Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[F:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: CO
Reactant: O=C(O)c1ccc(O)cc1F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(O)cc1F
Temperature: 40 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a solution of 2-fluoro-4-hydroxy-benzoic acid (5.32 g, 34.1 mmol) in methanol (21 mL) was added thionyl chloride (4.86 g, 3 mL, 40.9 mmol) dropwise and the reaction mixture was stirred at 40° C. for 3 hours. The reaction mixture was concentrated in vacuo and diluted with DCM (100 mL) and washed with aqueous saturated NaHCO3 (2×50 mL) solution. The organics were separated and dried with MgSO4, filtered and concentrated in vacuo to give methyl 2-fluoro-4-hydroxy-benzoate (2.3 g, 40%). ESI-MS m/z calc. 170.1. Found 171.3 (M+1)+; Retention time: 0.84 minutes (3 min run).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23]O)=[CH:19][CH:18]=1>>[F:15][C:16]([F:25])([F:26])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-(trifluoromethyl)phenyl]methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.31 (2H, s), 5.73 (1H, d, J=1.6 Hz), 7.42 (1H, dd, J=1.2 Hz, J=4.8 Hz), 7.55-7.57 (3H, m), 7.66-7.68 (2H, m), 8.05 (1H, s), 8.70 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H11F3N4O, 345; Found, 345.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH:25]([OH:27])[CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13](B1OC(C)(C)C(C)(C)O1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:36]2[NH:44][C:43]3[CH2:42][CH2:41][NH:40][C:39](=[O:45])[C:38]=3[CH:37]=2)O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([NH:5][C:6]1[C:7]([CH:25]([OH:27])[CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:36]1[NH:44][C:43]3[CH2:42][CH2:41][NH:40][C:39](=[O:45])[C:38]=3[CH:37]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(C)OB(c2cc3c([nH]2)CCNC3=O)OC1(C)C
Reactant: CC(O)c1nc2cccc(B3OC(C)(C)C(C)(C)O3)c2nc1NC(C)(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(O)c1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Temperature: 105 °C
Yield: 26 %

Procedure:
A mixture of 1-(3-(tert-butylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxalin-2-yl)ethanol (310b; 960 mg, 1.732 mmol), 2-bromo-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (608) (596 mg, 2.77 mmol), K2PO4 (1177 mg, 5.54 mmol), X-Phos (Strem Chemicals, Inc., 83 mg, 0.173 mmol), and Pd2dba3 (Aldrich) (79 mg, 0.087 mmol) in a mixture of 1,4-dioxane (15 mL) and water (3.00 mL) was heated under argon at 105° C. for 1.5 h. The reaction mixture was then cooled to RT, diluted with water (100 mL), and extracted with 5% MeOH/DCM (3×100 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) followed by trituration of the collected solid with Et2O (10 mL) furnished 2-(3-(tert-butylamino)-2-(1-hydroxyethyl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (310) (172 mg, 0.45 mmol, 26% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.99 (1H, br. s.), 7.85 (1H, dd, J=7.5, 1.3 Hz), 7.58 (1H, dd, J=8.0, 1.2 Hz), 7.47 (1H, s), 7.34 (1H, t, J=7.8 Hz), 7.04 (1H, d, J=2.2 Hz), 6.93 (1H, s), 6.43 (1H, br. s.), 4.96 (1H, q, J=6.8 Hz), 3.43 (2H, td, J=6.8, 2.5 Hz), 2.86 (2H, t, J=6.8 Hz), 1.54 (9H, s), 1.50 (3H, d, J=6.7 Hz). m/z (ESI, +ve) 380.1 (M+H)+. Separation of this material (310c) by supercritical-fluid chromatography (Chiralpak IC (150×30 mm, 10 μm), 70% liquid CO2/30% MeOH (+20 mM NH4OH), 70 mL/min) separately afforded: first-eluting peak, (S)-2-(3-(tert-butylamino)-2-(1-hydroxyethyl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one, (310; 35.0 mg, 0.092 mmol, m/z (ESI, +ve) 380.1 (M+H)+); and second-eluting peak, (R)-2-(3-(tert-butylamino)-2-(1-hydroxyethyl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (311; 39.0 mg, 0.103 mmol, m/z (ESI, +ve) 380.1 (M+H)+).
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([NH:21][CH2:22][CH2:23][CH2:24][NH2:25])[CH2:19][CH3:20].ClC1C=CC=CC=1Cl>O>[CH2:18]([N:21]1[C:1]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:9]3[C:10]([C:11](=[O:13])[N:25]2[CH2:24][CH2:23][CH2:22]1)=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:19][CH3:20]
Reactant: CCCNCCCN
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: CCCN1CCCN2C(=O)c3ccccc3C12c1ccccc1

