Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:18][CH3:19])=[C:8]2[C:13](O)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:22]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:18][CH3:19])=[C:8]2[C:13]([Cl:22])=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(O)c2c1OC
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1OC
Temperature: 110 °C

Procedure:
A mixture of 0.46 g of crude 393F in POCl3 (5 ml) was heated at 110° C. for 1 h. Excess of POCl3 was removed on a rotary evaporator, the residue was dissolved in CH2Cl2, washed with aqueous NaHCO3, dried and concentrated to give 0.37 g of crude 393G which was used in next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])[CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[C:17](=[S:22])([O:19][CH2:20][CH3:21])[S-:18].[K+].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])[CH:11]=[C:12]([S:22][C:17]([O:19][CH2:20][CH3:21])=[S:18])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)cc(C(=O)C=CC(=O)O)cc1Cl
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCOC(=S)SC(=CC(=O)c1cc(Cl)c(C)c(Cl)c1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
A suspension of 2.59 g (0.01 mole) of 4-(3,5-dichloro-4-methylphenyl)-4-oxo-2-butenoic acid and 1.60 g (0.01 mole) of potassium O-ethyl dithiocarbonate in 40 ml of water was stirred at room temperature for 3 hours. At the end of this time, the mixture was ice-cooled, acidified by the addition of concentrated hydrochloric acid and then extracted with diethyl ether. The extract was subjected to column chromatography through silica gel, to give 3.60 g (yield 94.5%) of the desired 4-(3,5-dichloro-4-methylphenyl)-2-ethoxythiocarbonylthio-4-oxobutenoic acid, melting at 126°-128° C.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].[CH2:10]1[O:12][CH:11]1[CH2:13][OH:14].[OH-].[Na+]>ClCCl>[Cl:3][C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([O:14][CH2:13][CH:11]2[O:12][CH2:10]2)[N:1]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: OCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Clc1nc(Cl)nc(OCC2CO2)n1
Reaction time: 3 h

Procedure:
A solution of 73.76 g (0.4 moles) cyanuric chloride in 360 ml of dichloromethane was chilled in an ice-water bath to about 0-5° C. and 31.85 g (0.43 moles) glycidol was added. A solution of 34.4 g 50% aqueous sodium hydroxide was added over about 30-45 minutes with stirring keeping the temperature between about 0° C. and about 10° C. Stirring was continued for an additional 3 hours after which time the layers were separated and the organic layer washed two times with water, and once with brine and the solution was dried over magnesium sulfate. Filtration and evaporation of the solution afforded a white solid, a sample of which was further purified by trituration with hexane-ethyl acetate. The proton and carbon nuclear magnetic resonance (NMR) spectra were consistent with the desired product, 2,4-dichloro-6-glycidoxy-1,3,5-triazine.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:18]=[C:17]([C:27]([F:30])([F:29])[F:28])[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N:19]1[C:15]([C:11]2[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][CH:12]=2)=[CH:16][C:17]([C:27]([F:30])([F:28])[F:29])=[N:18]1
Reactant: FC(F)(F)c1cc(-c2cccc(OCc3ccccc3)c2)n(-c2ccccc2Cl)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Oc1cccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)c1

Procedure:
To a solution of 5-(3-(benzyloxy)phenyl)-1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole in MeOH (100 mL) was added 10% palladium on carbon (1.04 g). The black suspension was shaken on the Pair hydrogenator at 40-50 psi hydrogen pressure for 5 hours. At this time the reaction was incomplete as evidenced by HPLC analysis. The reaction suspension was treated with additional Pd/C and shaken under 60 psi hydrogen pressure for an additional 16 hours. At this time HPLC showed no remaining starting 5-(3-(benzyloxy)phenyl)-1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazole. The reaction mixture was filtered through a pad of Celite that was then washed thoroughly with MeOH. The filtrate was concentrated under reduced pressure to afford 3-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenol as a brittle foam. This material was pure enough for use in subsequent transformations. MS(ES): 339 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]>>[C:23]([NH:22][C:17]1[CH:18]=[CH:19][C:20]([Cl:21])=[C:15]([NH:14][C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:13])[CH:16]=1)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: Nc1cc(NC(=O)c2ccccc2)ccc1Cl
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc3ncccc3c2)c1)c1ccccc1
Yield: 47 %

