Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C([Li])CCC.CN1C(=O)N(C)CCC1.I[C:38]1[C:51](I)=[CH:50][C:49]2[C:40](=[C:41]([CH2:56][CH2:57][CH3:58])[C:42]3[C:47]([C:48]=2[CH2:53][CH2:54][CH3:55])=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:39]=1>C1COCC1.Cl[Cu]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:44]3[C:45](=[CH:46][C:47]4[C:42]([CH:43]=3)=[C:41]([CH2:56][CH2:57][CH3:58])[C:40]3[C:49](=[CH:50][CH:51]=[CH:38][CH:39]=3)[C:48]=4[CH2:53][CH2:54][CH3:55])[C:15]([C:16]3[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=3)=[C:14]3[C:9]=2[CH2:10][CH2:11][CH2:12][CH2:13]3)=[CH:6][CH:7]=1
Reactant: CCCc1c2ccccc2c(CCC)c2cc(I)c(I)cc12
Reactant: Brc1ccc(C#CCCCCC#Cc2ccc(Br)cc2)cc1
Agent: Cl[Cu]
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCCc1c2ccccc2c(CCC)c2cc3c(-c4ccc(Br)cc4)c4c(c(-c5ccc(Br)cc5)c3cc12)CCCC4
Temperature: 50 °C
Yield: 57 %

Procedure:
1,8-Bis(p-bromophenyl)-1,7-octadiyne (0.191 g, 0.459 mmol) was added at −78° C. to a THF solution of bis(η5-cyclopentadienyl)dibutylzirconium in THF, which was prepared from bis(η5-cyclopentadienyl)dichlorozirconium (0.161 g, 0.551 mmol) and n-butyl lithium (0.7 ml, 1.6 M, 1.1 mol/l). The mixture was then allowed to stand at room temperature for an hour. CuCl (0.095 g, 0.964 mmol), DMPU (0.17 ml, 1.38 mmol) and 2,3-diiodo-9,10-dipropylanthracene (0.236 g, 0.459 mmol) were added to the mixture. After heating at 50° C. for an hour, the solvent in the mixture was removed in vacuum. Column chromatography (chloroform) was performed. By recrystallization in chloroform/methanol, the title compound (0.177 g) was obtained as orange red. The isolation yield was 57%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[CH:25]=[N:26][N:27]4[CH:32]=[CH:31][CH:30]=[N:29][C:28]=34)=[O:23])[C:18]([C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=3[O:40][CH:41]([F:43])[F:42])=[N:17]2)[CH2:10][CH2:9]1.Br[CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47]>CN(C=O)C>[Cl:39][C:37]1[CH:36]=[CH:35][C:34]([O:40][CH:41]([F:43])[F:42])=[C:33]([C:18]2[C:19]([NH:21][C:22]([C:24]3[CH:25]=[N:26][N:27]4[CH:32]=[CH:31][CH:30]=[N:29][C:28]=34)=[O:23])=[CH:20][N:16]([CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][CH:8]([NH:7][CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:9][CH2:10]3)[N:17]=2)[CH:38]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC1CCN(CCn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNC1CCN(CCn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
Potassium carbonate (98 mg, 0.71 mmol) was added to a solution of N-[1-[2-(4-aminopiperidin-1-yl)ethyl]-3-[5-chloro-2-(difluoromethoxy)phenyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (290 mg, 0.55 mmol) and tert-butyl 2-bromoacetate (96 mg, 0.49 mmol) in DMF (5 mL). The resulting mixture was stirred at 50° C. overnight. The resulting mixture was concentrated under vacuum. The residue was purified by flash chromatography on silica eluting with 15% MeOH in DCM to afford 150 mg (43%) of tert-butyl 2-[[1-(2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]ethyl)piperidin-4-yl]amino]-acetate as a yellow solid. LCMS (Method 24) [M+H]+=645.2, RT=1.39 min.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH:9]=[CH:8][N:7]=1)([CH3:5])[C:3]#[N:4].