyridine was added dropwise a solution of 5-bromothiophene-2-sulfonyl chloride (1.88 g, 0.0072 moles) in dichloromethane. The mixture was stirred for 1 hour at room temperature. The mixture was evaporated to dryness then purified by chromatography over silica, eluting with hexane up to 50% EtOAc/hexane, affording the title compound D6 as a brown solid (2.1 g, 90%). M-H 532. 1H NMR: δ MeOD 1.45 (9H,s), 2.76 (2H, m), 3.02 (2H, m), 3.30 (6H,s), 3.48 (2H, m), 3.58 (2H, m), 6.47 (1H, s), 7.26 (2H, m), 7.76 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[O:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH:8]=2)[N:4]=[CH:3]1.[C:24]1([CH2:30][C:31]([N:33]=[C:34]=[S:35])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:34]([NH:33][C:31](=[O:32])[CH2:30][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[S:35])=[CH:19][CH:18]=3)[CH:8]=2)[N:4]=[CH:3]1
Reactant: Cn1cnc(-c2cc3nccc(Oc4ccc(N)cc4)c3s2)c1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: C1CCOC1
Product: Cn1cnc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4)c3s2)c1
Reaction time: 1 h
Yield: 15 %

Procedure:
To a suspension of the 226 (385 mg, 0.99 mmol) in THF (10 mL) was added 2-phenylacetyl isothiocyanate (263 mg, 1.49 mmol). The reaction mixture was stirred for 1 hr, transferred onto a chromatography column and eluted with EtOAc/MeOH (9:1) producing a solid material which was re-crystallized from MeCN to afford title compound 227 (74.3 mg, 15% yield) as a white solid. 1HNMR: (DMSO-d6) d(ppm): 12.39 (s, 1H), 11.73 (s, 1H), 8.43 (d, J=5.3 Hz, 1H), 7.84 (s, 1H), 7.72 (m, 3H), 7.66 (s, 1H), 7.34-7.27 (m, 7H), 6.69 (d, J=5.3 Hz, 1H), 3.82 (s, 2H), 3.72 (s, 3H). MS (m/z): 500.1 (M+1).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2[F:35])=CSC=1C(OC)=O.C(OCC)(OCC)OCC.NC1C=C(C=CC=1)[C:54]#[N:55]>C(O)(=O)C>[F:35][C:22]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:16]1[C:10]2[N:9]=[CH:8][N:7]([C:1]3[CH:6]=[C:5]([CH:4]=[CH:3][CH:2]=3)[C:54]#[N:55])[C:12](=[O:13])[C:11]=2[S:14][CH:15]=1
Reactant: N#Cc1cccc(N)c1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: N#Cc1cccc(-n2cnc3c(-c4ccccc4F)csc3c2=O)c1
Yield: 18 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (80 mg, 0.3 mmol), triethyl orthoformate (0.79 ml), 3-aminobenzonitrile (70 mg, 0.59 mmol), and acetic acid (0.09 ml) were used to give 20 mg (0.06 mmol, 18.0% yield) of the title compound.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Br:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:9]([O:11]C)=O.C(OCC)(=O)C.O>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:5][C:6]1[CH:7]=[C:8]([C:9]2([OH:11])[CH2:2][CH2:1]2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: CC[Mg]Br
Reactant: COC(=O)c1ccc(OC)c(Br)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2(O)CC2)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethylmagnesium bromide (3M solution in diethyl ether, 54.4 ml) was added at room temperature to a solution of methyl 3-bromo-4-methoxybenzoate (CAS No. 35450-37-4, 10 g) and titanium (IV) isopropoxide (23.9 ml) in THF (100 ml). The reaction mixture was stirred at room temperature overnight. Ethyl acetate and water were added to the reaction mixture and the precipitate was removed through Celite. The organic layer was separated, washed with brine and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (7.77 g).
Reaction SMILES: [CH2:1]([C:3]1[CH2:7][CH2:6][C:5](=O)[C:4]=1[CH3:9])[CH3:2].C[Li].C([O:14][CH2:15][CH3:16])C.BrCBr.C([Mg]Cl)(C)(C)C>O>[CH2:7]([C@:3]12[CH2:9][C@@:4]1([CH3:5])[C:15]([CH3:16])([OH:14])[CH2:2][CH2:1]2)[CH3:6]
Reactant: CCC1=C(C)C(=O)CC1
Reactant: CCOCC
Agent: CC(C)(C)[Mg]Cl
Agent: [Li]C
Solvent: O
Solvent: BrCBr
Product: CC[C@@]12CCC(C)(O)[C@]1(C)C2
Reaction time: 18 h

