Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[CH2:32][CH2:33][NH2:34]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:34][CH2:33][CH2:32][CH:27]4[CH2:28][CH2:29][CH2:30][CH2:31][O:26]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: NCCC1CCCCO1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCCC3CCCCO3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 198 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 2-(tetrahydro-2H-pyran-2-yl)ethanamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.27 (m, 1 H) 1.38-1.50 (m, 3 H) 1.60 (d, J=12.9 Hz, 1 H) 1.62-1.70 (m, 2 H) 1.71-1.82 (m, 1 H) 2.44 (s, 3 H) 3.26-3.33 (m, 2 H) 3.35-3.45 (m, 2 H) 3.87 (dd, J=11.0, 1.9 Hz, 1 H) 7.66 (dd, J=8.0, 1.4 Hz, 1 H) 7.72 (s, 1 H) 7.80 (d, J=8.1 Hz, 1 H) 8.16 (s, 1 H) 8.40 (br. s., 2 H) 8.67 (t, J=5.6 Hz, 1 H) 8.90 (t, J=1.5 Hz, 1 H) 13.18 (br. s., 1 H). MS m/z 432 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[OH:15])=[O:4].[H][H]>C(O)(=O)C.[Pt]=O>[CH3:1][O:2][C:3]([C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[OH:15])=[O:4]
Reactant: [H][H]
Reactant: COC(=O)c1c(O)ccc2ccccc12
Agent: O=[Pt]
Solvent: CC(=O)O
Product: COC(=O)c1c(O)ccc2c1CCCC2
Reaction time: 8 h
Yield: 114.7 %

Procedure:
Under an atmosphere of nitrogen, platinum oxide (5 g) was added to a solution of 2-hydroxy-naphthalene-1-carboxylic acid methyl ester (10 g) in acetic acid (200 mL). The nitrogen atmosphere was replaced by hydrogen, the pressure was increased to 4 bar and the mixture was stirred overnight. The resulting suspension was filtered and the filtrate was concentrated under vacuum to give an oil. The residue was purified by chromatography on silica, eluting with DCM. The fractions containing the desired product were combined and evaporated under vacuum to give the title compound as a colorless oil (11.7 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][SH:13])=[O:9])[C:3]([OH:5])=[O:4].[CH:21](SC[C@@H](C(NCC(O)=O)=O)NC(=O)CC[C@@H](C(O)=O)N)=[O:22].OCSC[C@@H](C(NCC(O)=O)=O)NC(=O)CC[C@@H](C(O)=O)N>>[NH2:1][C@@H:2]([CH2:6][CH2:7][C:8]([NH:10][C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:12][SH:13])=[O:9])[C:3]([OH:5])=[O:4].[CH2:21]=[O:22]
Reactant: N[C@@H](CCC(=O)N[C@@H](CSC=O)C(=O)NCC(=O)O)C(=O)O
Agent: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: N[C@@H](CCC(=O)N[C@@H](CSCO)C(=O)NCC(=O)O)C(=O)O
Product: C=O

Procedure:
To be exact, the glutathione-dependent formaldehyde dehydrogenase (EC 1.2.1.1) used in the present invention is an enzyme reversibly catalyzes the production of S-formylglutathione and reduced coenzyme in the presence of oxidized coenzyme, using, as a substrate, S-hydroxylmethylglutathione non-enzymatically produced from glutathione and formaldehyde.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:23][C@@H:24]1[C:30](=[O:31])[N:29]([CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])[C:28]2[CH:40]=[CH:41][CH:42]=[CH:43][C:27]=2[S:26][CH2:25]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])=[O:5])[CH3:2].C(OCC)(=O)C.[ClH:50]>>[ClH:50].[CH2:1]([O:3][C:4]([C@@H:6]([NH:23][C@@H:24]1[C:30](=[O:31])[N:29]([CH2:32][C:33]([OH:35])=[O:34])[C:28]2[CH:40]=[CH:41][CH:42]=[CH:43][C:27]=2[S:26][CH2:25]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:13](=[O:22])[C:14]2=[CH:21][CH:20]=[CH:19][CH:18]=[C:15]2[C:16]1=[O:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Reaction time: 1 h