Procedure:
Using an analogous procedure to that described in Example 7, quinoline-6-carboxylic acid was reacted with N-(3-amino-4-chlorophenyl)benzamide to give the title compound in 47% yield; NMR Spectrum: (DMSOd6) 7.57 (m, 6H), 7.75 (m, 1H), 7.95 (d, 2H), 8.15 (d, 1H), 8.17 (d, 1H), 8.55 (d, 1H), 8.78 (s, 1H), 9.01 (m, 1H), 10.33 (s, 1H), 10.44 (s, 1H); Mass Spectrum: M−H− 400.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][OH:11])=[N:8][CH:9]=1.[CH:12]([CH:15]1[C:20]2[N:21]=[CH:22][NH:23][C:19]=2[CH2:18][CH2:17][N:16]1[C:24](OCC(Cl)(Cl)Cl)=[O:25])([CH3:14])[CH3:13]>C1COCC1>[CH:12]([CH:15]1[C:20]2[N:21]=[CH:22][NH:23][C:19]=2[CH2:18][CH2:17][N:16]1[C:24]([O:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][N:8]=1)=[O:25])([CH3:14])[CH3:13]
Reactant: CC(C)C1c2nc[nH]c2CCN1C(=O)OCC(Cl)(Cl)Cl
Reactant: OCc1ccc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1c2nc[nH]c2CCN1C(=O)OCc1ccc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 1.2 %

Procedure:
NaH (80.0 mg, 2.00 mmol, 60% dispersion in mineral oil) was suspended in THF (10 mL), the suspension was cooled to 0° C. and 5-chloropyridine-2-methanol (0.29 g, 2.00 mmol) was added. The suspension was stirred at 0° C. for 30 min then added to a solution of Intermediate 2 (0.65 g, 2.00 mmol, 70% pure) in THF (10 mL) and the reaction mixture was stirred at room temperature. Two additional such portions of NaH and 5-chloropyridine-2-methanol in THF were added after 2 and 3 d, respectively. After 4 d the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The solvents were removed in vacuo and the residue was dissolved in EtOAc (100 mL) washed with 1 M aq Na2CO3 solution (4×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 mL) followed by 2%, 4%, 5% and 10% MeOH in DCM (200 mL each)) and reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL/min, gradient 20% to 80% (over 12 min) to 100% (over 3 min) MeOH in water (1% formic acid)). The residue was de-salted using K2CO3 to give (5-chloropyridin-2-yl)methyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (7.91 mg, 1.2%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CC1C=CC(S(O[CH2:20][CH2:21][CH2:22][NH:23][C:24]2[C:25](=[O:41])[N:26]([C:37]([CH3:40])([CH3:39])[CH3:38])[S:27](=[O:36])(=[O:35])[C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=O)=O)=CC=1>>[C:37]([N:26]1[C:25](=[O:41])[C:24]([NH:23][CH2:22][CH2:21][CH2:20][O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[C:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[S:27]1(=[O:35])=[O:36])([CH3:38])([CH3:39])[CH3:40]
Reactant: Oc1cccc(F)c1
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Product: CC(C)(C)N1C(=O)C(NCCCOc2cccc(F)c2)=C(c2ccccc2)S1(=O)=O
Yield: 65 %