Procedure:
Prepared as described in Example 20 (System B) from 3-ethyl-2-methylcyclopent-2-enone (4 g, 32 mmol) (G. Berube, A. G. Fallix, Can. J. Chem. 69, 77-78, 1991), addition of methyl-lithium 1.6 M in diethyl ether (28 ml, 45 mmol) at −20° C., dibromomethane (2×8.4 g, 97 mmol) and tert-butyl magnesium chloride 2M in diethyl ether (2×24 ml, 97 mmol). Work-up after 18 h at 25° C. (as described in example 1) and bulb-to-bulb distillation gives 3 g (60%) of a waxy yellowish solid. 1H NMR (CDCl3): δ-0.1 (d, 1H), 0.75 (d, 1H), 0.95 (t, 3H), 1.1 (s, 3H), 1.25 (s, 1H), 1.2-1.3 (1H), 1.3-1.4 (2H), 1.5-1.6 (2H), 1.7 (1H) ppm. 13C-NMR (CDCl3): δ 11.4 (q), 12.7 (q), 18.4 (t), 24.9 (q), 25.8 (t), 28.5 (t), 32.35 (s), 34.6 (s), 36.5 (t), 81.3 (s). Cis-configuration determined by NMR-analysis in water-free DMSO. MS (EI): m/z (%) 154 (M+, 1), 139 ([M-15]+, 38), 136 ([M-18]+, 67), 125 (37), 121 (27), 107 (86), 96 (59), 81 (100), 67 (30), 57 (42), 55 (36), 43 (86), 41 (40). IR (film): 3297 (br, OH), 2959 (s), 2859 (m), 1452 (s), 1365 (s), 1300 (m), 1199 (s), 1167 (m), 1115 (vs), 1062 (m), 970 (s), 938 (s), 926 (s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH2:15][CH2:16][CH2:17][F:18])[N:11]=[N:10]1.Cl[CH2:20][C:21]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:22]=1[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:18][CH2:17][CH2:16][CH2:15][N:12]1[C:13](=[O:14])[N:9]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH2:20][C:21]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:22]=3[O:23][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:7][C:2]=2[F:1])[N:10]=[N:11]1
Reactant: O=c1n(CCCF)nnn1-c1ccc(O)cc1F
Reactant: COC(=O)C(C)Oc1cc(C)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(C)ccc1COc1ccc(-n2nnn(CCCF)c2=O)c(F)c1
Yield: 27.5 %

Procedure:
By the method Example 1, Step I, 0.85 g (0.0033 mole) of 1-(2-fluoro-4-hydroxyphenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one and 1.21 g (0.0050 mole) of methyl 2-(2-chloromethyl-5-methylphenoxy)propionate (Example 1, Step H) were reacted in the presence of 0.70 g (0.0050 mole) of anhydrous potassium carbonate in 60 mL of N,N-dimethylformamide, yielding 0.42 g of methyl 2-[2-[4-[1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-on-1-yl]-3-fluorophenoxymethyl]-5-methylphenoxy]propionate as an oil. The NMR spectrum was consistent with the proposed structure. NMR: 1.64 (d, 3H, JHH =8 Hz); 2.2-2.4 (m, 2H); 2.32 (s, 3H); 3.72 (s, 3H); 4.18 (t, 2H, JHH =8 Hz); 4.50-4.64 (dt, 2H, JHH =8 Hz, JHF =45 Hz); 4.84 (q, 1H, JHH =8 Hz), 5.20 (q, 2H, JHH =8 Hz); 6.58-7.40 (m, 6H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.CN(C)C=O.F[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1[N+:24]([O-:26])=[O:25]>O>[N+:24]([C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:14]=1[N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]1[CH3:1])([O-:26])=[O:25]
Reactant: C[C@H]1CCCCN1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1CCCCN1c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 99.2 %

