Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:34])[C@@H:24]([C:25](=[O:33])[CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@H:21]3[S:20][C:19]([NH2:35])=[C:18]2[CH2:36][C:37]2[S:41][CH:40]=[CH:39][CH:38]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1>C(N(CC)CC)C>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:34])[C@@H:24]([C:25](=[O:33])[CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C@H:21]3[S:20][CH:19]([NH2:35])[C:18]=2[CH2:36][C:37]2[S:41][CH:40]=[CH:39][CH:38]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1=C(Cc2cccs2)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](C(=O)Cc3ccccc3)[C@H]2S1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC1S[C@@H]2[C@H](C(=O)Cc3ccccc3)C(=O)N2C(C(=O)OC(c2ccccc2)c2ccccc2)=C1Cc1cccs1

Procedure:
A solution of 10.2 g of 7β-phenylacetyl-amino-3-(2-thenyl)-ceph-2-em-4ξ-carboxylic acid diphenylmethyl ester in 130 ml of a 9:1-mixture of pyridine and triethylamine is left to stand in the dark and under nitrogen for 31/2 days at room temperature, then evaporated under reduced pressure. The residue is evaporated several times to dryness with toluene and then triturated with ethyl acetate. The solid residue is recrystallised from ethyl acetate and yields the somewhat impure 7β-phenylacetyl-amino-3-(2-thenyl)-ceph-3-em-4-carboxylic acid diphenylmethyl ester. The mother liquors of trituration and crystallisation are evaporated to dryness and yield on evaporation a mixture of the 7β-phenylacetylamino-3-(2-thenyl)-ceph-2-em-4ξ-carboxylic acid diphenylmethyl ester and the 7β-phenylacetyl-amino-3-(2-thenyl)-ceph-3-em-4-carboxylic acid diphenylmethyl ester which is chromatographed on 160 g of silica gel. Elution is performed with methylene chloride containing 2% of ethyl acetate, fractions of 200 ml (of 100 ml from fraction 9) being taken. Fractions 5-8 yield some impure 7β-phenylacetyl-amino-3-(2-thenyl)-ceph-3-em-4-carboxylic acid diphenylmethyl ester and fractions 9-11 some impure 7β-phenylacetyl-amino-3-(2-thenyl)ceph-2-em-4ξ-carboxylic acid diphenylmethyl ester. The product of fractions 5-8 is crystallised from ethyl acetate and combined with the first crystalline product and chromatographed on 60 g of silica gel. Elution is performed with methylene chloride containing 0.5% of ethyl acetate, fractions of 60 ml being taken. Fractions 7-9 yields the pure 7β-phenylacetyl-amino-3-(2-thenyl)-ceph-3-em-4-carboxylic acid diphenylmethyl ester, which after crystallisation from ethyl acetate melts at 184°C; [α]D20 = -65° ± 1° (c = 0.968 in chloroform): thin-layer chromatogram (silica gel): Rf = 0.46 (system: toluene/ethyl acetate 4:1) and Rf = 0.57 (system: toluene/acetone 9:1); ultraviolet absorption spectrum (in 95% ethanol): λmax = 264μ (ε = 9600); infrared spectrum (in mineral oil); characteristic bands at 2,99μ, 5,59μ, 5,77μ, 5,98μ, 6,10μ and 6,50μ.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.[CH:8]1(O)[CH2:11][CH2:10][CH2:9]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH:8]1([O:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: OC1CCC1
Reactant: Oc1ccncc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OC2CCC2)ccn1
Reaction time: 0.17 h
Yield: 49.9 %