[NH2:21][C:22]1[C:23]([C:29]2[O:33][C:32]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][N:41]([CH3:49])[C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:36][CH:35]=3)=[N:31][N:30]=2)=[N:24][C:25](Br)=[CH:26][N:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:21][C:22]1[C:23]([C:29]2[O:33][C:32]([C:34]3[CH:35]=[CH:36][C:37]([CH2:40][N:41]([CH3:49])[C:42](=[O:48])[O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[CH:38][CH:39]=3)=[N:31][N:30]=2)=[N:24][C:25]([C:10]2[CH:9]=[CH:8][N:7]=[C:6]([C:2]([C:3]#[N:4])([CH3:1])[CH3:5])[CH:11]=2)=[CH:26][N:27]=1
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(Br)cnc3N)o2)cc1)C(=O)OC(C)(C)C
Reactant: CC(C)(C#N)c1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(Cc1ccc(-c2nnc(-c3nc(-c4ccnc(C(C)(C)C#N)c4)cnc3N)o2)cc1)C(=O)OC(C)(C)C
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of 2-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]propane nitrile (103 mg, 0.3784 mmol) in dioxane (1.133 mL) was added of tert-butyl N-[[4-[5-(3-amino-6-bromo-pyrazin-2-yl)-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (174.6 mg, 0.3784 mmol) and reaction was treated with 2 M aqueous solution of sodium carbonate (567.5 μL of 2 M, 1.135 mmol). The reaction mixture was degassed with 5× vacuum/nitrogen cycles. Then Pd(PPh3)4 (43.85 mg, 0.03795 mmol) was added to the reaction mixture. The reaction mixture was degassed further with 5× vacuum/nitrogen cycles and the reaction mixture was stirred in a microwave at 150° C. for 30 minutes. The reaction was diluted with ethyl acetate and aqueous sodium bicarbonate solution. The organic extracts were separated and washed with brine (×1), dried over MgSO4, filtered and concentrated in vacuo to give a black oil. Taken onto the next step without further purification (199.3 mg, assumed 100% yield).
Reaction SMILES: [NH:1]([C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].O.Cl.CO[CH:18](OC)[CH2:19][CH:20](OC)OC>CO>[N:1]1([C:3]2[NH:12][C:11](=[O:13])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=2)[CH:20]=[CH:19][CH:18]=[N:2]1
Reactant: NNc1nc2ccccc2c(=O)[nH]1
Reactant: COC(CC(OC)OC)OC
Agent: Cl
Solvent: CO
Solvent: O
Product: O=c1[nH]c(-n2cccn2)nc2ccccc12
Yield: 70.2 %

Procedure:
A mixture of 35.2 g (0.2 mole) of 2-hydrazino-4(3H)-quinazolinone, 250 ml of water, 30 ml of methanol and 36.6 ml of concentrated hydrochloric acid is stirred with 36.08 g (0.22 mole) of 1,1,3,3-tetramethoxy-propane at 40° C. The desired product precipitates after a short time from the solution initially formed. After a reaction of one hour in total at 40° C., 29.8 g of 2-(1H-pyrazol-1-yl)-4(3H)-quinazolinone (melting point 148°-50°) are isolated.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[C:7]([CH:8]=[O:9])[C:6]([OH:11])=[CH:5][CH:4]=1)#[CH:2].[CH2:12]([N:19]=[N+:20]=[N-:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CC(O)(C)C.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:12]([N:19]1[CH:2]=[C:1]([C:3]2[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH:10]=2)[CH:8]=[O:9])[N:21]=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#Cc1ccc(O)c(C=O)c1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: O=Cc1cc(-c2cn(Cc3ccccc3)nn2)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
