Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][C@H:7]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C:9]3([O:34][C@H:10]3[CH2:11][C@@H:12]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:33])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:8]1)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:35][CH2:36][CH2:37][C:38]1[N:42]=[CH:41][NH:40][CH:39]=1.C(O)CCC>COC(C)(C)C>[C:1]([O:6][C@H:7]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@:9]([OH:34])([C@H:10]([NH:35][CH2:36][CH2:37][C:38]3[N:42]=[CH:41][NH:40][CH:39]=3)[CH2:11][C@@H:12]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:33])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:24])[CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:8]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]4[C@@H]3C[C@@H]3OC32C1
Reactant: NCCc1c[nH]cn1
Solvent: CCCCO
Solvent: COC(C)(C)C
Product: CCCC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]4[C@@H]3C[C@@H](NCCc3c[nH]cn3)[C@@]2(O)C1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
5,6α-epoxicholestan-3β-yl butyrate (10.4 g, 22.1 mmol, 1 eq) and histamine (4.9 g, 44.1 mmol, 2 eq) were charged in a round-bottomed flask equipped with a magnetic stirrer bar. 1-Butanol (70 ml, 5 vol) was added and the mixture heated to reflux for 40 h. The reaction mixture was cooled at r.t., diluted with methyl-tertbutyl-ether (5 vol) and washed with water (5 vol) and with brine (5 vol). The organic layer was passed through a silica pad (40 g) eluted with methyl-tertbutyl-ether (3 vol) then 10% Methanol/ethyl acetate (60 vol). Fractions of interest were pooled and the solvent was removed under reduced pressure to give 5α-Hydroxy-6β-[2-(1H-imidazol-4-yl)-ethylamino]-cholestan-3β-yl butyrate as a white solid (7.8 g, 57%). In same conditions, use of ethanol as solvent (40 vol) and Ca(OTf)2 as catalyst gave a 13% yield.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>C(O)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: NC1CCOCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(Cl)nc1NC1CCOCC1
Temperature: 175 °C
Yield: 66.8 %

Procedure:
2,6-Dichloro-3-nitropyridine (0.222 g, 1.15 mmol), 4-aminotetrahydropyran (0.109 g, 1.08 mmol) and DIEA (0.300 mL, 1.72 mmol) were taken up in ethanol (3.0 mL) and heated to 175° C. for 15 minutes in a heavy walled sealed tube under microwave irradiation. The solvent was removed under reduced pressure and the residual solid was purified by preparative HPLC to give the title compound (0.186 g). LCMS m/z=258.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.60-1.75 (m, 2H), 2.8 (d, J=12.4 Hz, 2H), 3.60 (t, J=11.4 Hz, 2H), 4.02 (d, J=11.8 Hz, 2H), 4.30-4.45 (m, 1H), 6.63 (d, J=8.6 Hz, 1H), 8.29 (d, J=5.8 Hz, 1H), 8.35 (d, J=8.6 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH:25]1C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>C(O)(=O)C>[CH3:25][O:21][C:20]([C:17]1[CH:16]=[N:15][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)=[N:19][CH:18]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)O)cn2)CC1
Reactant: c1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To 2-(4-tert-Butoxycarbonyl-piperazin-1-yl)-pyrimidine-5-carboxylic acid (150 mg, 0.486 mmol) in an oven dried round-bottom flask is added methanol (1.0 mL) and benzene (3.7 mL) under nitrogen, and the reaction stirred for 10 min. Trimethylsilyldiazomethane (0.34 ml, 0.678 mmol) is added and the reaction stirred for 1 h. Glacial acetic acid (0.05 ml) is then added until the yellow color has disappeared. The reaction mixture is concentrated under reduced pressure and co-evaporated with benzene. It is dried under high vacuum to yield the title compound as a white solid (155 mg, 99% yield).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CS([C:17]1[N:22]=[CH:21][C:20]2=[CH:23][CH:24]=[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:32]([CH3:37])[S:33]([CH3:36])(=[O:35])=[O:34])[N:19]2[N:18]=1)=O.[F-].[Cs+].C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[CH3:37][N:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]1[N:19]2[C:20]([CH:21]=[N:22][C:17]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:12][N:11]=3)=[N:18]2)=[CH:23][CH:24]=1)[S:33]([CH3:36])(=[O:34])=[O:35]
Reactant: Nc1ccc(N2CCOCC2)cn1
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: CN(c1ccccc1-c1ccc2cnc(Nc3ccc(N4CCOCC4)cn3)nn12)S(C)(=O)=O
Temperature: 120 °C