Procedure:
(S)-2-methylpiperidine (270 μl, 2.24 mmol, commercially available product) was added at room temperature to an N,N-dimethylformamide (DMF; 0.5 ml) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (211 mg, 1.00 mmol, commercially available product). The resulting mixture was stirred for two hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=12/1). Thus, (S)-1-[2-nitro-4-(trifluoromethyl)phenyl]-2-methylpiperidine (286 mg, 99.2%) was yielded as an orange-colored oily material.
Reaction SMILES: N1([C:6](N2C=CN=C2)=[O:7])C=CN=C1.[CH:13]1([CH2:16][CH2:17][OH:18])[CH2:15][CH2:14]1.Cl.[F:20][C:21]1[CH:26]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:24]=[CH:23][C:22]=1[N:31]1[C:35]2=[N:36][CH:37]=[N:38][C:39]([S:40][CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)=[C:34]2[CH:33]=[N:32]1.C(N(CC)CC)C>CS(C)=O>[CH:13]1([CH2:16][CH2:17][O:18][C:6]([N:44]2[CH2:43][CH2:42][CH:41]([S:40][C:39]3[N:38]=[CH:37][N:36]=[C:35]4[N:31]([C:22]5[CH:23]=[CH:24][C:25]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:26][C:21]=5[F:20])[N:32]=[CH:33][C:34]=34)[CH2:46][CH2:45]2)=[O:7])[CH2:15][CH2:14]1
Reactant: OCCC1CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(SC4CCNCC4)ncnc32)c(F)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(-n2ncc3c(SC4CCN(C(=O)OCCC5CC5)CC4)ncnc32)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.4 %

Procedure:
Di-imidazol-1-yl-methanone (0.25 mmol, 41 mg), and 2-cyclopropyl-ethanol (0.25 mmol, 32 μL) were dissolved in DMSO (2 mL) and stirred for 30 minutes at room temperature. Then, 1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-ylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (0.18 mmol, 80 mg) and triethylamine (0.54 mmol, 75 μL) were added. The mixture was heated in a microwave for 5 minutes at 120° C. The progress of the reaction was monitored by thin layer chromatography and LCMS. Purification by HPLC provided Compound A114 as a white solid (35 mg, 36%). 1H NMR (400 MHz, CDCl3) δ (ppm): 8.71 (s, 1H); 8.21 (s, 1H); 7.86 (m, 3H); 4.37 (m, 1H); 4.10 (t, 2H); 3.96 (s broad, 2H); 3.19 (m, 2H); 3.04 (s, 3H); 2.12 (m, 2H); 1.72 (m, 2H); 1.48 (m, 2H); 1.39 (m, 2H); 1.00 (m, 2H); 0.65 (m, 1H). Exact mass calculated for C23H26FN5O4S2 519.61, found 520.3 (MH+).
Reaction SMILES: FC1C=C(S(C)(=O)=O)C=CC=1O[C:5]1N=C[N:8]=[C:7]2[N:11](C3CCC(C4ON=C(C(C)C)N=4)CC3)N=[CH:13][C:6]=12.C(O[C:41]([N:43]1[CH2:48][CH2:47][CH:46]([N:49]2[C:53]3=[N:54][CH:55]=[N:56][C:57](Cl)=[C:52]3[CH:51]=[N:50]2)[CH2:45][CH2:44]1)=[O:42])(C)(C)C.[F:59][C:60]1[CH:61]=[C:62]([OH:70])[CH:63]=[CH:64][C:65]=1[S:66]([CH3:69])(=[O:68])=[O:67]>CN(C)C=O>[F:59][C:60]1[CH:61]=[C:62]([CH:63]=[CH:64][C:65]=1[S:66]([CH3:69])(=[O:67])=[O:68])[O:70][C:51]1[C:52]2[C:53](=[N:54][CH:55]=[N:56][CH:57]=2)[N:49]([CH:46]2[CH2:45][CH2:44][N:43]([C:41]3[O:42][N:11]=[C:7]([CH:6]([CH3:13])[CH3:5])[N:8]=3)[CH2:48][CH2:47]2)[N:50]=1.[F:59][C:60]1[CH:61]=[C:62]([CH:63]=[CH:64][C:65]=1[S:66]([CH3:69])(=[O:67])=[O:68])[O:70][C:57]1[N:56]=[CH:55][N:54]=[C:53]2[N:49]([CH:46]3[CH2:45][CH2:44][N:43]([C:41]4[O:42][N:11]=[C:7]([CH:6]([CH3:13])[CH3:5])[N:8]=4)[CH2:48][CH2:47]3)[N:50]=[CH:51][C:52]=12
Reactant: CC(C)c1noc(C2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5F)ncnc43)CC2)n1
Reactant: CS(=O)(=O)c1ccc(O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Solvent: CN(C)C=O
Product: CC(C)c1noc(N2CCC(n3nc(Oc4ccc(S(C)(=O)=O)c(F)c4)c4cncnc43)CC2)n1
Product: CC(C)c1noc(N2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)c(F)c5)ncnc43)CC2)n1
Yield: 22 %