Procedure:
In 5 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 0.12 g of tert-butyl 3(R)-[1(S)-ethoxycarbonyl-6-phthalimidohexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and the solution is left standing at room temperature for 1 hour. Petroleum ether (50 ml) is added to the solution and the deposited precipitate is dried under reduced pressure to give 0.1 g of 3(R)-[1(S)-ethoxycarbonyl-6-phthalimidohexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid hydrochloride as a colorless powder.
Reaction SMILES: [CH3:1][C@H:2]([NH:9][C:10]([NH:12][C:13]1[N:28]=[C:16]2[N:17]=[CH:18][CH:19]=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[N:15]2[N:14]=1)=[O:11])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].[CH3:35][O:36][CH2:37][CH2:38]Br.C(Cl)Cl>C(C(C)=O)C>[CH3:1][C@H:2]([NH:9][C:10]([NH:12][C:13]1[N:28]=[C:16]2[N:17]=[CH:18][CH:19]=[C:20]([C:21]3[CH:22]=[CH:23][C:24]([O:27][CH2:38][CH2:37][O:36][CH3:35])=[CH:25][CH:26]=3)[N:15]2[N:14]=1)=[O:11])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: COCCBr
Reactant: CC(C)CCC[C@H](C)NC(=O)Nc1nc2nccc(-c3ccc(O)cc3)n2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: COCCOc1ccc(-c2ccnc3nc(NC(=O)N[C@@H](C)CCCC(C)C)nn23)cc1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
(S)-1-(1,5-dimethylhexyl)-3-[7-(4-hydroxyphenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]urea (the compound obtained in Example 255; 30 mg) and potassium carbonate (108 mg) were suspended in methyl ethyl ketone (3 ml). Thereafter, 2-methoxyethyl bromide (327 mg) was added to the obtained suspension, and the obtained mixture was stirred at 80° C. for 10 hours. Thereafter, the reaction solution was cooled to a room temperature, and methylene chloride (5 ml) was then added thereto. The obtained mixture was washed with an aqueous 1 M hydrochloric acid solution (5 ml×3), an aqueous saturated sodium bicarbonate solution (5 ml×2), and distilled water (5 ml×2). The organic layer was concentrated under a reduced pressure, and the obtained residue was purified by reverse phase liquid chromatography (Inertsil PREP-ODS; 20 Φ×250 mm; eluted with water-containing acetonitrile) to obtain the captioned compound (14 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:22]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=2)=[CH:21][NH:20][N:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[CH:21][C:22]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=4)=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Reactant: Cc1cc(-c2c[nH]nc2N)ccn1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)ccn1
Yield: 43.2 %

Procedure:
Reaction of 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (125 mg, 0.5 mmol), prepared from commercially available 4-chloro-acetophenone according to general procedure A, and 3-amino-4-(2-methyl-4-pyridinyl)-pyrazole [see part synthesis of amino-pyrazole derivatives] (87 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (84 mg, 43%). MS (ISP) 389.1 [(M+H)+]; mp 220° C.
Reaction SMILES: O[CH:2]1[O:17][C:5]2=[C:6]([O:15][CH3:16])[C:7]3[O:12][C:11](=[O:13])[CH:10]=[CH:9][C:8]=3[CH:14]=[C:4]2[CH2:3]1>C(O)=O>[CH3:16][O:15][C:6]1[C:7]2[O:12][C:11]([CH:10]=[CH:9][C:8]=2[CH:14]=[C:4]2[CH:3]=[CH:2][O:17][C:5]=12)=[O:13]
Reactant: COc1c2c(cc3ccc(=O)oc13)CC(O)O2
Solvent: O=CO
Product: COc1c2occc2cc2ccc(=O)oc12

Procedure:
A solution of 52.2 g. (0.223 mole) of crude 2-hydroxy-9-methoxy-2,3-dihydro-7H-furo[3,2-g][1]benzopyran-7-one in 900 ml of 98% formic acid was heated under argon at 100° for 45 min. The solvent was removed in vacuo and the dark residue crystallized. After drying on the high vac, the crude product, was taken up in the minimum amount of warm methylene chloride and filtered through an alumina column. Evaporation of fractions afforded pure methoxsalen, mp 145°-146°.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:22][C@H:23]1[CH2:28][NH:27][CH2:26][C@@H:25]([CH3:29])[NH:24]1>CN(C)C=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([N:27]4[CH2:26][C@H:25]([CH3:29])[NH:24][C@H:23]([CH3:22])[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2c(F)c(F)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In the same manner as described in Example 1, a mixture of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, cis-2,6-dimethylpiperazine, and dimethylformamide was stirred at room temperature for 24 hours to give 1-cyclopropyl-5,6,8-trifluoro-7-(cis-3,5-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, which was recrystallized from chloroform-ethanol, m.p. 259°-260° C.
Reaction SMILES: [N:1]#[N:2].Cl.[C:4]([C:6]1[C:19]2[N:18]([CH:20]([CH3:27])[CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[CH:9]=[CH:8][C:7]=1[C:28]([NH2:30])=[NH:29])#[N:5].[CH2:31](N)[CH2:32][CH3:33]>C(O)C.C1(C)C=CC=CC=1>[N:1]#[N:2].[C:4]([C:6]1[C:19]2[N:18]([CH:20]([CH3:27])[CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[S:11][C:10]=2[CH:9]=[CH:8][C:7]=1[C:28]([NH:30][CH2:31][CH2:32][CH3:33])=[NH:29])#[N:5]
Reactant: CCCN
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=N)N)c(C#N)c21
Agent: Cl
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCNC(=N)c1ccc2c(c1C#N)N(C(C)CN1CCCC1)c1ccccc1S2