5-ethynylsalicylaldehyde (2{26}, 50 mg, 0.34 mmol, 1.0 equiv.) and benzyl azide (91 mg, 86 μL, 0.68 mmol, 2.0 equiv.) were suspended in 1:1 t-BuOH:H2O (1.2 mL). Sodium L-ascorbate (24 mg in 100 μL H2O, 0.34 mmol, 1.0 equiv.) was added, followed by copper (II) sulfate pentahydrate (67 mg in 200 μL H2O, 0.10 mmol, 0.33 equiv.). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with H2O (10 mL), and the aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over Mg504, filtered, and concentrated. The crude product was purified by silica gel column chromatography (25-50% EtOAc/hexanes) to yield 2{27} (47.5 mg, 0.17 mmol, 50.0%) as an off-white solid. 1H-NMR (500 MHz, CDCl3): δ 11.03 (s, 1H), 9.92 (s, 1H), 8.07 (d, 1H, J=2.5 Hz), 7.86 (dd, 1H, J=2.0, 8.0 Hz), 7.65 (s, 1H), 7.41-7.35 (m, 3H), 7.31 (dd, 2H, J=2.0, 7.5 Hz), 7.01 (d, 1H, J=8.5 Hz), 5.57 (s, 2H). 13C-NMR (125 MHz, CDCl3): δ 196.5, 161.3, 134.4, 134.2, 130.6, 129.1, 128.8, 128.1, 124.9, 122.9, 120.6, 118.9, 118.1, 54.3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:26][CH2:27][C:28](Cl)=[O:29]>C1COCC1>[Cl:26][CH2:27][C:28]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[N:13]=[C:12]([OH:14])[CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[N:9]=2)=[CH:4][CH:3]=1)=[O:29]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccc(-c2nc(O)cc(C(F)(F)F)n2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of compound of example 15 (0.10 g, 0.39 mmol) in THF (6 mL), at 0° C. was added triethylamine (0.059 g, 0.58 mmol) and chloroacetylchloride (0.066 g, 0.58 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×15 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][N:6]=1.[Cl:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:16]=1[C:17]([N:19]=[C:20]=[O:21])=[O:18]>C(OCC)(=O)C>[Cl:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:16]=1[C:17]([NH:19][C:20]([NH:11][C:8]1[CH:7]=[N:6][C:5]([O:4][CH2:3][C:2]([F:1])([F:12])[F:13])=[CH:10][CH:9]=1)=[O:21])=[O:18]
Reactant: Nc1ccc(OCC(F)(F)F)nc1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Solvent: CCOC(C)=O
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1ccc(OCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-(2,2,2-Trifluoroethoxy)-5-aminopyridine (0.5 gram) and 2,6-dichlorobenzoyl isocyanate (0.5 gram) were mixed in ethyl acetate, and the reaction mixture stirred overnight (about 18 hours) at room temperature. Solvent was removed by evaporation and the product residue crystallized from ethyl acetate-hexanes, yield 0.6 gram, m.p., 146°-148° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][C:12](=O)[CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16].[N:18]1([CH2:24][CH2:25][OH:26])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+].[OH-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH:12]([N:21]3[CH2:22][CH2:23][N:18]([CH2:24][CH2:25][OH:26])[CH2:19][CH2:20]3)[CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[N+:15]([O-:17])=[O:16]
Reactant: COc1c([N+](=O)[O-])ccc2c1CCCC(=O)C2
Reactant: OCCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1c([N+](=O)[O-])ccc2c1CCCC(N1CCN(CCO)CC1)C2
Temperature: 50 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
