Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8](COCC[Si](C)(C)C)COCC[Si](C)(C)C)[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:4]2[N:3]=1.C(N(CC)C(C)C)(C)C.[C:47]([N:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1)([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48].[Br:60]N1C(=O)CCC1=O>C(#N)C.CN1C(=O)CCC1>[NH2:8][C:6]1[N:5]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:4]2[N:3]=[C:2]([N:57]2[CH2:56][CH2:55][N:54]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:59][CH2:58]2)[C:7]=1[Br:60]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2c(-c3cnc4ccccc4c3)cnn12
Solvent: CN1CCCC1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)CC1
Temperature: 200 °C
Reaction time: 2 h

Procedure:
To a 20 mL scintillation vial was charged 5-chloro-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)-ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (0.09 mmol, 50 mg), NMP (1 mL), N,N-diisopropylethylamine (0.36 mmol, 63 μL), and 4-N-Boc-piperazine (0.27 mmol, 50 mg). The resulting solution was heated to 200° C. in microwave synthesizer for 30 minutes. Upon completion, the NMP was removed in vacuo as an azeotrope using chlorobenzene. This residue was dissolved in acetonitrile (1 mL) to which N-bromosuccinimide (0.10 mmol, 17.7 mg) was added. This reaction mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and tert-butyl 4-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]([OH:20])=O)[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:21]([NH:28][C:18]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:17]2)=[O:20])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(C(=O)O)cc2C1
Reactant: NCc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1Cc2ccc(C(=O)NCc3ccccc3)cc2C1
Yield: 86.8 %

Procedure:
Using 2-(tert-butoxycarbonylamino)-5-carboxyindan (400 mg, 1.44 mmol), benzylamine (0.24 ml, 2.2 mmol), triethylamine (1.4 ml, 10 mmol), propanephosphonic acid anhydride (2.1 ml), dimethylaminopyridine (a catalytic amount) and methylene chloride (12 ml), a similar procedure to a) in Example 29 was carried out. The product obtained was purified by silica gel chromatography (methylene chloride:methanol=95:5) to obtain N-benzyl-2-(tert-butoxycarbonylamino)-5-indan carboxamide (460 mg, 1.25 mmol) having the following physical properties:
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([F:20])([C:18]#N)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:21].[Na+].Cl.C([OH:26])C>>[CH:1]([N:14]1[CH2:17][C:16]([F:20])([C:18]([OH:26])=[O:21])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1(F)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: [OH-]
Reactant: CCO
Agent: Cl
Agent: [Na+]
Product: O=C(O)C1(F)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 13 %

Procedure:
1-Benzhydryl-3-fluoroazetidine-3-carbonitrile (3.5 g, 1.0 eq.) was dissolved in ethanol, and aq. NaOH solution (1N) was added. The reaction mixture was refluxed for 5 h, then was allowed to cool to room temperature, at which temperature, it was acidified with dilute HCl (pH=3) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to obtain 0.5 g of 1-benzhydryl-3-fluoroazetidine-3-carboxylic acid (13% yield). The product was used in the next step without further purification.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32]2([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]2)/[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:69][C@@H:70]1[C:88](=[O:89])[N:72]2[C:73]([C:85]([OH:87])=[O:86])=[C:74]([CH2:77][S:78][C:79]3[N:83]([NH2:84])[N:82]=[N:81][N:80]=3)[CH2:75][S:76][C@H:71]12.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC(N(C)C)=O.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32]2([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]2)/[C:27]([NH:69][C@@H:70]2[C:88](=[O:89])[N:72]3[C:73]([C:85]([OH:87])=[O:86])=[C:74]([CH2:77][S:78][C:79]4[N:83]([NH2:84])[N:82]=[N:81][N:80]=4)[CH2:75][S:76][C@H:71]23)=[O:28])[N:25]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)C1(O/N=C(\C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CCCC1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1(O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4nnnn4N)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 77.2 %