Procedure:
A solution of N2 -cyano-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamidine hydrochloride (0.93 g) and propylamine (1.86 cc) in ethanol (25 cc) is brought to 100° C. for 16 hours. The reaction mixture is concentrated to dryness at 50° C. under reduced pressure (30 mm Hg; 4 kPa) to give a residue which is purified by chromatography on a column (height: 13.6 cm; diameter: 2.4 cm) of silica (0.04-0.06 mm) with a slight excess pressure of nitrogen (40 kPa), eluting with a 20:80 (by volume) mixture (750 cc) of cyclohexane and ethyl acetate, then with pure ethyl acetate (750 cc) and finally with a 90:10 (by volume) mixture (750 cc) of ethyl acetate and methanol, while collecting 50-cc fractions. The first 1000 cc are discarded and fractions 5 to 10 are combined and concentrated to dryness at 50° C. under reduced pressure (30 mm Hg; 4 kPa) to give a solid which is dissolved hot in toluene (4 cc). Crystallization is primed and, after cooling, the crystals are separated by filtration on sintered glass and dried under reduced pressure (1 mm Hg; 0.13 kPa) at 40° C. to give N2 -cyano-N1 -propyl-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamidine (0.15 g) in the form of yellow crystals, m.p. 154° C.
Reaction SMILES: CS(O)(=O)=O.[OH:6][N:7]1[C:12]([CH3:14])([CH3:13])[CH2:11][CH:10]([O:15][CH3:16])[CH2:9][C:8]1([CH3:18])[CH3:17].OO.S([O-])([O-])=O.[Na+].[Na+].C(O[CH2:31][CH3:32])(=O)C>O.C1CCCCC1.C(#N)C>[CH:32]1([O:6][N:7]2[C:12]([CH3:13])([CH3:14])[CH2:11][CH:10]([O:15][CH3:16])[CH2:9][C:8]2([CH3:18])[CH3:17])[CH2:31][CH2:10][CH2:9][CH2:8][CH2:17]1
Reactant: CCOC(C)=O
Reactant: COC1CC(C)(C)N(O)C(C)(C)C1
Agent: CS(=O)(=O)O
Agent: O=S([O-])[O-]
Agent: OO
Solvent: C1CCCCC1
Solvent: O
Solvent: CC#N
Product: COC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Temperature: 52 °C
Yield: 59 %

Procedure:
A solution of 0.246 g (0.885 mmol) of ferrous sulfate heptahydrate and 0.246 g (2.6 mmol) of methanesulfonic acid in 2 ml of water is added to a mixture of 4.85 g (26.0 mmol) of 1-oxyl-4-methoxy-2,2,6,6-tetramethylpiperidine, 35 ml of acetonitrile, and 22 ml of cyclohexane. The reaction mixture is heated to 52° C. A solution of 5.68 g (83 mmol) of 50% aqueous hydrogen peroxide is added dropwise to the reaction mixture over 2.5 hours while the reaction temperature is brought to and maintained at reflux (62° C). After the peroxide is added, the reaction mixture is stirred at reflux for 1.75 hours, and then allowed to cool slowly to 33° C. Peroxide is decomposed by the addition of aqueous sodium sulfite solution. The reaction mixture is diluted with ethyl acetate, and the organic layer is washed with water and then concentrated. Purification by flash chromatography with 20:1 heptane-ethyl acetate affords 4.11 g (59% yield) of the title compound, a colorless liquid. Structure is verified by NMR analysis.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:12][CH3:13])[C:5]([CH:14]=[O:15])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[O:21][CH2:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([O:30][CH3:31])[C:24]=1[S:32][Sn](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.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>[CH:14]([C:5]1[CH:4]=[CH:3][C:2]([S:32][C:24]2[C:25]([O:30][CH3:31])=[CH:26][C:27]([CH3:29])=[CH:28][C:23]=2[CH2:22][OH:21])=[C:7]([C:6]=1[O:12][CH3:13])[C:8]([O:10][CH3:11])=[O:9])=[O:15]
Reactant: COC(=O)c1c(Br)ccc(C=O)c1OC
Reactant: CCCC[Sn](CCCC)(CCCC)OCc1cc(C)cc(OC)c1S[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1c(Sc2c(CO)cc(C)cc2OC)ccc(C=O)c1OC