1-Methoxy-2-nitro-5,7,8,9-tetrahydro-benzocyclohepten-6-one (15.09 g, 64.15 mmol) in methylene chloride (870 ml)treated with 2-Piperazin-1-yl-ethanol (3 eq) followed by acetic acid (10 eq). The mixture was stirred at 50° C. for 2 hrs and cooled to 0° C. and sodium triacetoxyborohydride (4 eq) was added, then warmed to RT and stirred. After a few hours starting material was still present. Added 0.4 eq further of sodium triacetoxyborohydride, then again after 6 hours. Stirred overnight. Poured into a solution of sat. aq. Sodium bicarbonate and ice and made basic to pH 10 with 1N sodium hydroxide, extracted 2× dichloromethane, dried MgSO4, filtered and concentrated. This material was taken up into ethanol and HCl ethanol was added. The resulting precipitate was triturated for 2 hours then filtered. The solid was free-based using NaOH followed by sodium bicarbonate and extracted into dichloromethane to give the title compound (19 g, 85% yield). 1H-NMR (400 MHz, CDCl3) 7.56 (d, J=8.2 Hz, 1H), 7.00 (d, J=8.2 Hz, 1H), 3.82 (s, 3H), 3.63-3.06 (m, 2H), 3.29-3.24 (m, 1H), 3.00-2.86 (m, 3H), 2.72-2.67 (m, 2H), 2.60-2.51 (m, 8H), 2.46-2.37 (m, 2H), 2.12-2.07 (m, 2H), 1.87-1.78 (m,1H), 1.37-1.29 (m, 1H). LC/MS (ESI+) m/z=350 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[NH:8][C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([Cl:29])=[CH:11][N:10]=2)=[O:5])[CH3:2].Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[N:8]([CH2:32][C:33](=[O:34])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([Cl:29])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)cnc2[nH]c1=O
Reactant: O=C(CBr)c1ccccc1
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)cnc2n(CC(=O)c2ccccc2)c1=O

Procedure:
This compound was prepared from 6-chloro-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (82) and 2-bromoacetophenone according to General Procedure B. Yield 333 mg (59%), MP 227° C.; 1H-NMR (DMSO-d6): δ 1.29 (t, J=7.2 Hz, 3H), 3.20 (m, 4H), 3.92 (m, 4H), 4.32 (q, J=7.2 Hz, 2H), 5.87 (s, 2H), 7.17 (dd, J=3.6, 4.8 Hz, 1H), 7.48 (dd, J=1.2, 3.6 Hz, 1H), 7.61 (m, 2H), 7.73 (m, 1H), 7.81 (dd, J=1.2, 4.8 Hz, 1H), 8.11 (m, 2H), 8.32 (d, J=2.6 Hz, 1H), 8.64 (d, J=2.8 Hz, 1H); EIMS: 565 (M+1). Anal. (C28H25ClN4O5S) C, H, N.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:8][CH2:7][CH2:6][CH2:5][CH:4]=1.[H-].[Na+].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CN(C)C=O>[CH2:11]([O:1][CH2:2][C:3]1[O:8][CH2:7][CH2:6][CH2:5][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCC1=CCCCO1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C1=C(COCc2ccccc2)OCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of 5.71 g of 6-hydroxymethyl-3,4-dihydro-2H-pyran dissolved in 100 ml of dimethylformamide was added dropwise to a mixture of 2.18 g of sodium hydride (as a 55% w/w dispersion in mineral oil) and dimethylformamide, whilst ice-cooling. The mixture was then stirred at room temperature for 1 hour, after which 6.33 g of benzyl chloride were added to it. The mixture was stirred for 16 hours, after which it was poured into 1 liter of water. The resulting mixture was then extracted twice with ethyl acetate. The combined extracts were washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The oily residue (13 g) was subjected to column chromatography through 200 g of silica gel. 9.40 g of the title compound were obtained as a colorless oil from those fractions eluted with mixtures of diethyl ether and hexane ranging from 4:100 to 5:100 by volume. It boiled at 125°-130° C. (bath temperature)/1 mmHg (133 Pa).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:5][N:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:19]>COCCOC.CCCCCCC>[F:13][C:2]([F:1])([F:12])[C:3]1[C:11]2[C:6](=[N+:7]([O-:19])[CH:8]=[CH:9][CH:10]=2)[NH:5][N:4]=1
