Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:70]=[CH:69][C:53]([CH2:54][NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([F:64])=[C:60]([C:65]([F:68])([F:67])[F:66])[CH:59]=2)=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:70]=[CH:69][C:53]([CH2:54][N:55]([CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([F:64])=[C:60]([C:65]([F:67])([F:68])[F:66])[CH:59]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([F:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:52][CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: O=C(O)c1c(F)c(F)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)c(C(F)(F)F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)c(C(F)(F)F)c2)C(=O)c2c(F)c(F)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38.8 %

Procedure:
To a solution of 59 mg (0.3 mmol) of 5,6-difluoro-1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 3 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 106 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-amine in 2 ml DMF were added. After stirring for 3 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by two successive column chromatographies (8 g silica gel; EtOAc/heptane 1:4; second column eluted with n-hexane/EtOAc 9:1) to give 62 mg yellow viscous oil (35%). MS (ISP) 533.2 (M+H)+.
Reaction SMILES: [C:1]([S:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@H:12]([C:28]([OH:30])=O)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[N+:56]([C:59]1[CH:81]=[CH:80][C:62]([CH2:63][O:64][C:65]([NH:67][CH2:68][CH2:69][C@H:70]([OH:79])[C:71]([N:73]2[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]2)=[O:72])=[O:66])=[CH:61][CH:60]=1)([O-:58])=[O:57]>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[C:1]([S:9][C@@H:10]1[CH2:14][N:13]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C@H:12]([C:28]([N:76]2[CH2:75][CH2:74][N:73]([C:71](=[O:72])[C@@H:70]([OH:79])[CH2:69][CH2:68][NH:67][C:65]([O:64][CH2:63][C:62]3[CH:80]=[CH:81][C:59]([N+:56]([O-:58])=[O:57])=[CH:60][CH:61]=3)=[O:66])[CH2:78][CH2:77]2)=[O:30])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCC[C@H](O)C(=O)N1CCNCC1)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(S[C@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCC[C@H](O)C(=O)N1CCN(C(=O)[C@@H]2C[C@H](SC(=O)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A 1.04 g portion of (2S,4S)-4-benzoylthio-1-(p-nitrobenzyloxycarbonyl)proline was dissolved in 20 ml of tetrahydrofuran, and, with cooling on an ice bath, 0.55 g of N-hydroxybenzotriazole and 1.49 g of dicyclohexylcarbodiimide were added to the solution, followed by 1 hour of reaction with stirring at room temperature. To the solution were added 0.88 g of 1-((2S)-4-(p-nitrobenzyloxycarbonyl)amino-2-hydroxybutyryl)piperazine and 0.49 g of triethylamine, followed by 1 hour of reaction at room temperature. After concentration of the solvent, the residue was mixed with ethyl acetate to remove insoluble material, washed with sodium bicarbonate aqueous solution, citric acid aqueous solution and sodium chloride aqueous solution in that order and then dried over sodium sulfate, followed by evaporation of the solvent under a reduced pressure. Thereafter, the resulting residue was subjected to a silica gel column chromatography to yield 1.80 g of (2S,4S)-4-benzoylthio-1-(p-nitrobenzyloxycarbonyl) -2-((1-((2S)-4-(p-nitrobenzyloxycarbonyl) amino-2-hydroxybutyryl)piperazine-4-yl)carbonyl)pyrrolidine.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30].N12CCCNC1=NCCC2.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[OH:30][CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Reactant: NCCCCO
Agent: C1CN=C2NCCCN2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCCCCO)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 37.2 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (180 mg, 0.55 mmol) and 4-amino-1-butanol (59 mg, 0.66 mmol) in toluene (1 mL) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (23 mg, 0.17 mmol) and the reaction stirred under argon for 6 h at room temperature. Saturated aqueous sodium bicarbonate (1 mL) was then added and the resulting mixture was extracted with ethyl acetate (3×5 mL). The combined organic extracts were then dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, dichloromethane:methanol=100:0 to 9:1) afforded the title compound (78 mg, 37%) which was obtained as a white solid. MS: m/e=382.2 [M+H]+.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][C:16]1[CH:25]=[C:24]2[C:19]([C:20]([O:26][C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[NH:32][C:31]([CH3:36])=[CH:30]4)=[N:21][CH:22]=[N:23]2)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:56]1([CH2:61][CH2:62][CH2:63]O)[CH2:60][CH2:59][CH2:58][CH2:57]1>C(Cl)Cl>[CH3:36][C:31]1[NH:32][C:33]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:26][C:20]1[C:19]3[C:24](=[CH:25][C:16]([O:15][CH2:63][CH2:62][CH2:61][N:56]4[CH2:60][CH2:59][CH2:58][CH2:57]4)=[CH:17][CH:18]=3)[N:23]=[CH:22][N:21]=1)=[CH:35][CH:34]=2
Reactant: OCCCN1CCCC1
Reactant: Cc1cc2cc(Oc3ncnc4cc(O)ccc34)ccc2[nH]1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc2cc(Oc3ncnc4cc(OCCCN5CCCC5)ccc34)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
Diisopropyl azodicarboxylate (146 mg, 0.72 mmol) was added to a solution of 7-hydroxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg, 0.34 mmol), triphenyl phosphine (189 mg, 0.72 mol), and 3-pyrrolidinopropan-1-ol (89 mg, 0.686 mmol), (J. Org. Chem. 1988, 53, 3164), in methylene chloride (2.5 ml). After stirring overnight at ambient temperature, the solid was filtered. The filtrate was purified by column chromatography eluting with ethyl acetate/methylene chloride (1/1) followed by ethyl acetate/methylene chloride/methanol (4/5/1), methylene chloride/methanol (9/1) and 3N ammonia in methanol/methylene chloride (1/9). After removal of the solvent, the residue was triturated with ether, filtered, and dried under vacuum to give 4-(2-methylindol-5-yloxy)-7-(3-(pyrrolidin-yl)propoxy)quinazoline (49 mg, 35%)
Reaction SMILES: [Si]([C:5]#[N:6])(C)(C)C.[CH2:7]([O:14][C:15](=[O:18])[CH2:16][NH2:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[ClH:19].C([O-])(O)=O.[Na+].[CH:25](=O)[CH3:26].CCO>C(Cl)Cl.CCOC(C)=O>[ClH:19].[CH2:7]([O:14][C:15](=[O:18])[CH2:16][NH:17][CH:25]([C:5]#[N:6])[CH3:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)C#N
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: ClCCl
Product: CC(C#N)NCC(=O)OCc1ccccc1