Procedure:
The title compound was prepared as described for Example 12 from 3-fluorophenol and 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate with a reaction time of 15 mins. The reaction mixture was evaporated and the residue was purified by silica gel column chromatography (Horizons Biotage) using 15% EtOAc in hexane as eluent to give the title compound (0.069 g, 65%). 1H NMR (500 MHz CDCl3): δ 7.54-7.50 (m, 2H), 7.46-7.42 (m, 3H), 7.26-7.20 (m, 1H), 6.70-6.60 (m, 2H), 6.59-6.55 (m, 1H), 5.69 (t, 1H), 3.86 (t, 1H), 3.12-3.07 (q, 2H), 1.90-1.82 (m, 2H), 1.75 (s, 9H); 13C NMR (125 MHz CDCl3): δ 164.8, 162.8, 159.9, 159.8, 135.3, 131.8, 130.5, 130.4, 129.8, 128.8, 125.3, 110.4, 108.2, 108.1, 107.3, 102.5, 102.3, 66.3, 61.7, 42.3, 28.9, 27.8; Mass Spectrum: M+H+ 433.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:6][C:7]1[C:14]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O)[CH2:4][CH3:5].[BH4-].[Na+]>CO>[CH3:1][NH:2][CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][C:16]([F:19])([F:18])[F:17])[C:7]=1[O:6][CH2:3][CH2:4][CH3:5]
Reactant: CCCOc1c(C=O)cccc1OC(F)(F)F
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCOc1c(CNC)cccc1OC(F)(F)F
Reaction time: 18 h
Yield: 73 %

Procedure:
A solution of methylamine (19 mL of a 2.0 M solution in MeOH, 38 mmol) was added to 2-propoxy-3-trifluoromethoxybenzaldehyde (1.15 g, 4.60 mmol). The mixture was stirred for 18 h. The solution was concentrated under reduced pressure. The resulting clear oil was dissolved in EtOH (19 mL) and treated with NaBH4 (0.174 g, 4.60 mmol). After stirring for 5.5 h, the reaction mixture was concentrated under reduced pressure, then dissolved in 1 N NaOH (19 mL). The mixture was extracted with Et2O (3×50 mL). The organics were collected, washed with brine (2×100 mL), dried (Na2SO4) and concentrated to yield the title compound (0.89 g, 73%) as an orange oil: 1H NMR (300 MHz, DMSO-d6) δ 7.41 (dd, J=7.7, 1.6 Hz, 1H), 7.25 (dd, J=6.7, 1.3 Hz, 1H), 7.16 (t, J=7.7 Hz, 1H), 3.87 (t, J=6.3 Hz, 2H), 3.68 (s, 2H), 2.27 (s, 3H), 2.07 (br s, 1H), 1.74 (q, J=6.4 Hz, 2H), 1.02 (t, J=3.1 Hz, 3H).
Reaction SMILES: [Na:1].[CH3:2][CH2:3][C@@H:4]([C:23]([C@H:25]([C@@H:27]([OH:43])[C@@H:28]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([OH:39])[C:33]=1[C:40]([OH:42])=[O:41])[CH3:29])[CH3:26])=[O:24])[C@H:5]1[O:9][C@@:8]([C@@H:12]2[O:17][C@@H:16]([CH3:18])[C@@:15]([OH:21])([CH2:19][CH3:20])[CH2:14][CH2:13]2)([CH2:10][CH3:11])[CH2:7][C@@H:6]1[CH3:22].[Br:44]Br>C(=S)=S>[Br:44][C:37]1[C:32]([CH2:31][CH2:30][CH:28]([CH3:29])[CH:27]([OH:43])[CH:25]([CH3:26])[C:23](=[O:24])[CH:4]([CH2:3][CH3:2])[CH:5]2[CH:6]([CH3:22])[CH2:7][C:8]([CH2:10][CH3:11])([CH:12]3[CH2:13][CH2:14][C:15]([CH2:19][CH3:20])([OH:21])[CH:16]([CH3:18])[O:17]3)[O:9]2)=[C:33]([C:40]([OH:42])=[O:41])[C:34]([OH:39])=[C:35]([CH3:38])[CH:36]=1.[Na:1]
Reactant: CC[C@@H](C(=O)[C@@H](C)[C@@H](O)[C@H](C)CCc1ccc(C)c(O)c1C(=O)O)[C@H]1O[C@](CC)([C@H]2CC[C@](O)(CC)[C@H](C)O2)C[C@@H]1C
Reactant: BrBr
Agent: [Na]
Solvent: S=C=S
Product: CCC(C(=O)C(C)C(O)C(C)CCc1c(Br)cc(C)c(O)c1C(=O)O)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C