Reactant: FC(F)(F)c1n[nH]c2ncccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCCCCCC
Solvent: COCCOC
Product: [O-][n+]1cccc2c(C(F)(F)F)n[nH]c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Compound (1a) was dissolved in ethylene glycol dimethyl ether (100 mL) and heptane (200 mL), and m-chloroperoxybenzoic acid (33.9 g) was added to the resulting solution at 0° C., followed by stirring at room temperature for 1 hr. The precipitate was collected by filtration to obtain compound (1b) (33.3 g, 96%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])=[CH:4][CH:3]=1.[OH2:16]>O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[O:7][C:6]([C:5]3[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:8][C:9](=[O:16])[C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][CH:15]=1
Reactant: O
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc(-c2ccc(F)cc2)cc1=O

Procedure:
25 gms of ethyl 4-fluorobenzoylacetate was dissolved in 250 gms of 1:10 P2O5 /methanesulfonic acid and heated at 45° for 4 days. The mixture was cooled, poured into 1200 mls of water and extracted with (3×100 mls) methylene chloride. Evaporation of the solvent and chromatography of the resulting oil (silica gel/ether) provided 12.9 gms of crystalline 2,6-di(4'-fluorophenyl)-3-ethoxycarbonyl-pyr-4-one. mp=113°-4°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([N:8]2[C:12]([NH2:13])=[CH:11][C:10]([CH3:14])=[N:9]2)[CH:7]=1.[N:16]1[N:20]2[CH:21]=[CH:22][CH:23]=[N:24][C:19]2=[C:18]([C:25](O)=[O:26])[CH:17]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([N:8]2[C:12]([NH:13][C:25]([C:18]3[CH:17]=[N:16][N:20]4[CH:21]=[CH:22][CH:23]=[N:24][C:19]=34)=[O:26])=[CH:11][C:10]([CH3:14])=[N:9]2)[CH:7]=1
Reactant: Cc1cc(N)n(-c2cc(Cl)ccc2C)n1
Reactant: O=C(O)c1cnn2cccnc12
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)c2cnn3cccnc23)n(-c2cc(Cl)ccc2C)n1
Temperature: 75 °C
Reaction time: 72 h
Yield: 31.7 %

Procedure:
A mixture of 1-(5-chloro-2-methylphenyl)-3-methyl-1H-pyrazol-5-amine (95.3 mg, 0.430 mmol, 1 eq), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (79.5 mg, 0.487 mmol, 1.13 eq), 7-azabenzotriazol-1-yloxy-tris-(pyrrolidino)phosphonium hexafluorophosphate (0.290 g, 0.558 mmol, 1.30 eq), N,N-diisopropylethylamine (0.2 mL, 1.1 mmol, 2.7 eq), and 4-dimethylaminopyridine (11.0 mg, 0.09 mmol, 0.21 eq) in 4.0 mL N,N-dimethylformamide was stirred at 75° C. for 3 days. The reaction mixture was partitioned between ethyl acetate and water, and the organic portion washed with brine, dried over magnesium sulfate, filtered through a silica gel plug, and concentrated. The crude product was purified by reverse phase HPLC and lyophilized to give 50.0 mg (30%) of N-(1-(5-chloro-2-methylphenyl)-3-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=367.0; 1H NMR (400 MHz, DMSO-d6) δ: 10.03 (s, 1H), 9.32 (d, 1H), 8.68 (s, 1H), 8.36 (d, 1H), 7.60 (d, 1H), 7.58 (s, 1H), 7.55 (d, 1H), 7.27 (d of d, 1H), 6.53 (s, 1H), 2.24 (s, 3H), 2.05 (s, 3H).