Procedure:
A solution of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-(1-tert-butoxycarbonylcyclopentyloxyimino)acetic acid (2.80 g, 4.7 mmol), 1-hydroxybenzotriazole (0.73 g, 5.4 mmol) and N,N'-dicyclohexylcarbodiimide (1.07 g, 5.17 mmol) in dimethylacetamide (26 ml) was stirred at room temperature for 2.5 hours. To the solution was added a solution of 7β-amino-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (1.70 g, 5.17 mmol) and triethylamine (1.05 g, 10.3 mmol) in dimethylacetamide (13 ml) and water (1.7 ml), and the mixture was stirred at room temperature for 17 hours. The mixture was acidified with citric acid to pH 3.5 and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated. The residue was treated with isopropyl ether to give pale brown powder of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-(1-tert-butoxycarbonylcyclopentyloxyimino)acetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (3.3 g).
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:30]=[CH:29][C:13]([CH2:14][N:15]2[C:19]3=[N:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:23]=[C:18]3[N:17]=[C:16]2[CH3:28])=[C:12]([Cl:31])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:34]I>CN(C)C=O>[C:1]([N:9]([C:10]1[CH:30]=[CH:29][C:13]([CH2:14][N:15]2[C:19]3=[N:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:23]=[C:18]3[N:17]=[C:16]2[CH3:28])=[C:12]([Cl:31])[CH:11]=1)[CH3:34])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(NC(=O)c4ccccc4)cc3Cl)c2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(N(C)C(=O)c4ccccc4)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.5 %

Procedure:
To a solution of methyl 3-(4-(N-benzoylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (300 mg) in N,N-dimethylformamide (3 ml) was added 60% sodium hydride (in mineral oil, 30.4 mg) at room temperature. After 15 min, methyl iodide (108 mg) was added and the mixture was stirred at room temperature for 2 hr. Ice water was poured thereinto and the mixture was extracted with ethyl acetate. The organic layer was successively washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the objective compound (305 mg) as a pale-yellow powder.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](O)=[O:12])[CH:9]=2)[N:4]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1.[C:24]1([C:30]([NH:33][C:34]([NH:36][NH2:37])=S)([CH3:32])[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.O>CN(C=O)C.CCOC(C)=O>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:12][C:34]([NH:33][C:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)([CH3:32])[CH3:31])=[N:36][N:37]=3)[CH:9]=2)[N:4]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)O)ccc32)cc1
Reactant: CC(C)(NC(=S)NN)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(NC(C)(C)c5ccccc5)o4)ccc32)cc1
Temperature: 25 °C
Yield: 22.7 %

