Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Mg].II.[CH3:13][C:14]([CH3:34])([CH3:33])[CH2:15][C:16]([NH:18][C:19]1[C:20]([CH3:32])=[C:21]([CH3:31])[C:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24](=[O:29])[C:23]=2[CH:30]=1)=[O:17]>C1COCC1>[OH:29][C:24]1([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:23]2[CH:30]=[C:19]([NH:18][C:16](=[O:17])[CH2:15][C:14]([CH3:34])([CH3:33])[CH3:13])[C:20]([CH3:32])=[C:21]([CH3:31])[C:22]=2[O:26][C:25]1([CH3:27])[CH3:28]
Reactant: ClCCc1ccccc1
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2=O
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
A solution of 2-chloroethylbenzene (648 mg, 4.6 mmol) in THF (5 mL) was added dropwise under an argon atmosphere to a mixture of magnesium (112 mg, 4.6 mmol) and a catalytic amount of iodine, and the mixture was stirred for 30 minutes. To the reaction solution was added dropwise a solution of 3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamide (300 mg, 0.98 mmol) obtained in Reference Example 65 in THF (3 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to ice and the product was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:3) and recrystallized from ethyl acetate-hexane to obtain 201 mg (yield: 51%) of the title compound. Melting point: 99-100° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9](=O)[C:10]([F:13])([F:12])[F:11].[Cl:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](Cl)=[O:23])=[CH:18][CH:17]=1.C(N(CC)CC)C>ClCCl>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][C:22](=[O:23])[C:21]([O:20][C:19]1[CH:25]=[CH:26][C:16]([Cl:15])=[CH:17][CH:18]=1)=[C:9]2[C:10]([F:13])([F:12])[F:11]
Reactant: Nc1ccc(Br)cc1C(=O)C(F)(F)F
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccc(Br)cc2c(C(F)(F)F)c1Oc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(2-amino-5-bromophenyl)-2,2,2-trifluoroethanone (2.76 g, 10.3 mmol, Intermediate 7, step b) in dichloromethane (20 mL) was added commercially available 2-(4-chlorophenoxy)acetyl chloride (2.11 g, 10.3 mmol). The resulting white solution was cooled with an ice bath to 0° C. and treated with triethylamine (4.29 mL, 30.9 mmol) dropwise. The reaction mixture was stirred at room temperature for 12 hours and at 60° C. for 2 hours. The mixture was diluted with dichloromethane at room temperature and washed with water. The organic phase was dried (MgSO4), filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 25% EtOAc-Heptane), affording the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]([N:27]([C:65](=[O:70])[CH2:66][CH2:67][CH2:68][CH3:69])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]2[N:45](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:44]=[N:43][N:42]=2)=[CH:31][CH:30]=1)[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1>[CH2:1]([O:8][C:9]([C@@H:11]([N:27]([C:65](=[O:70])[CH2:66][CH2:67][CH2:68][CH3:69])[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:41]2[NH:45][N:44]=[N:43][N:42]=2)=[CH:33][CH:34]=1)[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 4.5 h