Procedure:
Into a 8-dram vial, 5-Morpholin-4-yl-pyridin-2-ylamine (0.108 g, 0.604 mmol), N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (0.100 g, 0.274 mmol), Cesium fluoride (0.104 g, 0.686 mmol), N,N-Diisopropylethylamine (0.1051 mL, 0.6036 mmol) and tert-Butyl alcohol (1.50 mL) were added. The reaction was heated at 120° C. overnight. LCMS suggested presence of desired product. The solvent was removed under vacuum. The reaction mixture was purified via HPLC reverse phase chromatography with 0.1% TFA in Water and 0.1% TFA in ACN. The collected fractions were lyophilized to give a yellow solid (40 mg, 33%). LCMS (E/I+) 480.14 (M+H). NMR 1H (DMSO-d6)-10.49 (bs, 1H), 9.09 (s, 1H), 7.86-7.92 (m, 1H), 7.84 (bs, 1H), 7.70-7.80 (m, 1H), 7.66-7.73 (m, 1H), 7.50-7.64 (m, 3H), 7.13 (bs, 1H), 7.11 (bs, 1H), 3.75 (bs, 4H), 3.14 (s, 3H), 3.11 (bs, 4H), 2.83 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[C:15](#[N:20])/[CH:16]=[CH:17]/[C:18]#[N:19]>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH:14][CH:17]([CH2:16][C:15]#[N:20])[C:18]#[N:19]
Reactant: N#C/C=C/C#N
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: CS(C)=O
Solvent: O
Product: N#CCC(C#N)NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 100 °C

Procedure:
A mixture of 2,6-dichloro-4-trifluoromethylphenylhydrazine (1.0 g) and fumaronitrile (1.0 g) in dimethylsulfoxide (10 ml) was heated at 100° C. for 7 hours. The cooled mixture was diluted with water and extracted (ether) to give, after evaporation and crystallization from dichloromethane/hexane, the title compound (0.828 g, 63%), m.p. 101-102° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].I[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:16]([F:19])([F:18])[F:17])[N:15]=[N:14]2)=[CH:9][CH:8]=1>CO>[N:1]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2([C:16]([F:19])([F:17])[F:18])[N:14]=[N:15]2)=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: FC(F)(F)C1(c2ccc(CI)cc2)N=N1
Agent: [Na+]
Solvent: CO
Product: [N-]=[N+]=NCc1ccc(C2(C(F)(F)F)N=N2)cc1
Temperature: 45 °C
Reaction time: 6 h
Yield: 76.2 %