Procedure:
To a solution of 1.53 g of the sodium salt of antibiotic X-537A in 30 ml carbon disulfide was added dropwise a solution of 0.14 ml bromine 10 ml carbon disulfide at -5° over 10 minutes. The solvent was removed under a stream of nitrogen at room temperature (approximately 2 hours). The residue was purified by dissolving it in ethyl acetate and the solution washed successively with aqueous sodium bisulfite and sodium carbonate. After drying (Na2SO4), the solution was evaporated under reduced pressure and the residue crystallized from ethyl acetate to give 5-bromo-3-methyl-6-{7-ethyl-4-hydroxy-3,5-dimethyl-6-oxo-7-[5-ethyl-3-methyl-5-(5-ethyl-5-hydroxy-6-methyl-2-tetrahydropyranyl)-2-tetrahydrofuryl]heptyl} salicylic acid, sodium salt as colorless cubes, m.p. 185°, [α]D25 -7.36° (1% in methanol).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C1C(=O)N([Br:18])C(=O)C1>OS(O)(=O)=O>[Br:18][C:7]1[CH:8]=[C:9]([F:10])[C:2]([F:1])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=Cc1cccc(F)c1F
Agent: O=S(=O)(O)O
Product: O=Cc1cc(Br)cc(F)c1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 26.6 %

Procedure:
To a solution of 2,3-difluorobenzaldehyde (42 g, 0.296 mol) in H2SO4 (150 mL), was added NBS (63 g, 0.354 mol) in three portions over a period of 30 minutes at 60° C. The resulting mixture was heated for 6 hours at this temperature under N2. Work-up: the reaction mixture was poured into ice water. Petroleum ether (300 mL) was added, and the mixture was stirred for 10 minutes. The organic layer was separated, and the aqueous layer was extracted with more petroleum ether (300 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-0.5% EtOAc in petroleum ether) to give 5-bromo-2,3-difluorobenzaldehyde (17.4 g). 1H NMR (300 MHz, CDCl3): δ 10.32 (s, 1H), 7.81-7.79 (m, 1H), 7.65-7.60 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][C:10]([O:17][CH3:18])=[CH:11][CH:12]=3)[O:7][C:6]=2[C:5]([CH3:19])=[CH:4][CH:3]=1.[CH2:20]([N:22]([CH2:27][CH3:28])[CH2:23][CH2:24][NH:25][NH2:26])[CH3:21]>>[CH2:20]([N:22]([CH2:27][CH3:28])[CH2:23][CH2:24][N:25]1[C:2]2[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]3[O:7][C:8]4[CH:9]=[C:10]([O:17][CH3:18])[CH:11]=[CH:12][C:13]=4[C:14]([C:15]=23)=[N:26]1)[CH3:21]
Reactant: COc1ccc2c(=O)c3c(Cl)ccc(C)c3oc2c1
Reactant: CCN(CC)CCNN
Product: CCN(CC)CCn1nc2c3c(c(C)ccc31)Oc1cc(OC)ccc1-2

Procedure:
By the condensation of 1-chloro-6-methoxy-4-methyl-9-xanthenone with 2-(diethylamino)ethyl hydrazine was obtained 2-(2-(diethylamino)ethyl)-8-methoxy-5-methyl-2H(1)benzopyrano[4,3,2-cd]indazole. To 0.27 g. of this base in acetone (4 ml.) was added 30% aqueous hydrogen peroxide (0.35 ml.). After standing for 90 hours at room temperature the solution was evaporated under reduced pressure. Addition of ether to an ethanolic solution of the residue gave an oil which slowly crystallized. Further crystallization from acetonitrile gave yellow crystals m.p. 132°-133° (decomp.) of 2-(2-(diethylamino)ethyl)-8-methoxy-5-methyl-2H(1)benzopyrano[4,3,2-cd]indazole N-oxide 1.75 hydrate.
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.O.[NH2:13][NH2:14]>C(O)(=O)C>[C:4]1(=[O:5])[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1](=[O:6])[NH:14][NH:13]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH][nH]c(=O)c2ccccc12