Procedure:
1.08 g (3.94 mmol) of the compound from Example 5 and 2 g (2.6 mmol) of the compound from Example 16 and 30 mg of tetrakis(triphenylphosphine)palladium are heated under reflux in 40 ml of toluene under a nitrogen atmosphere for 50 h. After concentrating in vacuo, the residue is taken up in acetonitrile and washed five times with pentane. The acetonitrile phase is concentrated in vacuo and the remaining oil (1.33 g) is chromatographed on a silica gel column using ethyl acetate/petroleum ether 1:5.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[OH:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27](O)=[O:28].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O>[OH:24][C:25]([CH3:31])([CH3:30])[CH2:26][C:27]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1)=[O:28]
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: CC(C)(O)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(O)CC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Yield: 16.6 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.323 mmol), 3-hydroxy-3-methylbutanoic acid (57 mg, 0.485 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (99 mg, 0.517 mmol), 1-hydroxybenzotriazole (71 mg, 0.522 mmol), triethylamine (0.08 mL, 0.549 mmol) and N,N-dimethylformamide (4.0 mL), and by a reaction in the same manner as in Example 187, the title compound (22 mg, 16%) was obtained as pale-yellow crystals.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].S(=O)(=O)(O)O.[NH2:13][C:14]1[C:15]([I:28])=[C:16]([C:25]([Cl:27])=[O:26])[C:17]([I:24])=[C:18]([C:22]=1[I:23])[C:19]([Cl:21])=[O:20]>C1C=CC=CC=1.CC(C)=O>[C:1]([NH:13][C:14]1[C:22]([I:23])=[C:18]([C:19]([Cl:21])=[O:20])[C:17]([I:24])=[C:16]([C:15]=1[I:28])[C:25]([Cl:27])=[O:26])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CC(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reaction time: 1 h

Procedure:
A mixture of 50 ml. of acetic anhydride and 0.1 ml. of conc. sulfuric acid was stirred at room temperature for 5 minutes. To this mixture was added 15 g. (0.025 mole) of 5-amino-2,4,6-triiodoisophthaloyl chloride in one portion and stirring was continued at room temperature for one hour. The mixture was stored overnight at 0°. Filtration furnished 16 g. of solid material. The product was recrystallized from ethyl acetate to furnish 10 g. (63%) of pure product. The compound was shown to be pure by tlc (silica plate-benzene/acetone 80/20).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11][CH2:12]/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])[C:5](Br)=[CH:6][CH:7]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[C:13](=[CH:14][C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][N:10]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:9][C:4]=2[CH:3]=1
Reactant: COC(=O)/C=C/CCN(Cc1cc(N)ccc1Br)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)C=C1CCN(C(=O)OC(C)(C)C)Cc2cc(N)ccc21
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a stirring solution of methyl (2E)-5-{N-[(3-amino-6-bromophenyl)methyl](tert-butoxy)carbonylamino}pent-2-enoate (1 eq) in toluene (0.08 M) at room temperature was added tetrakis(triphenylphosphine) palladium(0.03 eq) and triethylamine (3 eq). The reaction mixture was stirred at 100° C. for 18 hr and filtered through celite. The reaction solvent was removed by rotary evaporation. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (30% EtOAc/Hexane). EI-MS m/z 333 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH:6]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[OH:7].[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.Cl.C(OCC)C>N1C=CC=CC=1>[C:8]1([CH:6]([OH:7])[CH2:5][O:4][CH2:3][CH2:2][O:1][S:24]([C:21]2[CH:22]=[CH:23][C:18]([CH3:28])=[CH:19][CH:20]=2)(=[O:26])=[O:25])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: OCCOCC(O)c1cccc2ccccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCC(O)c2cccc3ccccc23)cc1
Temperature: -25 °C
Reaction time: 4 h