Procedure:
NaN3 (0.42 g, 6.2 mmol) was added to a MeOH (30 mL) solution of 3-[4-(iodomethyl)phenyl]-3-(trifluoromethyl)-3H-diazirine (1.01 g, 3.1 mmol). The solution was stirred at 45° C. (6 h). The methanol was evaporated and CH2Cl2 (30 mL) and water (30 mL) were added. The organic layer was extracted and the aqueous layer was washed with CH2Cl2 (1×30 mL). The organic layers were combined and concentrated in vacuum. Finally, the residue was purified by silica gel flash chromatography (0→30% EtOAc in hexanes) to obtain 570 mg (77%) of a pale yellow liquid: Rf=0.85 (1/9 EtOAc/hexanes); IR (nujol) 3298, 2927, 2859, 2100 (N3), 1694, 1615, 1459, 1374, 1236, 1162, 1055, 939, 805, 728 cm−1; 1H NMR (CDCl3): δ 4.37 (s, CH2), 7.21 (d, J=7.9 Hz, 2 C6H4), 7.35 (d, J=7.9 Hz, 2 C6H4); 13C NMR (CDCl3): δ 28.3 (q, J=40.2 Hz, C diazirine), 54.1 (CH2N3), 122.1 (q, J=273.0 Hz, CF3), 127.0 (C6H2), 128.5 (C6H2), 129.2 (C6H2), 137.2 (C6H2).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:10]([O:23][CH3:24])[CH:9]=1)=[O:6].[NH3:26]>CO>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:26])=[O:2])=[CH:9][C:10]=1[O:23][CH3:24]
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)c(OC)c1
Reactant: N
Solvent: CO
Product: COc1cc(NC(=O)CC(N)=O)ccc1OCc1cccc(F)c1
Yield: 71 %

Procedure:
Prepared in analogy to example 3 from N-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-malonamic acid methyl ester and 7M ammonia in methanol. Yield=71%. Colorless solid. MS: m/e=333.0 (M++H).
Reaction SMILES: ClC1C=C(OC)C=CC=1N1[C:14]([CH3:15])=[C:13]([C:16]([OH:18])=[O:17])[N:12]=[N:11]1.[Cl:19][C:20]1[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=1[NH2:22]>>[Cl:19][C:20]1[CH:26]=[C:25]([O:27][C:28]([F:29])([F:30])[F:31])[CH:24]=[CH:23][C:21]=1[N:22]1[C:14]([CH3:15])=[C:13]([C:16]([OH:18])=[O:17])[N:12]=[N:11]1
Reactant: Nc1ccc(OC(F)(F)F)cc1Cl
Reactant: COc1ccc(-n2nnc(C(=O)O)c2C)c(Cl)c1
Product: Cc1c(C(=O)O)nnn1-c1ccc(OC(F)(F)F)cc1Cl

Procedure:
The title compound was prepared analogously to 1-(2-chloro-4-methoxyphenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (Example step 2) by replacing 2-chloro-4-methoxyaniline (step 1) with 2-chloro-4-trifluoromethoxyaniline.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:26][C:27]1([CH3:33])[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]1>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:29]4[CH2:30][CH2:31][CH2:32][C:27]([CH3:33])([CH3:26])[CH2:28]4)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CCCNC1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Solvent: CN(C)C=O
Product: CC1(C)CCCN(Cc2nc(-c3ncn4c3[C@@H]3CCN3C(=O)c3c(Cl)cccc3-4)no2)C1
Yield: 98.6 %

Procedure:
1.13 g (3 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature overnight with 2 g (17.7 mmol) of 3,3-dimethylpiperidine and 15 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there were obtained 1.34 g (98%) of (S)-8-chloro-1-[5-(3,3-dimethyl-piperidin-1-yl)methyl-1,2,4-oxadiazol-3-yl]-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride (amorphous).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]1[C:22]3[C:17](=[CH:18][C:19]([CH:23]=[CH2:24])=[CH:20][CH:21]=3)[CH:16]=[CH:15][C:14]=1[O:25][Si](C(C)(C)C)(C)C)=[C:8]([O:33][Si](C(C)(C)C)(C)C)[CH:7]=[CH:6]2)=[CH2:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH:23]([C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[C:13]([C:9]1[C:10]3[C:5](=[CH:4][C:3]([CH:1]=[CH2:2])=[CH:12][CH:11]=3)[CH:6]=[CH:7][C:8]=1[OH:33])=[C:14]([OH:25])[CH:15]=[CH:16]2)=[CH2:24]
Reactant: C=Cc1ccc2c(-c3c(O[Si](C)(C)C(C)(C)C)ccc4cc(C=C)ccc34)c(O[Si](C)(C)C(C)(C)C)ccc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C=Cc1ccc2c(-c3c(O)ccc4cc(C=C)ccc34)c(O)ccc2c1