Procedure:
Pyridin-4-ol (6.0 g, 63.09 mmol), cyclobutanol (5.00 g, 69.40 mmol) and triphenylphosphine (18.20 g, 69.40 mmol) were added to THF (250 mL) and stirred for 10 minutes. To this was slowly added diisopropylazodicarboxylate (13.49 mL, 69.40 mmol). Once the addition was complete the reaction was stirred at 50° C. for 1 hour. The solvent was evaporated and the crude residue was dissolved in diethyl ether. To this was added a small amount of triphenylphoshine oxide and the reaction was stirred for 30 minutes to afford a solid, this was filtered and discarded. The solvent was evaporated and the pale yellow gum was acidified with 2.0M HCl, extracted with diethyl ether (1×75 mL) and the aqueous was then basified with solid potassium hydroxide. This was then extracted with diethyl ether (3×75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford yellow gum. This was purified by distillation at 0.60 mBar, collecting fractions that distilled at 80° C. to afford the desired compound as a colourless oil (4.70 g, 49.9%); 1H NMR (400.132 MHz, CDCl3) δ 1.78-1.66 (1H, m), 1.95-1.86 (1H, m), 2.24-2.14 (2H, m), 2.51-2.43 (2H, m), 4.69 (1H, quintet), 6.70 (2H, d), 8.40 (2H, d); m/z (LC-MS, ESI+), RT=1.76 (M+H 150).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1.C([Li])CCC.CCCCCC.[CH2:22]([CH:24]([C:27]1[C:28]2[N:29]([C:34](I)=[C:35]([CH3:37])[N:36]=2)[N:30]=[C:31]([CH3:33])[CH:32]=1)[CH2:25][CH3:26])[CH3:23]>C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[C:34]1[N:29]2[N:30]=[C:31]([CH3:33])[CH:32]=[C:27]([CH:24]([CH2:22][CH3:23])[CH2:25][CH3:26])[C:28]2=[N:36][C:35]=1[CH3:37]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Clc1csc2ncccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(CC)c1cc(C)nn2c(-c3sc4ncccc4c3Cl)c(C)nc12
Temperature: -78 °C
Reaction time: 0.05 h

Procedure:
250 mg of 3-Chloro-thieno[2,3-b]pyridine (1.5 mmol) is dissolved in 2.0 ml of dry THF and cooled to −78° C. 0.59 ml of n-butyl lithium 2.5 M in hexane (1.5 mmol) is added slowly and stirred at room temperature for 3 min and cooled to −78° C. 3.0 ml of 0.5 M ZnCl2 in THF (1.5 mmol) is added and stirred at room temperature for 20 min. 343 mg of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (1.0 mmol) and 41 mg of PdCl2(dppf) (0.05 mmol) are added and the reaction vial is capped with a Teflon cap and heated at 80° C. overnight. The reaction mixture is concentrated and applied onto a chromatography silica-gel column (Hexane:AcOEt=3:1); mass spectrum (m/e): 385; 1H-NMR (CDCl3): 8.66 (dd, 1H, J=4.5 Hz, 1.5 Hz), 8.10 (dd, 1H, J=8.1 Hz, 1.5 Hz), 7.44 (1H, J=8.1 Hz, 4.5 Hz), 6.74 (s, 1H), 3.33 (m, 1H), 2.55 (s, 3H), 2.53 (s, 3H), 1.85 (m, 4H), 0.89 (t, 6H, J=7.5 Hz) ppm.
Reaction SMILES: C([O:5][C:6](=[O:60])[C@@H:7]([NH:11][C:12]([C@@H:14]1[CH2:18][C@@H:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=3)[N:23]=[C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:21]=2)[CH2:16][C@H:15]1[C:38](=[O:59])[NH:39][C@H:40]([C:45](=[O:58])[NH:46][C@@H:47]([CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1)[C:48](=[O:51])[NH:49][CH3:50])[C:41]([CH3:44])([CH3:43])[CH3:42])=[O:13])[CH2:8][CH2:9][CH3:10])(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:52]1([C@H:47]([NH:46][C:45]([C@@H:40]([NH:39][C:38]([C@@H:15]2[CH2:16][C@H:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:21]=3)[CH2:18][C@H:14]2[C:12]([NH:11][C@@H:7]([CH2:8][CH2:9][CH3:10])[C:6]([OH:60])=[O:5])=[O:13])=[O:59])[C:41]([CH3:42])([CH3:43])[CH3:44])=[O:58])[C:48](=[O:51])[NH:49][CH3:50])[CH2:57][CH2:56][CH2:55][CH2:54][CH2:53]1
Reactant: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)NC)C1CCCCC1)C(C)(C)C)C(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)NC)C1CCCCC1)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.6 %