Procedure:
1.07 g of (S)-N-(1-benzyloxycarbonyl-5-benzyloxycarbonylamino-pent-1-yl)-N-pentanoyl-N-[2'-(1-triphenylmethyl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine are dissolved in 15 ml of dioxane. This solution is treated with 1.5 ml of a solution of hydrogen chloride in dioxane (7 N), the mixture is stirred for 4.5 hours at 40° and then evaporated, and the residue is purified by means of flash-chromatography (200 g of silica gel; system N6). The (S)-N-(1-benzyloxycarbonyl-5-benzyloxycarbonylamino-pent-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine [Rf : 0.42 (system N7)] is thus obtained.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]([C:28]2[N:32]([CH3:33])[C:31]3[CH:34]=[CH:35][C:36]([OH:38])=[CH:37][C:30]=3[N:29]=2)[CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:39](O)[CH2:40][CH3:41].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>ClCCl>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]([C:28]2[N:32]([CH3:33])[C:31]3[CH:34]=[CH:35][C:36]([O:38][CH2:39][CH2:40][CH3:41])=[CH:37][C:30]=3[N:29]=2)[CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:9][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCOC(=O)c1ccc2c(c1)CCC2N(c1nc2cc(O)ccc2n1C)[C@H]1CC[C@H](C(C)(C)C)CC1
Reactant: CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCOC(=O)c1ccc2c(c1)CCC2N(c1nc2cc(OCCC)ccc2n1C)[C@H]1CC[C@H](C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of butyl 1-[(trans-4-tert-butylcyclohexyl)(5-hydroxy-1-methyl-1H-benzimidazol-2-yl)amino]indane-5-carboxylate (49.0 mg, 0.095 mmol) in dry dichloromethane was added 1-propanol (18.0 □L, 0.24 mmol), diisopropyl azodicarboxylate (37.0 μL, 0.19 mmol) and Ph3P (50.0 mg, 0.19 mmol). After stirring at room temperature for 2 h, solvent was removed. Chromatography (15% EtOAc in Hexane) afforded butyl 1-[(trans-4-tert-butylcyclohexyl)(1-methyl-5-propoxy-1H-benzimidazol-2-yl)amino]indane-5-carboxylate. HPLC/MS: m/z=560.5 (M+1), Rt=2.43 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][N:10]=[C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:8]=2[CH:17]=1)([O-])=O>C(O)(=O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[S:11][N:10]=[C:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:8]=2[CH:17]=1
Reactant: COC(=O)Cc1nsc2ccc([N+](=O)[O-])cc12
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)Cc1nsc2ccc(N)cc12
Temperature: 50 °C

Procedure:
Iron (0.74 g, 13.3 mmol) is added portionwise to a solution of methyl 5-nitro-1,2-benzisothiazole-3-acetate (0.67 g, 2.7 mmol) in acetic acid at 50° C. The reaction mixture is stirred at 50° C. for several minutes, cooled and filtered through diatomaceous earth. The resultant filtrate, which contains the title product, is used in Example 22 without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[CH3:12][C:13]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]=[C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)[C:14]=1[C:34](OC)=[O:35]>O1CCCC1>[OH:35][CH2:34][C:14]1[C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)=[N:16][C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:18][C:13]=1[CH3:12]
Reactant: COC(=O)c1c(C)nc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CO
Temperature: 0 °C

Procedure:
To a suspension of lithium aluminum hydride (12.24 g) in a mixture of dry tetrahydrofuran (180 ml) and diethyl ether (360 ml) was dropwise added a solution of methyl 6-methyl-2-phenyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylate in dry tetrahydrofuran (180 ml) under cooling at -50°~-40° C. The excess lithium aluminum hydride was decomposed by a careful addition to ice water. The separated organic layer was washed with 15% sulfuric acid (400 ml) and extracted with ethyl acetate (1 l). The organic layer was washed with saturated aqueous sodium bicarbonate and aqueous sodium chloride successively and concentrated in vacuo. The residue was recrystallized from diethyl ether to give 5-hydroxymethyl-6-methyl-2-phenyl-4-(3-nitrophenyl)-pyrimidine (30 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=S)[NH:7][C:6]=2[CH:17]=1.[NH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>C(OCCO)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:7][C:6]=2[CH:17]=1
Reactant: S=C1Nc2cc(Cl)ccc2Nc2ccccc21
Reactant: NCc1cccnc1
Solvent: CCOCCO
Product: Clc1ccc2c(c1)N=C(NCc1cccnc1)c1ccccc1N2
Yield: 39.8 %

Procedure:
A solution of 0.39 g (1.5 mmol) of 8-chloro-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-thione (Hunziker F., et al., Helv. Chim. Acta, 50:1588 (1967)) in 10 mL of 2-ethoxyethanol was treated with 0.3 mL (2.99 mmol) of 3-(aminomethyl)pyridine and heated at reflux for 30 hours. The solvent was removed under reduced pressure and the residue mixed with EtOAc and filtered to give 200 mg of the product. The filtrate was chromatographed on silica gel, eluting with EtOAc to give an additional 200 mg of product. Total yield 400 mg (80% yield) of the product as a yellow solid, mp 230-234° C. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =335.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH:7]=O.Cl.[NH2:10][OH:11].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[CH:7]=[N:10][OH:11]
Reactant: NO
Reactant: Cc1ncoc1C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ncoc1C=NO
Reaction time: 2 h