Procedure:
An optically active binaphthol (VII) is reacted with bromine in acetic anhydride to obtain 6,6′-dibromo-2,2′-dihydroxy-1,1′-binaphthyl (XII). The hydroxyl groups of compound (XII) are protected using tert-butyldimethylsilyl oxytriflate (TBDMSOTf) and 2,6-lutidine to obtain 6,6′-dibromo-2,2′-bis(tert-butyldimethylsilyloxy)-1,1′-binaphthyl (XIII). Compound (XIII) is converted to an anion form using sec-butyllithium (sec-BuLi), and dimethylformamide (DMF) is caused to act thereon to obtain 6,6′-diformyl-2,2′-bis(tert-butyldimethylsilyloxy)-1,1′-binaphthyl (XIV). Compound (XIV) is reacted with triphenylmethylphosphonium bromide (Ph3P+CH3Br−) and potassium t-butoxide (t-BuOK) to obtain 6,6′-divinyl-2,2′-bis(tert-butyldimethylsilyloxy)-1,1′-binaphthyl (XV). Compound (XV) is reacted with tetrabutylammonium fluoride (TBAF) for silyl removal to obtain 6,6′-divinyl-2,2′-dihydroxy-1,1′-binaphthyl, which is heated together with phosphorus trichloride to obtain 6,6′-divinyl-1,1′-binaphthalene-2,2′-dioxychlorophosphine (XVI). The 6,6′-divinyl-1,1′-binaphthalene-2,2′-dioxychlorophosphine (XVI) is reacted with 2′-diphenylphosphino-2-hydroxy-1,1′-binaphthyl (XI) in the presence of triethylamine (NEt3) to obtain 2′-diphenylphosphino-1,1′-binaphthalen-2-yloxy(6,6′-divinyl-1,1′-binaphthalene-2,2′-diyloxy)phosphine (XVII).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:14]=[O:15])C1C=CC=CC=1.[CH3:16][C:17]1[C:23]([OH:24])=[CH:22][CH:21]=[CH:20][C:18]=1[OH:19]>CCOCC>[OH:19][C:18]1[C:17]([CH3:16])=[C:23]([OH:24])[CH:22]=[CH:21][C:20]=1[CH:14]=[O:15]
Reactant: CN(C=O)c1ccccc1
Reactant: Cc1c(O)cccc1O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: Cc1c(O)ccc(C=O)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
Phosphorus oxychloride (80 mL, 0.86 mol) was added to a stirred mixture of N-methylformanilide (102 mL, 0.82 mol) in ether (250 mL). The mixture was stirred for 1 hour at room temperature and then cooled in ice. 2-Methyl resorcinol (Aldrich, 100 g, 0.81 mol) was added and the mixture was allowed to warm to room temperature while stirring overnight. The precipitated intermediate product was collected by filtration and rinsed with ether (3×). The intermediate was hydrolyzed by dissolving in a mixture of acetone (250 mL) and water (250 mL) and stirring for 30 minutes. Water (2 L) was added, the mixture was brought to a boil, and then allowed to cool and deposit crystalline product. This was recrystallized a second time from water (4 L) to afford pure product (70 g, 57%). M.p. 150° C. (Lit. 152°-3° C. [W. Baker et al., J. Chem. Soc., 2834-5 (1949)⟧ NMR (DMSO-d6): δ1.973 (s, 3H), 6.551 (d, J=8.5 hz, 1H), 7.428 (d, J-8.5 hz, 1H), 9.703 (s, 1H), 10.745 (s, 1H), and 11.592 (s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]#[CH:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].O.S(=O)(=O)(O)[OH:20]>C(O)(=O)C>[C:16]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:14][C:13]2=[O:15])(=[O:20])[CH3:17]
Reactant: C#Cc1ccc2[nH]c(CCCC)nc(=O)c2c1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CCCCc1nc(=O)c2cc(C(C)=O)ccc2[nH]1
Temperature: 25 °C