Procedure:
Compounds of this invention with Formulae I-VIII could be prepared as illustrated by the exemplary reaction in Scheme 20. Reaction of phthalic anhydride with hydrazine hydrate in acetic acid produces 2,3-dihydro-phthalazine-1,4-dione. Chlorination of 2,3-dihydro-phthalazine-1,4-dione and subsequent reaction with an amine, such as N-methyl-p-anisidine, produces the substituted 4-chlorophthalazine, such as (4-chlorophthalazin-1-yl)(4-methoxyphenyl)-amine. The chloro group can then be removed via hydrogenation to produce the substituted phthalazine, such as (4-methoxyphenyl)-methylphthalazin-1-yl-amine.
Reaction SMILES: [CH2:1]([S:3]([NH2:6])(=[O:5])=[O:4])[CH3:2].[N+:7]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](O)=[O:14])([O-:9])=[O:8].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([S:3]([NH:6][C:13]([C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([N+:7]([O-:9])=[O:8])[CH:11]=1)=[O:14])(=[O:5])=[O:4])[CH3:2]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: CCS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCS(=O)(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Yield: 84.5 %

Procedure:
The title compound was prepared in the same way as that described in Example 11, Step 1, using ethyl sulphonamide (3 g, 27.5 mmol), 3-nitrobenzoic acid (4.6 g, 27.5 mmol), 4-dimethylaminopyridine (3.36 g, 27.5 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (5.28 g, 27.5 mmol) and anhydrous dichloromethane (200 ml). The title compound (6 g, 84%) was afforded as a colourless solid. mp 178°-181° C. 1H NMR (360 MHz, D6 -DMSO) δ 1.28 (3H, t, J=7.4 Hz), 3.54 (2H, q, J=7.4 Hz), 7.83 (1H, dd, J=8.0 and 8.0 Hz), 8.33-8.38 (1H, m), 8.47-8.50 (1H, m), 8.75-8.90 (1H, m), 12.40 (1H, brs).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)([O-])[O-].[Na+].[Na+].[CH2:18]([NH2:21])[CH2:19][CH3:20].Cl>O>[N+:9]([C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1[NH:21][CH2:18][CH2:19][CH3:20])([O-:11])=[O:10]
Reactant: CCCN
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCNc1ccc(O)cc1[N+](=O)[O-]
Reaction time: 5 h

Procedure:
34.7 g (0.2 mole) of 4-chloro-3-nitrophenol, 21 g of sodium carbonate, 0.1 g of copper-I chloride and 20 g of n-propylamine are heated in a bath from room temperature up to a bath temperature of 120° C. After 5 hours, the reaction mixture is taken up in water, acidified (pH 2) with hydrochloric acid and extracted 3 times with ethyl acetate in order to remove unreacted starting material. After neutralisation, the aqueous phase is again extracted 3 times with ethyl acetate. After drying and concentration, these extracts give the desired product in the form of a red oil.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[N:8]2[N:9]=[CH:10][CH:11]=[C:7]2[N:6]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:4]=1.CC([O-])=O.[Na+].[I:29]Cl>C(O)(=O)C.O>[I:29][C:11]1[CH:10]=[N:9][N:8]2[C:3]([C:2]([F:1])([F:22])[F:23])=[CH:4][C:5]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[N:6][C:7]=12
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3nccc3n2)cc1
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred solution of 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (21.60 g, 65 mmol) in acetic acid (130 mL) containing anhydrous NaOAc (6.045 g, 74 mmol), was slowly added iodine monochloride (19.65 mL, 3.75M in HOAc). The reaction mixture was stirred at rt overnight. The suspension was diluted with water, the yellow crystalline filtrated, washed with water and dried in vacuum overnight to give 3-iodo-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (31.1 g, 100%) as yellow crystalline solid. MS (ISP) 458.2 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]Br.[CH3:13][CH:14]1[CH2:19][CH:18]([CH3:20])[CH2:17][NH:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:13][CH:14]1[CH2:19][CH:18]([CH3:20])[CH2:17][N:16]([CH2:5][C:4]2[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH3:1])[CH:3]=2)[CH2:15]1
Reactant: Cc1cc(CBr)ccc1[N+](=O)[O-]
Reactant: CC1CNCC(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cc(CN2CC(C)CC(C)C2)ccc1[N+](=O)[O-]
Yield: 61 %