Procedure:
4-(3-Fluoro-4-methanesulfonyl-phenoxy-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine was prepared using the procedure described for the preparation of 4-(2-fluoro-4-methanesulfonyl-phenoxy)-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine (Example 131) by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 3-fluoro-4-methanesulfonyl-phenol (Intermediate 2) in dimethylformamide. The product was purified by flash chromatography, eluting with 5% methanol/dichloromethane to give 4-(3-fluoro-4-methanesulfonyl-phenoxy)-1-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine (12 mg, 22%) as a white solid. Mass spectrum: Observed 501.9.
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:6])[CH2:2][C:3]([O-:5])=O.[C:15](Cl)([CH3:18])([CH3:17])[CH3:16].[NH2:20][CH2:21][C:22]([OH:24])=[O:23].C(N(CC)CC)C.O>CN(C)C=O>[CH3:16][C:15]([O:24][C:22](=[O:23])[CH2:21][NH:20][C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])([CH3:18])[CH3:17]
Reactant: CC(C)(C)Cl
Reactant: NCC(=O)O
Reactant: O=C([O-])CC(=O)OCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CNC(=O)CC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 45.9 %

Procedure:
To a solution of monobenzyl malonate (2.00 g) in N,N-dimethylformamide (51.5 mL), glycine tert-butyl hydrochloride (2.07 g), triethylamine (3.13 g) and propylphosphonic acid anhydride (cyclic trimer) (48%, solution in N,N-dimethylformamide, 8.22 g) were added and the mixture was stirred at room temperature for an hour. To the reaction mixture, water was added and extraction was conducted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=67:33-50:50) to give benzyl 3-({2-[(2-methyl-2-propanyl)oxy]-2-oxoethyl}amino)-3-oxopropanoate as a colorless oil (1.46 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12]([OH:14])=O)[CH:8]=2)[CH:3]=[CH:2]1.Cl.C[N:17](C)[CH2:18][CH2:19][CH2:20]N=C=NCC.C(N)CC.N=C=N>CN(C)C1C=CN=CC=1.C(Cl)Cl.CN(C)C=O>[CH2:18]([NH:17][C:12](=[O:14])/[CH:11]=[CH:10]/[C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1)[CH2:19][CH3:20]
Reactant: O=C(O)/C=C/c1ccc2cc[nH]c2c1
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: N=C=N
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCCN
Product: CCCNC(=O)/C=C/c1ccc2cc[nH]c2c1
Reaction time: 18 h
Yield: 61.2 %