Procedure:
Compound 44 (21 mg, 0.025 mmol) was dissolved in CH2Cl2 (1.5 mL) and triethylsilane (10 uL, 0.063 mmol) and TFA (1.5 mL) were added. The solution was stirred for 2 hours at room temperature after which the solvents were evaporated and co-evaporated with toluene to provide compound 45 (20 mg, 100%) as a colorless solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[C:17]3=[N:18][CH:19]=[N:20][C:21]([NH2:22])=[C:16]3[C:15](I)=[N:14]2)[CH2:9][CH2:8]1.[CH3:24][O:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[CH:28][C:27]=1[NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[NH2:22][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:13]([CH:10]3[CH2:11][CH2:12][N:7]([CH2:6][C:2]4[NH:3][CH:4]=[CH:5][N:1]=4)[CH2:8][CH2:9]3)[N:14]=[C:15]([C:30]3[CH:29]=[CH:28][C:27]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[C:26]([O:25][CH3:24])[CH:31]=3)[C:16]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Reactant: Nc1ncnc2c1c(I)nn2C1CCN(Cc2ncc[nH]2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn(C3CCN(Cc4ncc[nH]4)CC3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Yield: 41.2 %

Procedure:
1-[1-(1H-2-Imidazolylmethyl)-4-piperidyl]-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (127 mg, 0.299 mmol), tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (115 mg, 0.329 mmol), palladium tetrakistriphenyphosphine (21 mg, 0.018 mmol) and sodium carbonate (76 mg, 0.718 mmol) were mixed with ethylene glycol dimethyl ether (3 mL) and water (1.5 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5) as mobile phase to give tert-butyl N-(4-{4-amino-1-[1-(1H-2-imidazolylmethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)carbamate (64 mg, 41%). 1H NMR (DMSO-d6) δ 1.48 (m, 9H), 1.87 (m, 2H), 2.23 (m, 4H), 2.94 (m, 2H), 3.56 (s, 2H), 3.88 (s, 3H), 4.66 (m, 1H), 6.92(s, 2H), 7.21 (m, 2H), 7.90 (d, J=8.14, 1H), 8.04 (s, 1H), 8.22 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCCCC1)C.C(Cl)(=O)C(C)(C)C.[CH3:35][O:36][C:37](=[O:47])[C@H:38]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[NH2:39].Cl>ClCCl.N1C=CC=CC=1>[CH3:35][O:36][C:37](=[O:47])[C@H:38]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[NH:39][C:17](=[O:19])[C@H:12]([CH2:13][C:14](=[O:16])[NH2:15])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: CCN1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.04 h
Yield: 68 %

Procedure:
A solution of benzyloxycarbonylasparagine (13.3 g; 50 mmoles), N-ethylpiperidine (7.0 ml) and pyridine (5.0 ml) in dichloromethane (100 ml) cooled to -20° C. is treated under constant stirring with pivaloylchloride (6.3 ml); the mixture is then stirred and cooled (0° C.) for 8 minutes. After that, within 2 to 3 minutes, a solution of phenylalanine methyl ester, liberated from its hydrochloride (10.7 g; 50 mmoles) by the addition of N-ethylpiperidine (7.0 ml), in dichlormethane (100 ml) is added. The reaction mixture is stirred for an additional 2 hours at room temperature, the precipitated crystalline substance is collected on filter and triturated successively with 1 M hydrochloric acid, water, 5% aqueous sodium hydrogencarbonate solution and water. Crystallization from methanol yields 14.5 g (68%) of the title product, melting at 196° -197° C. An analytical sample is crystallized from dimethylformamide and 2-propanol, and the m.p. remains unchanged. Chromatography: Rf 0.71/S1, 0.75/S2. Optical rotation [α]D20 -2.0° (c 0.2; dimethylformamide). The elemental composition corresponds to the summary formula C22H25N3O6.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:13]([O-])=O)[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[Sn](Cl)Cl.O>CN(C)C=O>[NH2:13][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([Br:1])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Br)c(O)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(N)c(O)c(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 205 %