Procedure:
3-Methyl-4-nitrobenzyl bromide (1.00 g), 3,5-dimethylpiperidine (0.60 ml) and potassium carbonate (0.90 g) were dissolved in acetone (20 ml), followed by heating under reflux for 6 hours. The reaction solution was concentrated under reduced pressure, dissolved in chloroform (10 ml), poured into water (100 ml) and extracted with chloroform (50 ml). The organic layer was washed with saturated brine (100 ml), dried over anhydrous sodium sulfate and, after filtration, concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (developing solvent: n-hexane/ethyl acetate=10:1) to obtain the subject compound (NCR-7) (0.70 g, yield 61%) as a yellow oil.
Reaction SMILES: [OH:1][C@:2]12[C@@H:15]3[NH:16][CH2:17][CH2:18][C@:7]1([C:8]1[CH:9]=[C:10]([O:19][CH3:20])[CH:11]=[CH:12][C:13]=1[CH2:14]3)[CH2:6][CH2:5][CH2:4][CH2:3]2.N1C=CC=CC=1.[CH:27]1([C:31](O)=[O:32])[CH2:30][CH2:29][CH2:28]1>C(Cl)Cl>[CH:27]1([C:31]([N:16]2[CH2:17][CH2:18][C@@:7]34[C:8]5[CH:9]=[C:10]([O:19][CH3:20])[CH:11]=[CH:12][C:13]=5[CH2:14][C@@H:15]2[C@:2]3([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6]4)=[O:32])[CH2:30][CH2:29][CH2:28]1
Reactant: O=C(O)C1CCC1
Reactant: COc1ccc2c(c1)[C@@]13CCCC[C@@]1(O)[C@@H](C2)NCC3
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc2c(c1)[C@@]13CCCC[C@@]1(O)[C@@H](C2)N(C(=O)C1CCC1)CC3

Procedure:
To a stirred and cooled solution of 400 mg. (0.00146 mole) of the amino alcohol XXI in 0.16 g. (0.002 mole) of dry pyridine and 5 ml. of methylene chloride, there was added, dropwise, a solution of 0.19 g. (0.0016 mole) of the acid chloride of cyclobutylcarboxylic acid in 5 ml. of methylene chloride. After stirring for ten minutes, the reaction mixture was washed successively with cold dilute aqueous hydrochlorid acid, dilute aqueous sodium hydroxide, water and finally with a saturated aqueous sodium chloride solution. After drying over Na2SO4 and evaporation of the solvent, there was obtained 400 mg. of an oil which crystallized on standing. The oil was treated with a small amount of cold ether and filtered to yield 320 mg. (61.6 %) of crystals which after recrystallization from methanol melted at 183°-85° C. The IR and NMR spectra were consistent with the structure.
Reaction SMILES: [C:1]([C:4]1[C:27]([CH3:28])=[CH:26][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH2:22][CH:23]4[CH2:25][CH2:24]4)[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:37])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(=O)([O-])O.[Na+]>[C:1]([C:4]1[C:27]([CH3:28])=[CH:26][C:7]2[NH:8][C:9]([S:11]([CH2:12][C:13]3[C:18]([O:19][CH3:20])=[C:17]([O:21][CH2:22][CH:23]4[CH2:25][CH2:24]4)[CH:16]=[CH:15][N:14]=3)=[O:37])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: COc1c(OCC2CC2)ccnc1CSc1nc2cc(C(C)=O)c(C)cc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(OCC2CC2)ccnc1CS(=O)c1nc2cc(C(C)=O)c(C)cc2[nH]1
Temperature: 25 °C

Procedure:
5-Acetyl-6-methyl-2-[[(4-cyclopropylmethoxy-3-methoxy-2-pyridinyl)methyl]thio]-1H-benzimidazole (40 mg, 0.10 mmol) was dissolved in methylene chloride (10 ml) and sodium hydrogen carbonate (3 ml,1M). The mixture was stirred at ambient temperature and MCPBA (25 mg, 0.10 mmol, 70%) dissolved in methylene chloride (5 ml) was added portionwise. After 10 min sodium thiosulphate (30 mg) was added whereupon the phases were separated. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica (CH2Cl2 /MeOH/NH3, 97.5:2.5:sat.) Yield 30 mg (73%) of the title compound.