Procedure:
A mixture of E-indole-6-acrylic acid (0.96 g), 4-dimethylaminopyridine (0.635 g), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.96 g) was dissolved in methylene chloride (50 ml) and N,N-dimethylformamide (60 ml) and stirred for 1 hour. Propylamine (0.591 g) was added and stirring continued for 18 hr. Further quantities of 4-dimethylaminopyridine (0.635 g), the carbodiimide (0.96 g) and propylamine (0.591 g) were added; and the mixture stirred for a further 30 hr. The solvents were evaporated; the residue partitioned between ethyl acetate and 1M hydrochloric acid; and the organic phase washed with water and brine; dried (MgSO4); and evaporated. The residue was purified by flash chromatography, eluting with 1:10 methanol:chloroform, to give E-N-propylindole-6-acrylamide (0.7 g, 60%) as an off-white solid; partial NMR (250 MHz, DMSO-d6): 0.89(t, 3H, CH2CH2CH3, 1.48(m, 2H, CH2CH2CH3), 3.15(m, 2H, CH2CH2CH3); 6.44(d, J=2.8 Hz H3 -indole), 6.55(d, J=15.7 Hz, 1H, olefinic H), 8.00(br t, 1H, NHCO), 11.28(br s, 1H, H1 -indole).
Reaction SMILES: C([O:4][CH:5]1[C@@:17]2([CH2:18][CH2:19][CH3:20])[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]2)[C:11]2[C:6]1=[CH:7][C:8]([O:24][CH2:25][C:26]([O:28]CC)=[O:27])=[C:9]([Cl:23])[C:10]=2[Cl:22])(=O)C.CO.[OH-].[Na+].Cl>O>[Cl:22][C:10]1[C:9]([Cl:23])=[C:8]([O:24][CH2:25][C:26]([OH:28])=[O:27])[CH:7]=[C:6]2[C:11]=1[C:12]1[C@:17]([CH2:18][CH2:19][CH3:20])([CH:5]2[OH:4])[CH2:16][CH2:15][C:14](=[O:21])[CH:13]=1
Reactant: CCC[C@@]12CCC(=O)C=C1c1c(cc(OCC(=O)OCC)c(Cl)c1Cl)C2OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC[C@@]12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl [(9-acetoxy-5,6-dichloro-3-oxo-9a(R)-propyl-2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]acetate (4.27 g, 0.0094 mol), methanol (75 ml) and 1N sodium hydroxide (21 ml) was stirred at 25° C. for 4 hours, diluted with water (250 ml), acidified with HCl and extracted with ether and methylene chloride. The combined organic extracts were combined, washed with H2O, dried over MgSO4 and evaporated in vacuo to give [(5,6-dichloro-9-hydroxy-3-oxo-9a(R)-propyl-2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]acetic acid which melted at 206°-208° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([NH2:13])=[CH:7][C:8]=2[CH3:12])[CH2:3]1.Cl[C:15]1[N:20]=[C:19]2[NH:21][C:22](=[O:34])[N:23]([C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:33])[C:24](=[NH:25])[C:18]2=[CH:17][N:16]=1.ClC1N=C2NC(=O)N(C3C(Cl)=CC=CC=3Cl)C(=N)C2=CN=1>>[Cl:33][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([CH3:32])[C:26]=1[N:23]1[C:24](=[NH:25])[C:18]2[C:19](=[N:20][C:15]([NH:13][C:6]3[CH:5]=[C:4]4[C:9]([CH2:10][CH2:11][N:2]([CH3:1])[CH2:3]4)=[C:8]([CH3:12])[CH:7]=3)=[N:16][CH:17]=2)[NH:21][C:22]1=[O:34]
Reactant: Cc1cccc(Cl)c1-n1c(=O)[nH]c2nc(Cl)ncc2c1=N
Reactant: Cc1cc(N)cc2c1CCN(C)C2
Agent: N=c1c2cnc(Cl)nc2[nH]c(=O)n1-c1c(Cl)cccc1Cl
Product: Cc1cc(Nc2ncc3c(=N)n(-c4c(C)cccc4Cl)c(=O)[nH]c3n2)cc2c1CCN(C)C2

Procedure:
7 mg of the entitled compound was obtained as a white solid according to the same method as in Example 2, for which, however, 2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine was used in place of 2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine in Example 2, and 7-chloro-3-(2-chloro-6-methylphenyl)-4-imino-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one obtained in Production Example 2 was used in place of 7-chloro-3-(2,6-dichlorophenyl)-4-imino-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([C:21]#[N:22])=[CH:6][CH:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10](OC)=[C:9]([O:17][CH3:18])[C:8]1=C=O)[CH3:2].[H][H]>[Pd].[Hg].C(O)C>[CH2:1]([O:3][C:4](=[O:23])[C:5]([C:21]#[N:22])=[CH:6][CH:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([C:4]([O:3][CH3:1])=[O:23])=[C:9]([O:17][CH3:18])[CH2:8]1)[CH3:2]
Reactant: CCOC(=O)C(C#N)=CC1C=C(OC)C(OC)=C(OC)C1=C=O
Reactant: [H][H]
Agent: [Pd]
Agent: [Hg]
Solvent: CCO
Product: CCOC(=O)C(C#N)=CC1C=C(OC)C(C(=O)OC)=C(OC)C1