Procedure:
A solution of 3-iodo-1-tosyl-1H-indole-5-carboxylic acid (1.330 g, 3.01 mmol), N-(2-phenylpropan-2-yl)hydrazinecarbothioamide (0.631 g, 3.01 mmol), and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (1.156 g, 6.03 mmol) (Sigma-Aldrich) in DMF (5.0 mL) was heated at 80° C. for 2 h. The solution was cooled to RT. Water (precipitate formed), EtOAc and Celite were added, and the solids were removed by filtration and washed with EtOAc (3×). The organic layer was evaporated to reduce solvent volume. The aqueous layer was then extracted with EtOAc (2×50 mL). The combined organic layers were concentrated in vacuo, and the crude material was purified by flash chromatography (20-100% EtOAc in Hex) to give 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(2-phenylpropan-2-yl)-1,3,4-oxadiazol-2-amine (408.1 mg, 0.682 mmol, 22.62%). MS (ESI, pos. ion) m/z: 599.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37]CC1C=CC(OC)=C(OC)C=1)[C:5]([NH:7][C:8]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][C:9]=1[C:10]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])=[O:11])=[O:6].C(O)(C(F)(F)F)=O.CCOC(C)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([NH:7][C:8]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:23][C:9]=1[C:10]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])=[O:11])=[O:6]
Reactant: COc1ccccc1CCNC(=O)c1cc(Oc2ccccc2)ccc1NC(=O)c1ccc(OCc2ccc(OC)c(OC)c2)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1CCNC(=O)c1cc(Oc2ccccc2)ccc1NC(=O)c1ccc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
A solution of 1E (27 mg, 0.04 mmol) in CH2Cl2 (2 mL) at 0° C. was treated with TFA (100 μL). The reaction was warmed to room temperature and stirred for three hours. The mixture was poured into EtOAc:buffer (1:1, pH 7, 40 mL) and the layers were separated. The organic layer was washed with pH 7 buffer (1×10 mL), dried (Na2SO4), filtered and concentrated to a yellow oil. The crude product was purified by preparative HPLC to afford 1F as a white solid (19 mg, 88%). 1H NMR (Acetone-d6) δ 8.80 (d, 1H, J=7.5 Hz), 8.17 (brs 1H), 8.01 (d, 1H, J=1.8 Hz), 7.81 (d, 1H, J=7.0 Hz), 7.45 (d, 1H, J=1.8 Hz), 7.36 (m, 2H), 7.15 (m, 5H), 6.97 (d, 1H, J=6.6 Hz), 6.89 (d, 1H, J=7.0 Hz), 6.79 (t, 1H, J=7.8 Hz), 3.77 (s, 3H), 3.64 (q, 2H, J=5.28 Hz), 2.93 (t, 2H, J=5.24 Hz). HPLC retention time=3.297 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). m/z=516.9 (M+H+).
Reaction SMILES: C([Li])CCC.[N:6]([CH2:9][CH2:10][C:11]#[CH:12])=[N+:7]=[N-:8].[CH2:13]=[O:14].[Cl-].[NH4+]>C1COCC1>[N:6]([CH2:9][CH2:10][C:11]#[C:12][CH2:13][OH:14])=[N+:7]=[N-:8]
Reactant: C=O
Reactant: C#CCCN=[N+]=[N-]
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCC#CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
n-Butyl lithium (1.6 M in hexane, 18.8 mmol, 11.7 ml) was added dropwise at −78° C. to a solution of 4-azido-1-butyne II-32 (1.28 g, 17.3 mmol) in THF (35 ml). After stirring the resulting green solution for 1 h, paraformaldehyde was added in one portion, the solution was stirred for 5 min, and then warmed to room temperature for 2 h (an orange suspension gradually formed). The reaction mixture was poured into saturated aqueous ammonium chloride (100 ml) and extracted with ether (3×50 ml). The combined extracts were washed with brine (50 ml), dried over sodium sulphate and evaporated to give a yellow oil. This was purified by flash chromatography eluting with pentane/ether 1:1 to afford the title compound II-33 as a pale yellow oil (930 mg, 70.7%): IR (CHCl3) 3600 (m), 3000 (m), 2940 (m), 2880 (m), 2100 (s), 1550 (w), 1380 (m), 1270 (m), 1220 (br), 1140 (m), 1000 (s) cm−1; 1H NMR (500 MHz, CDCl3) δ 4.24-4.22 (m, 2H), 3.37 (t, J=6.8 Hz, 2H), 2.51-2.48 (m, 2H), 1.84 (t, J=6.0 Hz, 1H); 13C NMR (62.9 MHz, CDCl3) δ 77.42, 70.47, 49.68, 19.45.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38].Cl.Cl.[NH:41]1[CH:45]=[CH:44][N:43]=[C:42]1[CH2:46][NH2:47]>>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:47][CH2:46][C:42]3[NH:41][CH:45]=[CH:44][N:43]=3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27]([C:29]4[S:30][CH:31]=[CH:32][CH:33]=4)=[O:28])[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38]
Reactant: Cc1ccc(NC(=O)c2cccs2)cc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NCc1ncc[nH]1
Agent: Cl
Product: Cc1ccc(NC(=O)c2cccs2)cc1-c1nc(NCc2ncc[nH]2)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The title compound was prepared as described in Example 1d from N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-2-thiophenecarboxamide and (1H-imidazol-2-ylmethyl)amine dihydrochloride: LC-MS m/z 570 (M+H)+, 1.70 min (ret time).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[CH2:16]([Sn:20](Cl)([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19].[F:30][C:31]1[N:32]=[CH:33][N:34]2[CH:38]=[CH:37][S:36][C:35]=12.O>C1COCC1>[F:30][C:31]1[N:32]=[CH:33][N:34]2[CH:38]=[C:37]([Sn:20]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:17][CH2:18][CH3:19])[S:36][C:35]=12
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Fc1ncn2ccsc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(F)c2s1
Reaction time: 0.17 h