Procedure:
0.50 g (4.50 mmol) of 4-methyl-1,3-oxazole-5-carbaldehyde [prepared from the corresponding alcohol (Chem. Ber. 1961, 1248) by Swern oxidation (Tetrahedron 34, 1651 (1978))] is initially charged in 3 ml of water and treated with 0.66 g (9.45 mmol) of hydroxylamine hydrochloride in 2 ml of water. 0.68 g (4.95 mmol) of potassium carbonate is then added. After 2 h, the mixture is filtered off with suction and the product is washed with water and dried at room temperature. The yield is 0.41 g (72.2% of theory).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].O1[CH2:22][CH2:21][NH:20]C1=O>>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[O:15][CH2:22][CH2:21][NH2:20])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1NCCO1
Reactant: O=C1c2ccccc2Cc2ccccc21
Agent: [K+]
Agent: [OH-]
Product: NCCOc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.2 %

Procedure:
ExxonMobil™ Aromatic 100 solvent vvas added into a 3-neck round bottom flask containing anthrone (10 g, 51.5 mmol) at room temperature. Potassium hydroxide pellets (0.33 g, 5.15 mmol) and 2-oxazolidinone (7.62 g, 87.5 mmol) were added, and the reaction mixture was heated to reflux and stirred for 2.5 h under nitrogen. The reaction mixture was cooled to room temperature, decanted, and filtered. The solvent was evaporated in vacuo to give 4.3 g (35%) of the desired amine. The crude reaction mixture could be further purified by flash column chromatography. 1H NMR (DMSO-d6, 400 MHz) δ 8.38-8.31 (m, 3H), 8.08-8.02 (m, 2H), 7.56-7.47 (m, 4H), 4.13 (dd, 2H, J=5.58, 5.58 Hz), 3.15 (dd, 2H, J=5.60, 5.60 Hz), 2.91 (bs, 2H). 13C NMR (DMSO-d6, 400 MHz) δ 150.7, 132.8, 128.4, 125.6, 125.4, 124.1, 122.1, 121.9, 78.2, 42.1.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[O:41]1[CH:45]=[CH:44][CH:43]=[C:42]1[S:46](Cl)(=[O:48])=[O:47]>O1CCCC1.O>[F:25][C:11]1[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[CH:13][N:14]([S:46]([C:42]2[O:41][CH:45]=[CH:44][CH:43]=2)(=[O:48])=[O:47])[C:10]=1[C:9]1[C:4]([F:3])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccco1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2ccco2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a suspension of sodium hydride (60% in oil, 37 mg) in tetrahydrofuran (2 mL) were added dropwise a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (200 mg) in tetrahydrofuran (1 mL), 15-crown-5 (205 mg) and 2-furansulfonyl chloride (132 mg) under ice-cooling and the mixture was stirred for 1 hr and half. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a pale-yellow oil (yield 243 mg, 87%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][Si](C)(C)C)=[CH:9][CH:10]=2)[N:5]([CH:18]([CH3:20])[CH3:19])[C:4](=[O:21])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:22][C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[CH:13])=[CH:9][CH:10]=2)[N:5]([CH:18]([CH3:19])[CH3:20])[C:4](=[O:21])[CH2:3]1
Reactant: CC(C)N1C(=O)CC(C)(C)c2ccc(C#C[Si](C)(C)C)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2c(c1)N(C(C)C)C(=O)CC2(C)C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-1-isopropyl-7-[(trimethylsilyl)ethynyl]quinoline (Compound 29) in 7.0 ml of methanol was added potassium carbonate. The mixture was stirred at room temperature for 10 h. The reaction mixture was then concentrated in vacuo and the resulting oil was dissolved in water, and extracted using methylene chloride (2×). The organic layers were dried (MgSO4), filtered and concentrated in vacuo to give the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:4]=1[CH2:5][N:6]([CH2:27][CH2:28][CH2:29][CH3:30])[C:7](=[O:26])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C@H:17]([O:23][CH2:24][CH3:25])[C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=1.[Li+].[OH-].Cl>C(#N)C>[CH2:27]([N:6]([CH2:5][C:4]1[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:3]=1[O:2][CH3:1])[C:7](=[O:26])[CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][C@H:17]([O:23][CH2:24][CH3:25])[C:18]([OH:20])=[O:19])=[CH:14][CH:15]=1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCN(Cc1cccc(OC)c1OC)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCN(Cc1cccc(OC)c1OC)C(=O)COc1ccc(C[C@H](OCC)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.4 %