Procedure:
To a solution of methyl 3-bromo-4-hydroxy-5-nitrobenzoate (2.00 g, 7.25 mmol) in N,N-dimethylformamide (36 mL) was slowly added tin(II) chloride dehydrate (5.50 g, 24.4 mmol). The mixture was stirred at ambient temperature. After 10 min, water was added, and organics were extracted using ethyl acetate (5×). Combined organics were dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→85% dichloromethane/methanol) gave the title compound (3.657 g, 50% purity). LC-MS [M]=246.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:14])[CH3:13].[CH3:15][O:16][CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1.[OH-].[Na+].Cl>C(O)C>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:14])[CH:13]=[CH:23][C:22]1[CH:21]=[CH:20][C:19]([O:18][CH2:17][O:16][CH3:15])=[CH:26][CH:25]=1
Reactant: COc1cc(O)c(C(C)=O)c(OC)c1
Reactant: COCOc1ccc(C=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCOc1ccc(C=CC(=O)c2c(O)cc(OC)cc2OC)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 28.3 %

Procedure:
To a stirred solution containing 1.57 g (8 m moles) of 2'-hydroxy-4',6'-dimethoxyacetophenone and 1.33 g (8 m moles) of 4-(methoxymethoxy)benzaldehyde in 3 ml of ethanol, there were added 30 ml of 15% by volume aqueous sodium hydroxide. After being stirred at room temperature for 2 days, the mixture was poured into 70 ml of ice-water. The pH was adjusted to 7 by adding hydrochloric acid, and the mixture was extracted with two 150 ml portions of dichloromethane. The combined extracts were washed with water, dried over sodium sulfate and then evaporated. The oily residue was crystallized from methanol to yield 780 mg of 2'-hydroxy-4',6'-dimethoxy-4-(methoxymethoxy)chalcone as yellow needles: mp 104.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:25][CH2:24][C:19]3([CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[C:26]([CH2:28][C:29](O)=[O:30])#[N:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:25][CH2:24][C:19]3([CH2:23][N:22]([C:29](=[O:30])[CH2:28][C:26]#[N:27])[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cc1cnc(Nc2cnn(C)c2)nc1NC1CCC2(CCNC2)CC1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CCC2(CC1)CCN(C(=O)CC#N)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
To a solution of 5-methyl-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(2-azaspiro[4.5]decan-8-yl)pyrimidine-2,4-diamine (186 mg, 0.545 mmol), 2-cyanoacetic acid (48.4 mg, 0.569 mmol) in a mixture of DCM (32 mL) and DMF (8 mL) were added HATU (423.4 mg, 1.087 mmol) and Et3N (0.21 g, 2.075 mmol). After addition, the reaction mixture was stirred at rt for 2 h, quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the title compound as a beige solid (170 mg, 76.4%).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[NH:4][N:3]=1.O=[C:12]([CH:19]([CH3:21])[CH3:20])[CH2:13][C:14](OCC)=[O:15].Cl>C(O)(=O)C>[OH:15][C:14]1[N:3]2[N:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=[C:2]2[N:1]=[C:12]([CH:19]([CH3:21])[CH3:20])[CH:13]=1
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: COC(=O)c1nc(N)n[nH]1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)c1nc2nc(C(C)C)cc(O)n2n1
Temperature: 25 °C
Yield: 55.6 %