Procedure:
TMSCN (4.27 ml, 32 mmol) was added cautiously (reaction is exothermic) to a stirred solution of glycine benzyl ester (5.3 g, 32 mmol, prepared from the HCl salt by partitioning between EtOAc and NaHCO3 solution) and acetaldehyde (1.8 ml, 32 mmol) in methylene chloride (11 ml). After 4 h the volatiles were removed in vacuo and the residue was taken up in EtOAc and was washed with brine, dried (Na2SO4) and evaporated in vacuo to an oil. The oil was redissolved in EtOAc and 9.9 M HCl in EtOH (38.4 mmol) was added to give a crystalline precipitate which was isolated by filtration and washing with EtOAc, to give 1-11: 1H NMR (CDCl3) δ1.49 (d, J=7.1 Hz, 3 H, CH3), 3.54 (d, J=17.3 Hz, 1 H, CHAHB), 3.64 (d, J=17.3 Hz, 1 H, CHAHB), 3.74 (q, J=7.0 Hz, 1 H, a-CH), 5.18 (s, 2 H, CH2O), 7.36 (s, 5 H, Ph).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH2:14][O:15][C:16]([CH3:21])([CH3:20])[C:17](O)=[O:18])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[OH-].[NH4+:27]>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH2:14][O:15][C:16]([CH3:21])([CH3:20])[C:17]([NH2:27])=[O:18])=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)oc1COC(C)(C)C(=O)O
Reactant: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1nc(-c2ccc(Cl)cc2)oc1COC(C)(C)C(N)=O
Reaction time: 16 h
Yield: 49 %

Procedure:
4.44 g (14.5 mmol) of 2-[[2-(4-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropionic acid were dissolved in 40 ml of dry dichloromethane and 1 drop of dimethylformamide was added. 1.96 (16 mmol) of thionyl chloride were added and the mixture was heated to reflux for 4 hours. The cooled solution of the resulting acid chloride was added while stirring to 70 ml of aqueous ammonium hydroxide solution (specific gravity 1.880) and crushed ice. After stirring for 16 hours the suspension was extracted with 200 ml of dichloromethane. The organic phase was separated and washed twice with 100 ml of water each time. The organic phase was dried over magnesium sulphate and filtered, and the solvent was then removed by evaporation under reduced pressure. Recrystallization of the crude solid from ethyl acetate gave 2.2 g (49%) of 2-[[2-(4-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropionamide of melting point 177°-178° C.
Reaction SMILES: [C:1]([CH2:9][C:10](=O)[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:13]1([CH2:19][CH2:20][NH2:21])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[N:13]1([CH2:19][CH2:20][NH:21][C:10]([CH3:11])=[CH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: NCCN1CCOCC1
Solvent: Cc1ccccc1
Product: CC(=CC(=O)c1ccccc1)NCCN1CCOCC1