Procedure:
To a solution of ethyl(2S)-3-(4-{2-[(2,3-dimethoxybenzyl)(butyl)amino]-2-oxoethoxy}phenyl)-2-ethoxypropanoate (1.02 g, 2.0 mmol) in acetonitrile (80 mL) was added aqueous 0.10 M LiOH (40 mL) and the reaction mixture was stirred at room temperature overnight. The solvent volume was reduced in vacuo and the remaining aqueous phase was acidified with 5% HCl and extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with brine (75 mL), dried over Na2SO4, and concentrated in vacuo to afford 0.96 g (98%) of a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[C:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1)(=[O:11])[CH3:10]
Reactant: Nc1cccc(Br)n1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc(Br)n1
Yield: 68 %

Procedure:
20 g (0.116 mole) of 2-amino-6-bromopyridine was dissolved in 140 ml. acetic anhydride and heated at 70° C for 45 minutes. 2-Acetamido-6-bromopyridine was isolated by filtration as white flakes, m.p.=159.2°-160.0° C, in 68% yield. The excess acetic anhydride present in the reaction mixture was hydrolyzed by the addition of 300 ml. water to the filtrate; the reaction mixture was agitated and an additional 27% yield of 2-acetamido-6-bromopyridine was collected by filtration, giving a 95% yield of reaction product, 2-acetamido-6-bromopyridine which was recrystallized from benzene.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[F:14][B-:15]([F:18])([F:17])[F:16].[H+].[N:20](OCCCCC)=O>C(O)C.C(OCC)C>[F:14][B-:15]([F:18])([F:17])[F:16].[N+:1](=[C:2]1[CH:7]=[N:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[C:4]([CH3:13])[CH2:3]1)=[N-:20]
Reactant: CCCCCON=O
Reactant: Cc1cc(N)cnc1CCCCN
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCO
Solvent: CCOCC
Product: CC1=C(CCCCN)N=CC(=[N+]=[N-])C1
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) mixture of 5-amino-2-[4-amino-butyl]-3-methylpyridine (0.86 g) and fluoroboric acid (5 ml) in ethanol (30 ml) was reacted with amyl nitrite (3 ml) over 15 minutes and then stirred for a further 15 minutes, diluted with diethyl ether at 0° C. to give 5-diazo-2-(4-aminobutyl)-3-methylpyridine fluoroborate (1.88 g) m.p. 80°-120° C. (dec).
Reaction SMILES: [C:1]([CH:4]([C:15](=[O:17])[CH3:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2].[Cl-].[Mg+2].[Cl-].N1C=CC=CC=1.[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)#[N:28]>ClCCl>[C:1]([C:4]([C:33](=[O:34])[C:32]1[CH:36]=[CH:37][C:29]([C:27]#[N:28])=[CH:30][CH:31]=1)([C:15](=[O:17])[CH3:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:3])[CH3:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)CCCCCC(C(C)=O)C(C)=O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CCCCCC(C(C)=O)(C(C)=O)C(=O)c1ccc(C#N)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 5740.9 %