Procedure:
To a solution of 1.20 g of 2-butyl-6-ethynyl-4(1H)-quinazolinone in 90 ml of acetic acid is added 0.45 g of mercuric sulfate, 0.9 ml of water and 0.3 ml of sulfuric acid. The reaction mixture is heated at reflux for 5 hours, cooled to room temperature and quenched with 150 ml of water. The resulting mixture is concentrated in vacuo, diluted with 150 ml of water and extracted with 6:1 chloroform-methanol. The combined organics are dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by flash chromatography on silica gel, eluting with 1:1 ethyl acetate-hexanes to give 0.67 g of the desired product as a white solid. CI MASS SPEC 245(MH+).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH3:12]>>[C:1]([OH:6])(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4]([NH2:12])=[O:5]
Reactant: N
Reactant: O=C1OC(=O)c2ccccc21
Product: NC(=O)c1ccccc1C(=O)O
Temperature: 25 °C

Procedure:
With vigorous stirring, concentrated ammonia solution (900 ml, S.G. 0.9) was treated portionwise with phthalic anhydride (600 g, 4.0 moles) over a period of 11/2 hrs. After the reaction mixture had cooled to room temperature, the precipitated ammonium phthalamate was filtered, then dissolved in the minimum of water. When this solution was acidified to pH 2, phthalamic acid began to crystalize, M.P. 132°-6°.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH3:17])[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][N:26]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH3:17])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([OH:24])=[N:26][CH:27]=2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CN(CCCCN)[C@@H](C)c2ccccn2)c(C)c1
Reactant: O=C(O)c1ccc(O)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc(CN(CCCCNC(=O)c2ccc(O)nc2)[C@@H](C)c2ccccn2)c(C)c1
Yield: 29.7 %