Procedure:
A solution of 28.7 g. (0.177 mole) of benzoylacetone and 23.2 ml. (0.177 mole) of 2-(4-morpholinyl)ethylamine in 600 ml. of toluene was heated under reflux for ten and a half hours under a Dean-Stark trap and the solution then cooled and taken to dryness to give N-[2-(4-morpholinyl)ethyl]-N-(1-methyl-3-oxo-3-phenylpropenyl)amine as a yellow solid.
Reaction SMILES: CO[CH:3]([O:13]C)[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.CCN=C=NCCCN(C)C.[CH2:26]([NH2:32])[C:27]1[O:31][CH:30]=[CH:29][CH:28]=1>CN(C1C=CN=CC=1)C.C1COCC1.C(Cl)Cl>[CH:8]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([NH:32][CH2:26][C:27]2[O:31][CH:30]=[CH:29][CH:28]=2)=[O:13])=[CH:12][CH:11]=1)=[O:10]
Reactant: NCc1ccco1
Reactant: COC(OC)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=Cc1ccc(C(=O)NCc2ccco2)cc1
Reaction time: 2 h
Yield: 58 %

Procedure:
A solution of 4-(dimethoxymethyl)benzoic acid 5 (2.94 g, 15 mmol), EDCI (5.75 g, 30 mmol), furfurylamine (3.5 mL, 37.5 mmol), and DMAP (122 mg, 1 mmol) in THF (200 mL) and CH2Cl2 (50 mL) was stirred at r.t. for 16 h. The solvent was removed by rotary evaporation and the resulting yellow oil was dissolved in CHCl3 and was washed twice with 0.5 M HCl. The organic solution was then vigorously stirred with 1.0 M HCl for 2 h. The layers were separated and the organic phase was washed twice more with 1.0 M HCl and once with brine. The organic phase was dried over Na2SO4 and the solvent was removed by rotary evaporation. The crude product was crystallized from hot EtOAc, yielding the title compound as a pale yellow solid in 2 crops (2.09 g, 58% yield). 1H NMR (400 MHz, CDCl3): δ 10.09 (s, 1H), 7.97 (s, 4H), 7.42 (m, 1H), 6.54 (br s, 1H), 6.39 (dd, J=2.0, 3.3 Hz, 1H), 6.35 (d, J=3.3 Hz, 1H), 4.69 (d, J=5.3 Hz, 2H).
Reaction SMILES: C([SiH](C(C)C)C(C)C)(C)C.[F:11][C:12]([F:35])([C:16]([F:34])([F:33])[C:17]([F:32])([F:31])[C:18]([F:30])([F:29])[C:19]([F:28])([F:27])[C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[C:13](Cl)=[O:14].[SiH4]>[Pd]>[C:12]([CH:13]=[O:14])([C:16]([C:17]([C:18]([C:19]([C:20]([C:21]([F:22])([F:23])[F:24])([F:25])[F:26])([F:28])[F:27])([F:30])[F:29])([F:32])[F:31])([F:34])[F:33])([F:35])[F:11]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Pd]
Agent: CC(C)[SiH](C(C)C)C(C)C
Agent: [SiH4]
Product: O=CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
Catalyst 10% Pd/C (200 mg) was placed in a 3-necked round bottom flask and cooled at 0° C. Triisopropylsilane (3.32 g, 21 mmol) was added, followed by perflurooctanoyl chloride (7.9 g, 18.2 mmol). The mixture was allowed to warm to room temperature and was then controlled at 25°-27° C. during the exothermic reaction. After 3 hr, GC analysis showed aidehyde/acid chloride ratio=94/6. Another 0.26 mL of silane was added and stirring was continued for 1 hr. Vacuum transfer gave liquid which was chilled at -25° C. The resulting solid was shaken With petroleum ether, chilled at -25° C. and separated again. In this way, 6.48 g of product was obtained, mp ca. -5° C. NMR spectra were as described in Example 1.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:10][CH2:11][CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[CH3:13])=[N:4][CH:5]=[N:6][C:7]=1[CH2:8][CH3:9].[C:23]([O:31][CH2:32]Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[I-:34].[Na+]>CC(C)=O>[I-:34].[C:23]([O:31][CH2:32][N+:6]1[C:7]([CH2:8][CH3:9])=[C:2]([Br:1])[C:3]([NH:10][CH2:11][CH:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[CH3:22])[CH3:13])=[N:4][CH:5]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(OCCl)c1ccccc1
Reactant: CCc1ncnc(NCC(C)Oc2ccc(C)cc2C)c1Br
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCc1c(Br)c(NCC(C)Oc2ccc(C)cc2C)nc[n+]1COC(=O)c1ccccc1