Procedure:
A solution of 10.6 g. of α-cyano-3,5-dimethoxy-4-methoxy-carbonyl-cinnamic acid ethyl ester in 500 ml. of ethanol was hydrogenated in the presence of 0.5 g. of palladium-on-carbon (5%) at room temperature and 760 mm. of mercury. After the uptake of an equivalent of hydrogen (810 ml.), the hydrogenation was interrupted. The catalyst and partially precipitated product were removed by filtration with suction and washed on the filter with benzene. The filtrate was evaporated to dryness. The residue was recrystallized from ethyl acetate and yielded α-cyano-3,5-dimethoxy-4-methoxycarbonyl-dihydro-cinnamic acid ethyl ester having a m.p. of 119°-121°C.
Reaction SMILES: NC(N)=[S:3].CO.Cl.[CH2:8]([O:15][C:16]1[C:17]([CH3:26])=[N:18][CH:19]=[C:20]([CH:24]=[CH2:25])[C:21]=1[CH2:22]Cl)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>O>[CH3:26][C:17]1[C:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:21]([CH2:22][SH:3])[C:20]([CH:24]=[CH2:25])=[CH:19][N:18]=1
Reactant: C=Cc1cnc(C)c(OCc2ccccc2)c1CCl
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=Cc1cnc(C)c(OCc2ccccc2)c1CS

Procedure:
To a well stirred solution of 0.11 mole of thiourea in 250 ml. methanol, under N2 is added 0.1 mole of 3-benzyloxy-4-chloromethyl-2-methyl-5-vinylpyridine hydrochloride. The mixture is refluxed for 1 hour and then cooled. A solution of 0.4 mole of sodium hydroxide in 50 ml. of water is added, and the resulting mixture refluxed for 30 minutes. After concentration in vacuo the reaction mixture is taken up between benzene and water and enough acetic acid added to neutralize the mixture. The organic layer is separated, washed well with water, dried, and concentrated to give 2-methyl-3-benzyloxy-4-mercaptomethyl-5-vinylpyridine.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1.[Br:17]Br>C1COCC1>[Br:17][C:11]1[C:12](=[O:16])[O:13][C:14]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][Br:1])[CH:15]=2
Reactant: BrBr
Reactant: O=c1ccc2ccc(OCCCBr)cc2o1
Solvent: C1CCOC1
Product: O=c1oc2cc(OCCCBr)ccc2cc1Br

Procedure:
Into a 500 mL round bottom flask containing a 2.5 cm stirring bar was added 13 g of 7-(γ-bromopropyloxy)coumarin and 120-150 mL of THF. When the 7-(γ-bromopropyloxy)coumarin was completely dissolved, 3 mL of bromine was added by syringe. After stirring for 2-5 hours at room temperature, the solution was concentrated by rotary evaporator. 50 mL of a 1:1 mixture of ethyl acetate and hexane was added to the concentrate and the mixture was stirred for 30 minutes at room temperature. The solution was then filtered and the solids washed 3 times with 1:1 ethyl acetate and hexane and then dried for 2 hours. To obtain additional product, the filtrate was concentrated by rotary evaporator and 30 mL of a 1:1 mixture of ethyl acetate and hexane was added to the concentrate. The resulting mixture was then filtered, the solids washed three times with 1:1 ethyl acetate and hexane and then dried for 2-5 hours. The product was checked by TLC (ethyl acetate:hexane (4:6)).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH:12][NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[F:33][C:34]1[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=1[NH2:36]>C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C:10]1[N:36]([C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[F:33])[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)=[N:13][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1F
Reactant: O=C(COCc1ccccc1)NNC(=O)c1ccc(-c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1ccccc1-n1c(COCc2ccccc2)nnc1-c1ccc(-c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To biphenyl-4-carboxylic acid N′-(2-benzyloxyacetyl)hydrazide (9.38 g) was added phosphorus oxychloride (30 ml), and stirred at 100° C. for one hour. After the reaction solution was cooled to ambient temperature, the reaction solution was concentrated under reduced pressure. To the resulting residue was added ethyl acetate, and the separated organic layer was washed with aqueous 1 mol/liter sodium hydroxide solution and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to afford an oily product. Subsequently, 2-fluoroaniline (5 ml) and p-toluenesulfonic acid·monohydrate (200 mg) were added to the resulting oily product, and stirred at 140° C. for 4 hours. After the reaction solution was cooled to ambient temperature, ethyl acetate was added to the reaction solution. The separated organic layer was washed with aqueous 1 mol/liter sodium hydroxide solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (eluent: n-hexane/ethyl acetate=3/1–1/1), to afford the entitled compound 3-benzyloxymethyl-5-biphenyl-4-yl-4-(2-fluorophenyl)-4H-1,2,4-triazole as pale yellow solid (6.60 g, 58%). The physico-chemical values are as follows.