Procedure:
To a mixture of ethyl 7-acetyl-8-oxononanoate (4.0 g) and magnesium chloride (1.27 g) in dichloromethane (70 ml) was added pyridine (2.15 ml) at 0° C. The mixture was stirred at 20° C. for 1 hour, then a solution of 4-cyanobenzoyl chloride (2.87 g) in dichloromethane (10 ml) was added. After stirring for 3 hours at 20° C., the mixture was partitioned between ether and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 7-acetyl-7-(4-cyanobenzoyl)-8-oxononanoate (352 g) as an oil.
Reaction SMILES: OS(C(F)(F)F)(=O)=O.[C:9](=[NH:32])([O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=2)=[CH:16][CH:15]=1)[NH2:10].[C:33]([C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH:42]([CH:48]=O)[C:43](OCC)=[O:44])=[CH:37][CH:36]=1)#[N:34].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][O:11][C:9]3[NH:10][CH:48]=[C:42]([CH2:41][C:38]4[CH:37]=[CH:36][C:35]([C:33]#[N:34])=[CH:40][CH:39]=4)[C:43](=[O:44])[N:32]=3)=[CH:19][CH:18]=2)=[CH:22][C:23]=1[C:28]([F:31])([F:30])[F:29]
Reactant: CCOC(=O)C(C=O)Cc1ccc(C#N)cc1
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)C(F)(F)F
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cc1
Temperature: 160 °C
Yield: 30.6 %

Procedure:
The mixture of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl imidocarbamate triflate (120 mg, 0.236 mmol), ethyl 3-(4-cyanophenyl)-2-formylpropanoate (137 mg, 0.591 mmol) and K2CO3 (98 mg, 0.709 mmol) in DMA (5 mL) was heated with a microwave reactor at 160° C. for 1 hour. Purification via MDAP then afforded the title compound as a pale yellow solid (38 mg, 29.0% yield). LCMS: rt=3.90 min, [M+H+]=526.2
Reaction SMILES: [C:1]([C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11](Cl)[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH3:20][OH:21]>O>[C:1]([C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]([O:21][CH3:20])[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CO
Agent: [Na]
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(C(=O)c2ccccc2)n1

Procedure:
60 grams of 2-benzoyl-3-nitro-6-chloropyridine were added in portions to a solution of 10 grams of sodium metal in 500 ml. of methanol at 50° C. with stirring, whereby the temperature gradually increased. Then the mixture was heated under reflux for four hours and subsequently treated with two liters of water. The precipitated crystals were filtered off with suction after one hour and recrystallized from methanol.
Reaction SMILES: [N+:1]([CH:4]1[CH2:9][N:8]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[C:12]([C:13]#[N:14])=[C:7]2[NH:6][CH2:5]1)([O-])=O>CO.C(Cl)Cl.[Pd]>[NH2:1][CH:4]1[CH2:9][N:8]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][CH:20]=3)[C:12]([C:13]#[N:14])=[C:7]2[NH:6][CH2:5]1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC([N+](=O)[O-])C2
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(N)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.1 %

Procedure:
To a solution of 6-nitro-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile (600 mg, 1.67 mmol) in 30 mL of methanol and 10 mL of DCM was added 10% w/w Pd/C (100 mg). The mixture was stirred at RT under H2 for 2 hr and filtered. The filtrate was concentrated and purified by chromatography column on silica gel eluting with PE/EA to afford 200 mg (36%) of 6-amino-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile as a white solid. MS (ESI) m/e [M+1]+ 332.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]([C:16]([F:19])([F:18])[F:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:4][C:3]=1[O:20][CH3:21].[N+:22]([O-])([OH:24])=[O:23]>C(O)(=O)C>[OH:1][C:2]1[C:7]([N+:22]([O-:24])=[O:23])=[CH:6][C:5]([C:8]([C:10]2[C:11]([C:16]([F:17])([F:18])[F:19])=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:4][C:3]=1[O:20][CH3:21]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)c2cccnc2C(F)(F)F)ccc1O
Solvent: CC(=O)O
Product: COc1cc(C(=O)c2cccnc2C(F)(F)F)cc([N+](=O)[O-])c1O

Procedure:
To a solution of (4-hydroxy-3-methoxyphenyl)(2-(trifluoromethyl)pyridin-3-yl)methanone (0.472 g, 1.59 mmol) in acetic acid (10 mL) at room temperature was added 60% nitric acid (0.14 mL, 1.75 mmol) dropwise. The resulting mixture was allowed to stir for thirty minutes then poured onto ice-water (100 mL) and the resulting precipitate was filtered off, washed with water and dried. Recrystallisation from ethanol afforded (4-hydroxy-3-methoxy-5-nitrophenyl)(2-(trifluoromethyl)pyridin-3-yl)methanone as a yellow solid, 0.315 g (58%).