Procedure:
A 1.0 N lithiumbis(trimethylsilyl)amide/THF solution (3.2 ml) and 0.75 ml of tri-n-butylstannyl chloride were added in that order to a solution of 7-fluoroimidazo[5,1-b]thiazole in dry THF in an argon atmosphere at −78° C. The mixture was stirred at the same temperature for 10 min. Water was added thereto, followed by extraction with ethyl acetate and washing with saturated brine. The extract was dried over anhydrous magnesium sulfate and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=7:1) to give 820 mg of the title compound.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:40]2[C:41]([C:46]#[N:47])=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:39])[N:23]([CH:33]2[CH2:38][CH2:37][CH2:36][O:35][CH2:34]2)[C:24]2[N:25]([N:30]=[CH:31][N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]>C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[C:46]2[NH:3][C:4](=[O:7])[O:5][N:47]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:39])[N:23]([CH:33]2[CH2:38][CH2:37][CH2:36][O:35][CH2:34]2)[C:24]2[N:25]([N:30]=[CH:31][N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n(C2CCCOC2)c2ncnn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n(C2CCCOC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.37 g), sodium hydrogen carbonate (0.6 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 3′-fluoro-4′-{[5-oxo-7-propyl-4-(tetrahydro-2H-pyran-3-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.17 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.07 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.059 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.11 g, 56%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1.[CH3:16]I.O>CN(C=O)C>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[CH3:16])=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=1.[Br:3][C:4]1[CH:5]=[C:6]([N+:13]([O-:15])=[O:14])[C:7]2[C:11]([CH:12]=1)=[N:10][N:9]([CH3:16])[CH:8]=2
Reactant: CI
Reactant: O=[N+]([O-])c1cc(Br)cc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc2c([N+](=O)[O-])cc(Br)cc2n1
Product: Cn1ncc2c([N+](=O)[O-])cc(Br)cc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
60% Sodium hydride (including 40% liquid paraffin as an additive) (213 mg) was added to a solution of 6-bromo-4-nitro-1H-indazole (901 mg) in DMF (19 ml) in an ice bath. Subsequently, the reaction solution was stirred at 0° C. for 15 minutes, then methyl iodide (0.35 ml) was added, and the reaction solution was allowed to react at room temperature for 11 hours. The reaction solution was poured into water, and the deposited precipitate was filtrated to obtain a crude product. The crude product was purified by column chromatography on silica gel (developing solvent:hexane/ethyl acetate) to obtain 6-bromo-1-methyl-4-nitro-1H-indazole and 6-bromo-2-methyl-4-nitro-2H-indazole as a yellow solid, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:22]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:21][NH:20][N:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[CH:21][C:22]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Reactant: Nc1n[nH]cc1-c1cccnc1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc2c(-c3cccnc3)cnn12
Yield: 81.7 %

Procedure:
Reaction of 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (251 mg, 1.0 mmol), prepared from commercially available 4-chloro-acetophenone according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (160 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (306 mg, 82%). MS (ISP) 375.3 [(M+H)+]; mp 188° C.
Reaction SMILES: C[O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12](=O)[CH2:13][C:14](=O)[CH3:15])[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:18][NH:19][NH2:20].O>CO>[OH:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[CH:13]=[C:14]([CH3:15])[N:19]([CH3:18])[N:20]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CNN
Reactant: COc1cccc2oc(C(=O)CC(C)=O)cc12
Solvent: O
Solvent: CO
Product: Cc1cc(-c2cc3c(O)cccc3o2)nn1C
Temperature: -40 °C
Yield: 86.5 %

Procedure:
1-(4-Methoxybenzo(b)furan-2-yl)butan-1,3-dione (1.0 g) was dissolved in methanol (30 ml) and methylhydrazine (0.3 g) was added thereto. The mixture was refluxed under heating for 20 min. The reaction solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/acetone). To the obtained oil was added methylene chloride (30 ml), and the mixture was cooled to −40° C., and boron tribromide (1 ml) was added dropwise. After the completion of the reaction, the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and after filtration, the solvent was evaporated under reduced pressure to give 3-(4-hydroxybenzo(b)furan-2-yl)-1,5-dimethylpyrazole (0.85 g) as a brown oil. Using this and (S)-glycidyl nosylate (0.75 g) and in the same manner as in Starting Material Synthesis Example 1, the title compound (0.53 g) was obtained as a brown oil.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[H-].[Na+].[CH:9](NC(C)C)(C)C.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]C>O1CCCC1>[CH3:3][C:2]([CH3:9])([CH2:4][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:1]([OH:6])=[O:5]
Reactant: CC(C)NC(C)C
Reactant: CCCCCCCCCCBr
Reactant: CC(C)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Isobutyric acid (13.9 ml) was added dropwise to a mixture of 21.1 ml of 62.5% sodium hydride, 93.8 ml of diisopropylamine and 150 ml of tetrahydrofuran (THF) at 30° C. or lower. After refluxing the mixture for 30 minutes, to the mixture was added 31.0 ml of a 1.6M n-butyl lithium-hexane solution at 10° C. or lower and the mixture was stirred for 15 minutes at the same temperature and for 2 hours at room temperature. At 10° C. or lower, 5.76 g of 1-bromodecane was added dropwise to the mixture. The mixture was stirred at the same temperature for one hour and then at room temperature overnight. After adding 300 ml of ice water, the reaction mixture was washed with diethyl ether, and the aqueous layer was adjusted to pH=1 with conc. hydrochloric acid and extracted with isopropyl ether. After the extract was washed and dried, the solvent was removed under reduced pressure to give 2.36 g of 2,2-dimethyllauric acid (state: pale yellow oily product).