Procedure:
0.3 g (8.2 mmol) of 5-bromo-6-ethyl-4-[2-(2,4-dimethylphenoxy)-propylamino]pyrimidine (according to EP-A-57 440), 0.17 g (9.8 mmol) of chloromethyl benzoate and 0.12 g (8.2 mmol) of sodium iodide in 25 ml of acetone were heated under reflux for 8 hours. After cooling, the precipitated sodium chloride was filtered off and the filtrate was concentrated. The residue was taken up in dichloromethane and washed by stirring with water. The organic phase was dried and concentrated. The residue was digested with ethyl acetate. Filtration with suction gave 0.97 g (53.3% of theory) of light-yellow crystals. mp.: 159-161° C.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:20]([CH2:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[C:26]([O:33][CH3:34])[CH:25]=1)=[N+]=[N-].O>C1COCC1>[CH3:34][O:33][C:26]1[CH:25]=[C:24]([CH2:23][NH2:20])[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=1
Reactant: COc1cc(CN=[N+]=[N-])cc([N+](=O)[O-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CN)cc([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 67 %

Procedure:
PPh3 (0.0707 g, 0.27 mmol, 1.1 eq) was added to a stirred solution of 1-(azidomethyl)-3-methoxy-5-nitrobenzene (synthesis described herein) in 5 ml THF. After 5 min 1 ml of water was added, and the reaction was stirred overnight. The solvent was removed in vacuo. The residue was dissolved in EtOAc and extracted with 1N HCl (×1). The aqueous layer was adjusted to pH>8 with 1N NaOH and extracted with EtOAc (×1). This organic fraction was washed with brine (×1) and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo to yield 0.030 g (0.16 mmol, 67% yield) of the product.
Reaction SMILES: N#N.[Cl:3][C:4]1[N:9]=[C:8](Cl)[C:7]([F:11])=[CH:6][N:5]=1.[N+:12]([C:15]1[CH:21]=[CH:20][C:18](N)=[CH:17][CH:16]=1)([O-:14])=[O:13].CC[N:24](C(C)C)C(C)C>C(O)CCC.CCCCCC.C(OCC)(=O)C>[Cl:3][C:4]1[N:9]=[C:8]([NH:24][C:17]2[CH:18]=[CH:20][CH:21]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=2)[C:7]([F:11])=[CH:6][N:5]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: CCN(C(C)C)C(C)C
Reactant: Fc1cnc(Cl)nc1Cl
Agent: N#N
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=[N+]([O-])c1cccc(Nc2nc(Cl)ncc2F)c1
Temperature: 120 °C