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[C:17]([C:19]1[CH:20]=[C:21]([C:25]2[C:33]3[C:32](=[O:34])[NH:31][C:30]([C:35](OCC)=[O:36])=[N:29][C:28]=3[S:27][CH:26]=2)[CH:22]=[CH:23][CH:24]=1)#[N:18].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:83]2[CH:87]=[N:86][C:85]([O:88][CH2:89][CH2:90][O:91][C:92]3[CH:93]=[C:94]([CH2:98][NH2:99])[CH:95]=[CH:96][CH:97]=3)=[N:84]2)C=CC=CC=1>>[C:17]([C:19]1[CH:20]=[C:21]([C:25]2[C:33]3[C:32](=[O:34])[NH:31][C:30]([C:35]([NH:99][CH2:98][C:94]4[CH:95]=[CH:96][CH:97]=[C:92]([O:91][CH2:90][CH2:89][O:88][C:85]5[N:86]=[CH:87][NH:83][N:84]=5)[CH:93]=4)=[O:36])=[N:29][C:28]=3[S:27][CH:26]=2)[CH:22]=[CH:23][CH:24]=1)#[N:18]
Reactant: CCOC(=O)c1nc2scc(-c3cccc(C#N)c3)c2c(=O)[nH]1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: N#Cc1cccc(-c2csc3nc(C(=O)NCc4cccc(OCCOc5nc[nH]n5)c4)[nH]c(=O)c23)c1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-(3-cyanophenyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 75 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (124.4 mg, 61%).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.II.[I:21](O)(=O)=O>CO>[I:21][C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:13](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:12][C:11]=2[CH:10]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: [O-][I+2]([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: CO
Product: Ic1ccc2c(c1)Cc1ccccc1-2

Procedure:
56.8 parts of fluorene, 200 parts of methanol, 37 parts of 63% sulfuric acid aqueous solution, 31 parts of iodine, and 34 parts of 34% iodic acid aqueous solution were stirred at 60° C. for 5 hours. After completion of the stirring, the resultant was filtrated, and it was then washed with 100 parts of water twice. Thereafter, the resultant was dried at 70° C. overnight. After completion of the drying, the resultant was recrystallized in methanol to obtain 60 parts of 2-iodofluorene in the form of white powders.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)[CH3:12].C(N(CC)C(C)C)(C)C>O1CCOCC1.C(OCC)(=O)C>[CH2:11]([N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:15][CH2:14]1)[CH3:12]
Reactant: CCN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCN1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 70 °C
Yield: 88 %

Procedure:
2-Chloro-5-nitropyridine (800 mg, 5.05 mmol) was dissolved in dioxane (20 mL) and then 1-ethylpiperazine (1.7 g, 15.15 mmol) and N,N-diisopropylethylamine (927 mL, 5.05 mmol) were added. The reaction mixture solution was stirred at 70° C. for a day. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and then washed with brine. The organic layer was concentrated by drying with magnesium sulfate. The target compound (1.05 g, 87% yield) was used in the following reaction without purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14]([Br:19])=[CH:13][C:12]=3[N:11]=[C:10]([NH2:20])[C:9]=2[N:8]=[C:7]1[CH2:21][CH2:22][CH3:23].[CH:24]([N:27]=[C:28]=[O:29])([CH3:26])[CH3:25]>C(Cl)(Cl)Cl>[NH2:20][C:10]1[C:9]2[N:8]=[C:7]([CH2:21][CH2:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:28]([NH:27][CH:24]([CH3:26])[CH3:25])=[O:29])[C:18]=2[C:17]2[CH:16]=[CH:15][C:14]([Br:19])=[CH:13][C:12]=2[N:11]=1
Reactant: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCN
Reactant: CC(C)N=C=O
Solvent: ClC(Cl)Cl
Product: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCNC(=O)NC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
A suspension of 1-(4-aminobutyl)-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.3 mmol) in chloroform (20 mL) was cooled to 0° C., and a solution of isopropyl isocyanate (5.3 mmol) in chloroform (3 mL/g) was added slowly over a period of eight minutes. After one hour, additional isopropyl isocyanate (0.53 mmol) in chloroform was added. Additional isopropyl isocyanate (2.15 mmol) was added again after an additional 2.5 hours. A precipitate was present and was isolated by filtration, washed with cold chloroform, and dried overnight on the filter funnel to provide 1.99 g of N-{4-[4-amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-N′-(1-methylethyl)urea as a white solid.