Procedure:
8.3 g of 2-(2-hydroxyethoxy)-1-(1-naphthyl)ethanol was dissolved in 50 ml of pyridine. The solution was cooled to -25° C. Thereto was added 6.8 g of p-toluenesulfonyl chloride. The resulting mixture was allowed to stand at 0°-5° C. for 24 hours and further at room temperature for 4 hours. The reaction mixture was added to a mixture of 103 ml of 6N hydrochloric acid, 50 ml of ice water and 100 ml of diethyl ether. The resulting mixture was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with 20 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was remove. by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: toluene/ethyl acetate=10/1) to obtain 6.3 g of colorless, oily 1-(1-naphthyl)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethanol.
Reaction SMILES: O(C(C(F)(F)F)(C(F)(F)F)[F:4])[K].[N+:13]([C:16]([N+]([O-])=O)([N+:20]([O-:22])=[O:21])[N+:17]([O-:19])=[O:18])([O-:15])=[O:14]>CN(C=O)C>[F:4][C:16]([N+:20]([O-:22])=[O:21])([N+:17]([O-:19])=[O:18])[N+:13]([O-:15])=[O:14]
Reactant: FC(F)(F)C(F)(O[K])C(F)(F)F
Reactant: O=[N+]([O-])C([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])C(F)([N+](=O)[O-])[N+](=O)[O-]

Procedure:
In run 1 (control), 5 ml of 2.2 molar KOCF(CF3)2 in anhydrous DMF was added to a reaction vessel and diluted to 5.0 ml with anhydrous DMF. The reaction vessel consisted of a 50 ml round-bottom, three-neck flask which was equipped with a dropping funnel, an inlet tube with a safety trap, and an exit tube with a -80° C. cooled trap. Tetranitromethane (1.0 g, 5.10 mmoles) was placed in the dropping funnel and diluted with 10 ml of DMF. The system was flushed with nitrogen at 40 cc/min for 2 to 3 minutes. The C(NO2)4 -DMF solution was added to the KOCF(CF3)2 at ambient temperature. Fluorotrinitromethane yields and tetranitromethane conversions were obtained by gas-liquid chromatographic analyses of the reaction mixture as a function of reaction time.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH:10]1([NH:16][C:17]([CH:19]2[CH2:24][CH2:23][CH:22]([C:25]([F:28])([F:27])[F:26])[NH:21][CH2:20]2)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.CCOC(C)=O>O1CCOCC1>[CH:10]1([NH:16][C:17]([CH:19]2[CH2:24][CH2:23][CH:22]([C:25]([F:28])([F:26])[F:27])[N:21]([C:6]3[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([Cl:1])[N:7]=3)[CH2:20]2)=[O:18])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C(NC1CCCCC1)C1CCC(C(F)(F)F)NC1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(NC1CCCCC1)C1CCC(C(F)(F)F)N(c2cc(Cl)nc(Cl)n2)C1
Temperature: 80 °C
Reaction time: 72 h
Yield: 35.4 %

Procedure:
To a mixture of 2,4,6-trichloropyrimidine (0.18 mL, 1.59 mmol) and N-cyclohexyl-6-(trifluoromethyl)-3-piperidinecarboxamide (0.5 g, 1.588 mmol) in 1,4-dioxane (15 mL) was added Hunig's base (0.56 mL, 3.18 mmol), and the reaction mixture was stirred over the weekend (3 days) at 80° C. into a sealed tube. Approximately 35% starting material was remaining. The temperature was increased to 140° C., and the reaction mixture was stirred at this temperature for 3 hours. The reaction was then heated for 1 hour at 160° C. Since there was still remaining starting material, the reaction was stirred overnight at 140° C. The reaction mixture was poured onto water and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% Hexanes to 50% EtOAc in Hexanes) afforded the title compound (239 mg) as a white solid, and the corresponding regioisomer (196 mg) as a white solid. LC-MS (ES) m/z=425, 427 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:11][B-:12]([F:15])([F:14])[F:13].[H+].[N:17]([O-])=O.[Na+]>O>[F:11][B-:12]([F:15])([F:14])[F:13].[F:1][C:2]1[C:8]([CH3:9])=[C:7]([F:10])[CH:6]=[CH:5][C:3]=1[N+:4]#[N:17]
Reactant: Cc1c(F)ccc(N)c1F
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Cc1c(F)ccc([N+]#N)c1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To 2,4-difluoro-3-methylaniline (20 g) are added 42% tetrafluoroboric acid (56 ml) and water (28 ml) under ice cooling and thereto a solution of sodium nitrite (10 g) in water (20 ml) is added dropwise at below 10° C. After dropwise addition, the mixture is stirred at 0° C. for 15 minutes and the formed crystals are filtered, which is washed with a mixture of ethanol--diethyl ether (1:2), then with diethyl ether, followed by drying under reduced pressure to give 2,4-difluoro-3-methylbenzene diazonium tetrafluoroborate (28.95 g), m.p. 114-115° C.