Procedure:
In a 50 mL 3-neck RBF equipped with N2 bubbler and reflux condenser 2,4-dichloro-5-fluoropyrimidine (1.79 g) in 1-butanol (20 mL), 4-nitroaniline (1.0 g) and DIPEA (2.6 mL) were charge at room temperature. The reaction mixture was heated to 120° C. for 2 hr. The reaction was monitored on TLC using hexane:ethyl acetate (8:2) as mobile phase. After completion, the reaction mixture was cooled to room temperature. Solid precipitate was filtrated and washed with cold hexanes and dried to give 1.26 g of 2-chloro-5-fluoro-N-(3-nitrophenyl)pyrimidin-4-amine.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2].[CH3:22][CH2:23][CH2:24]CCC.C([Li])CCC.[CH3:33][C:34]([C:38]1[CH:39]=[CH:40][C:41](=[C:43]([CH3:45])[CH3:44])[CH:42]=1)([CH3:37])[CH2:35][CH3:36]>C1COCC1.CCOCC.O>[CH3:37][C:34]([C:38]1[CH:39]=[CH:40][CH:41]([C:43]2([C:11]3[C:10]4[CH2:9][C:8]5[C:16](=[CH:17][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=5)[C:15]=4[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=3)[CH2:44][CH2:24][CH2:23][CH2:22][CH2:45]2)[CH:42]=1)([CH3:33])[CH2:35][CH3:36]
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)ccc1C2
Reactant: CCC(C)(C)C1=CC(=C(C)C)C=C1
Reactant: CCCCCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(C)(C)C1=CC(C2(c3cc(C(C)(C)C)cc4c3Cc3ccc(C(C)(C)C)cc3-4)CCCCC2)C=C1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
To a solution of 2.38 g (8.5 mmol) of 3,6-di-tert-butylfluorene in 40 ml of THF, 5.7 ml (9.2 mmol) of a hexane solution of n-butyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. To the resulting red solution, a solution of 2.00 g (9.2 mmol) of 3-(1,1-dimethylpropyl)-6,6-dimethylfulvene in 30 ml of THF was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. After the reaction solution was diluted with 100 ml of ether, 50 ml of water was added. The separated organic phase was washed with water and a saturated saline solution, then dried over magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was isolated and purified by column chromatography (silica gel, developing solvent: hexane) to obtain 1.88 g (3.80 mmol) of a white solid (yield: 45%). The analyzed values are given below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[CH:11][N:10](/[CH:13]=[CH:14]\[C:15]([O:17]C(C)C)=[O:16])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1COCC1.O.[Li+].[OH-]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[CH:11][N:10](/[CH:13]=[CH:14]\[C:15]([OH:17])=[O:16])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)/C=C\n1cnc(-c2cccc(Cl)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)/C=C\n1cnc(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.8 %

Procedure:
In 3-neck 100 mL RBF, (Z)-isopropyl 3-(3-(3-chlorophenyl)-1H-1,2,4-triazol-1-yl)acrylate (1.0 g, 1 eq.) was mixed with THF-Water (1:1) (20 mL, 20 Vol.) and LiOH (0.288 g, 2.0 eq.) was added. The reaction mixture was stirred at RT for 2-3 h. Reaction completion was monitored on TLC using neat ethyl acetate as mobile phase. Reaction mixture was quenched into the ice-water slurry (50 mL) and acidified with approximately 5 N HCl to 4 PH. Compound was extracted in the ethylacetate (50 mL×3) and organic layer was washed with brine solution (50 mL×3) followed by drying using anhydrous sodium sulphate. Organic layer was concentrated under reduced pressure to afford 0.7 g of pure (Z)-3-(3-(3-chlorophenyl)-1H-1,2,4-triazol-1-yl)acrylic acid. Yield (81.8%). LC/MS: 250.0
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][NH:18][CH2:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1.CN(C)C(=O)C>[Cl:29][C:28]1[C:23]([N:18]2[CH2:17][CH2:16][C:12]3[N:13]=[CH:14][N:15]=[C:10]([NH:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:20])([F:1])[F:21])=[CH:4][CH:5]=4)[C:11]=3[CH2:19]2)=[N:24][CH:25]=[CH:26][CH:27]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CNCC3)cn1
Reactant: Clc1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CN(c2ncccc2Cl)CC3)cn1
Temperature: 150 °C
Yield: 27.9 %

Procedure:
N-(6-(Trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (130 mg, 0.44 mmol) was dissolved in a mixture of dioxane/N,N-dimethylacetamide (4:1) (2 mL). To the mixture was added 2,3-dichloropyridine (98 mg, 0.66 mmol) and N,N-diisopropylethylamine (0.11 mL, 0.66 mmol). The mixture was heated at 150° C. in a Personal Chemistry microwave for 16 h. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give a brown residue. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as an off-white powder (50 mg, 28%).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=1[O:38][CH3:39].CN(C)C=O>O>[O:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([CH:35]([OH:37])[CH3:36])=[CH:31][C:30]=3[O:38][CH3:39])[CH2:7][CH2:6]2)=[N:9]1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)O)ccc1OCCCCN1CCC(c2noc3ccccc23)CC1
Temperature: 75 °C
Yield: 94.2 %

Procedure:
A mixture of 3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (4.3 g, 0.018 mol), K2CO3 (5.5 g, 0.04 mol), and 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (5.5 g, 0.018 mol), and dimethylformamide (60 ml) was stirred and heated at 75° C. for 16 hours. The reaction was poured into water and was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4), and the solvent concentrated to afford 7.2 g of a beige solid. Recrystallization (twice) from ethyl alcohol yielded 3.3 g (43%) of 1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxy]3-methoxyphenyl]ethanone, m.p.=99°-101° C.