Procedure:
A mixture of 3-amino-5-methoxycarbonyl-s-triazole (60 g) and ethyl 3-oxo-4-methylvalerate (65 g) in 600 ml of acetic acid was refluxed for five hours, the reaction mixture was cooled to room temperature, its pH was lowered to 1 to 2 with concentrated hydrochloric acid, and the separated crystals were recrystallized from ethanol, affording 54 g of the objective compound as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:17]2[CH:16]=[C:15]3[C:7]([C:8]4[CH:9]=[C:10]5[C:20]([CH3:21])=[CH:19][C:18]([CH3:23])([CH3:22])[C:11]5=[CH:12][C:13]=4[CH2:14]3)=[CH:6][C:5]=2[C:4]([CH3:24])=[CH:3]1.C([Li])CCC.CCCCCC.[C:37]1([CH3:56])[CH:42]=[CH:41][C:40]([C:43]([C:49]2[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=2)=[C:44]2[CH:48]=[CH:47][CH:46]=[CH:45]2)=[CH:39][CH:38]=1.Cl>O1CCCC1.C(OCC)C>[CH3:1][C:2]1([CH3:25])[C:17]2[CH:16]=[C:15]3[C:7]([C:8]4[CH:9]=[C:10]5[C:20]([CH3:21])=[CH:19][C:18]([CH3:23])([CH3:22])[C:11]5=[CH:12][C:13]=4[CH2:14]3)=[CH:6][C:5]=2[C:4]([CH3:24])=[C:3]1[C:43]([CH:44]1[CH:45]=[CH:46][CH:47]=[CH:48]1)([C:40]1[CH:39]=[CH:38][C:37]([CH3:56])=[CH:42][CH:41]=1)[C:49]1[CH:50]=[CH:51][C:52]([CH3:55])=[CH:53][CH:54]=1
Reactant: CC1=CC(C)(C)c2cc3c(cc21)-c1cc2c(cc1C3)C(C)(C)C=C2C
Reactant: Cc1ccc(C(=C2C=CC=C2)c2ccc(C)cc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1=CC(C)(C)c2cc3c(cc21)-c1cc2c(cc1C3)C(C)(C)C(C(c1ccc(C)cc1)(c1ccc(C)cc1)C1C=CC=C1)=C2C
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 29.6 %

Procedure:
To a 200-ml two-neck flask equipped with a magnetic stirrer, a three-way cock and a 50 ml dropping funnel, 749 mg (2.29 mmol) of 1,1,3,6,8,8-hexamethyl-1H,8H-dicyclopenta[b,h]fluorene and 30 ml of tetrahydrofuran were charged under nitrogen atmosphere. 1.56 ml (2.43 mmol) of 1.56 mol/l n-butyllithium/hexane solution was gradually added thereto, while cooling it in an ice water bath, and the mixture was stirred at room temperature for 6.5 hours. 718 mg (2.78 mmol) of 6,6-di-p-tolylfulvene dissolved in 30 ml of tetrahydrofuran in advance was gradually added thereto over 20 minutes using the dropping funnel, while cooling it in a methanol/dry ice bath. The temperature of the reaction solution was gradually elevated back to room temperature, and the solution was stirred at room temperature for 20 hours. 50 ml of 1 N hydrochloric acid was gradually added thereto, and 50 ml of diethyl ether was further added to the mixture. The organic layer was separated, washed twice with 50 ml of water, once with 50 ml of saturated solution of salt. After the solution was dried over magnesium sulfate, the solvent was distilled off, and the obtained product was purified by column chromatography. The production quantity was 397 mg (0.679 mmol), and the yield was 29.6%. Identification was performed by 1H-NMR spectrum and FD-MS spectrum. The measurement results are shown as follows.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18]OS(C)(=O)=O)[O:15][N:14]=3)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.C(O)(C)C.[OH-].[NH4+:29]>O1CCCC1.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][NH2:29])[O:15][N:14]=3)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: CS(=O)(=O)OCc1cc(-c2ccc(-c3ccncc3)cc2)no1
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NCc1cc(-c2ccc(-c3ccncc3)cc2)no1
Temperature: 25 °C