Procedure:
Using General Procedure G: To a solution of (S)-N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-(1-pyridin-2-yl-ethyl)-butane-1,4-diamine (0.11 g, 0.35 mmol) in dry DMF (7 mL) was added 6-hydroxy-nicotinic acid (79 mg, 0.57 mmol) followed by EDCI (115 mg, 0.59 mmol), HOBT (86 mg, 0.63 mmol), and DIPEA (0.20 mL, 1.15 mmol). Purification of the crude material by radial chromatography on silica gel (1 mm plate, 10:1:1 CH2Cl2-MeOH—NH4OH) provided 45 mg (29%) of the free base of the title compound as a colorless oil. Using General Procedure D: Conversion to the HBr salt gave COMPOUND 147 (49 mg, 62%) as a white solid. 1H NMR (D2O) δ 1.19-1.57 (m, 4H), 1.58 (d, 3H, J=6.9 Hz), 2.35 (s, 3H), 2.39 (s, 3H), 2.51-2.71 (m, 2H), 3.20 (t, 2H, J=6.3 Hz), 4.22 (s, 2H), 4.55 (q, 1H, J=6.9 Hz), 6.64 (d, 1H, J=9.6 Hz), 7.82 (dd, 1H, J=2.7, 9.6 Hz), 7.94-7.99 (m, 2H), 8.05-8.12 (m, 2H), 8.35 (s, 1H), 8.55 (dt, 1H, J=1.5, 8.1 Hz), 8.75 (dd, 1H, J=1.2, 5.7 Hz); 13C NMR (D2O) δ 14.53, 16.73, 17.45, 24.48, 26.53, 39.24, 51.26, 53.06, 60.39, 115.68, 119.28, 126.70, 135.93, 137.14, 137.29, 137.42, 140.95, 141.95, 148.01, 148.77, 149.56, 156.29, 165.39, 166.54; ES-MS m/z 434 (M+H). Anal. Calcd. For C25H31N5O2.3.5HBr.3.0H2O: C, 38.96; H, 5.30; N, 9.09; Br, 36.28. Found: C, 38.99; H, 5.29; N, 8.95; Br, 36.24.
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])C.[Cl:9][C:10]1[CH:11]=[C:12]([N+]([O-])=O)[C:13](C)=[CH:14][C:15]=1[F:16].O.NN>CN(C)C=O>[Cl:9][C:10]1[CH:11]=[C:3]2[C:13]([CH:12]=[CH:6][NH:4]2)=[CH:14][C:15]=1[F:16]
Reactant: COC(OC)N(C)C
Reactant: Cc1cc(F)c(Cl)cc1[N+](=O)[O-]
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc2cc[nH]c2cc1Cl
Temperature: 130 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
N,N-Dimethylformamide dimethylacetal (6.3 ml, 45 mmol) was added in one portion to a stirred solution of 3-chloro-4-fluoro-6-methylnitrobenzene (7.0 g, 37 mmol) in N,N-dimethylformamide (30 mL) at 130° C. under Ar. The mixture was stirred at 130° C. for 2 h, cooled to room temperature, concentrated in vacuo and partitioned between ethyl acetate and water and the aqueous was extracted with ethyl acetate (2×). The combined organic extracts were washed with brine, dried (magnesium sulfate), concentrated in vacuo, dissolved in methanol/tetrahydrofuran (1:1; 100 mL) and Raney Nickel®, 50% wt. in water, (5 g) was added. The mixture was cooled to 0° C. and hydrazine hydrate (3 mL, 59 mmol) was added dropwise over 2 min. The mixture was warmed to room temperature, stirred for 1 h then cooled to 0° C. and hydrazine hydrate (1.5 mL) was added over 2 min. The mixture was warmed to room temperature, stirred for 1 h and filtered through celite®. The filter-cake was washed with tetrahydrofuran and the filtrate was concentrated in vacuo and purified by column chromatography [SiO2; heptane-dichloromethane (4:1)] to give the product (3.2 g, 51%) as an off-white solid. An analytical sample was recrystallised (heptane) to give a white solid: mp 105-107° C.; NMR δH (400 MHz, CDCl3) 8.01 (1H, br. s), 7.40 (1H, d, J 6 Hz), 7.35 (1H, d, J 9.4 Hz), 7.25 (1H, t, J 2.8 Hz), 6.50-6.51 (1H, m).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C([O-])([O-])=O.[K+].[K+]>>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: BrCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1ccc(OCCCCCCBr)cc1
Reaction time: 20 h

Procedure:
An amount of 16.6 g (100 mmol) of ethyl 4-hydroxybenzoate, 122 g (500 mmol) of 1,6-dibromohexane, 10.0 g of K2CO3 (finely powdered in a mortar and dried) are heated under reflux in 75 ml of absolute acetone. After 20 hours, first the acetone and then the excess of dibromohexane are removed by distillation at 15 mmHg. The crude product is purified in a high vacuum by means of a bulb tube distillation apparatus. After recrystallization from a little ethanol and drying in vacuo over P4O10, about 10 g of analytically pure product are obtained. The melting point is in the room temperature range.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[OH:27]C1C=C2C(=CC=1)OC(C1C=CC=CC=1)=CC2=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][C:16]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:15][C:14]3=[O:27])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Product: O=c1cc(-c2ccccc2)oc2ccc(Oc3ccc([N+](=O)[O-])cn3)cc12

Procedure:
6-(5-Nitropyridin-2-yloxy)-2-phenylchromen-4-one was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 500 mg of 6-hydroxyflavone. The product was recrystallised from a mixture of 2-propanol and acetone. 1H NMR (300 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.67 (dd, 1H, J 9.0, 2.9 Hz), 8.16-8.13 (m, 2H), 7.95 (d, 1H, J 9.0 Hz), 7.82 (d, 1H, J 2.9 Hz), 7.63 (dd, 1H, J 9.1, 2.9 Hz), 7.64-7.61 (m, 3H), 7.38 (d, 1H, J 9.1 Hz), 7.09 (s, 1H).