Procedure:
To a flame dried flask containing (R)-4,5-Dihydro[3-[4-(4-pyridinyl)phenyl]-5-(hydroxymethyl)]isoxazole (440 mg, 1.73 mmol) in methylene chloride (20 mL) at 0° C. under an inert atmosphere is added triethylamine (0.36 mL, 2.60 mmol) and methanesulfonyl chloride (0.14 mL, 1.82 mmol). The reaction is slowly warmed to ambient temperature, stirred 3 hours, and quenched with water (25 mL). The organic phase is separated, washed with saturated NaHCO3 (25 mL) and saline (25 mL), dried over sodium sulfate and concentrated in vacuo to give crude (R)-4,5-dihydro[3-[4-(4-pyridinyl)phenyl]-5-[[(methylsulfonyl)oxy]methyl]isoxazole. The crude (R)-4,5-dihydro[3-[4-(4-pyridinyl)phenyl]-5-[[(methylsulfonyl)oxy]-methyl]isoxazole (580 mg, 1.73 mmol) is dissolved in tetrahydrofuran (4 mL), isopropanol (4 mL), and concentrated ammonium hydroxide (4 mL) in a thick wall resealable vessel and heated to 100-110° C. for 15 hours. The reaction is cooled to ambient temperature, diluted with ethyl acetate (50 mL), washed with saline (20 mL), dried over sodium sulfate and concentrated in vacuo to give crude (R)-4,5-dihydro[3-[4-(4-pyridinyl)phenyl]-5-(aminomethyl)isoxazole. The crude (R)-4,5-dihydro[3-[4-(4-pyridinyl)phenyl]-5-(aminomethyl)isoxazole (320 mg, 1.57 mmol) is dissolved in methylene chloride (15 mL) and cooled to 0° C. under an inert atmosphere. Pyridine (0.31 mL, 3.78 mmol) and acetic anhydride (0.15 mL, 1.57 mmol) are added to the cooled solution and stirred 20 hours at ambient temperature. The reaction is concentrated in vacuo, diluted with methylene chloride (50 mL), washed with saline (25 mL), dried over sodium sulfate, concentrated in vacuo and chromatographed on silica gel (230-400 mesh, 200 mL), eluting with chloroform/methanol (97/3). The appropriate fractions are combined (Rf =0.14, TLC, chloroform/methanol, 95/5) and concentrated in vacuo to give the title compound, mp 244-245° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10](=[O:12])[CH3:11])=[N:2]1.Br[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:21])[O:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[C:10]([C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:1]([CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:21])[O:19][CH3:20])[N:2]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1n[nH]c2ncccc12
Reactant: COC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)NCCCn1nc(C(C)=O)c2cccnc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1-(1H-pyrazolo[3,4-b]pyridin-3-yl)ethanone (500 mg) and methyl (3-bromopropyl)carbamate (912 mg) in N,N-dimethylformamide (5 mL) was added potassium carbonate (864 mg), and the mixture was stirred at room temperature for 3 days. To the reaction solution was added ethyl acetate, and the mixture was washed with saturated saline, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=95/5→1/1) to give methyl [3-(3-acetyl-1H-pyrazolo-[3,4-b]pyridin-1-yl)propyl]carbamate) [REx(103-2)] (308 mg) as a red oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[CH:14][CH:13]=1.[CH3:24][N:25]1[CH:29]=[C:28]([S:30](Cl)(=[O:32])=[O:31])[N:27]=[CH:26]1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([S:30]([C:28]1[N:27]=[CH:26][N:25]([CH3:24])[CH:29]=1)(=[O:32])=[O:31])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[CH:16][CH:17]=1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: COC(=O)CCCCCCNCc1ccc(-c2nccs2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCN(Cc1ccc(-c2nccs2)cc1)S(=O)(=O)c1cn(C)cn1

Procedure:
The title compound of Step B was prepared from 7-(4-thiazol-2-yl-benzylamino)-heptanoic acid methyl ester of Step A and 1-methyl-1H-imidazole-4-sulfonyl chloride following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.90 (d, 2H), 7.85 (d, 1H), 7.49 (s, 1H), 7.43 (m, 3H), 7.32 (d, 1H), 4.47 (s, 2H), 3.74 (s, 3H), 3.62 (s, 3H), 3.20 (t, 2H), 2.20 (t, 2H), 1.48 (m, 2H), 1.40 (m, 2H), 1.15 (m, 4H); MS 477 (M+1).