Procedure:
22.6 Parts of o-benzoyl-benzoic acid and 11.6 parts of N-propyl-1,3-propanediamine are haeted within 11/2 hours with 50 parts by volume of o-dichlorobenzene until the boiling point of the latter is attained. Almost the theoretical amount of reaction water is azeotropically distilled off. The clear solution is evaporated to dryness in vacuo, the oily residue is dissolved in ethyl acetate and crystallised by the dropwise addition of pentane. In this way, 1-propyl-10b-phenyl-1,3,4,10b-tetrahydro-pyrimido[2,1-a]isoindol-6(2H)-one is obtained of the formula ##STR19## M.P. 135°-137°. 1-Ethyl-10b-phenyl-1,3,4,10b-tetrahydro-pyrimido[2,1-a]isoindol -6(2H)-one is obtained in the same manner from o-benzoyl-benzoic acid and N-ethyl-1,3-propanediamine. M.P. 131°-133°.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](=[O:37])[N:12]([C@H:28]1[CH2:32][CH2:31][C@H:30]([C:33]([O:35]C)=[O:34])[CH2:29]1)[CH2:13][CH2:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.[OH-].[Li+]>CO.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11](=[O:37])[N:12]([C@H:28]1[CH2:32][CH2:31][C@H:30]([C:33]([OH:35])=[O:34])[CH2:29]1)[CH2:13][CH2:14][CH:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)[C@H]1CC[C@H](N(CCC(c2ccccc2)c2ccccc2)C(=O)Nc2nc3ccccc3s2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@H]1CC[C@H](N(CCC(c2ccccc2)c2ccccc2)C(=O)Nc2nc3ccccc3s2)C1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
To a solution of (1S,3S)-methyl 3-(3-(benzo[d]thiazol-2-yl)-1-(3,3-diphenylpropyl)ureido)cyclopentanecarboxylate 42 (303 mg, 589 μmol) in 8:1 MeOH/H2O (18 ml) was added lithium hydroxide hydrate (49.5 mg, 1180 μmol). The reaction mixture was stirred for overnight at 55° C. Volatiles were removed by concentration under reduced pressure. The leftover residue was treated with 10 mL water and 10 mL of aqueous 10% HCl. A precipitate formed upon addition of the acid. After standing for 10 min the precipitate was filtered and washed with copious of amounts of water. After drying under vacuum, the precipitate was purified by injection as a solution in DMF on a reverse phase HPLC column using 5->95% CH3CN/0.1% aqueous TFA as eluant. Product 43 was isolated as white solid (250 mg). LCMS (ES) calcd for C29H29N3O3S 499.2 found 500.2 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH3:17])[CH:13]2[O:14][CH:12]2[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:15]#[N:16])[CH:10]=2)[O:5]1.[NH:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]1=[O:24].N1C=CC=CC=1>C(O)C>[CH3:1][O:2][CH2:3][C:4]1([CH3:17])[CH:13]([OH:14])[CH:12]([N:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]2=[O:24])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:15]#[N:16])[CH:10]=2)[O:5]1
Reactant: COCC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: O=c1cccc[nH]1
Solvent: CCO
Solvent: c1ccncc1
Product: COCC1(C)Oc2ccc(C#N)cc2C(n2ccccc2=O)C1O
Reaction time: 72 h

Procedure:
A mixture of 23.1 g of 2-methoxymethyl-2-methyl3,4-epoxy-6-cyanochroman, 9.5 g of 1H-2-pyridone, 12 ml of pyridine and 600 ml of ethanol is boiled for 72 hours. About 300 ml are removed by distillation, the mixture is cooled and filtered, the solution is evaporated and the residue is worked up in the customary manner. 2-Methoxymethyl-2-methyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-6-cyano3-chromanol, stereoisomer mixture ("A") is obtained, which can be separated into isomer "Al" (CH3 and OH in the cis-position; m.p. 216°-218° C.) and isomer "A2" (CH3 and OH in the trans-position; m.p. 210°-212° C.) by chromatography (silica gel; ethyl acetate/methanol).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH3:24][O:25][CH2:26][CH2:27][NH:28][CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1>CN(C=O)C>[CH3:24][O:25][CH2:26][CH2:27][NH:28][CH2:29][C:30]1[CH:31]=[CH:32][C:33]([NH:34]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:35][CH:36]=1
Reactant: COCCNCc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Solvent: CN(C)C=O
Product: COCCNCc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(2-methoxyethylaminomethyl)-aniline in DMF.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1>C1(C)C(C)=CC=CC=1>[CH3:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:18][C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(C)cc1
Reactant: NCc1ccncc1
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1nc(-c2ccncc2)[nH]c1-c1ccc(C)cc1
Yield: 395.1 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-methylphenyl)-3-oxopropionate (10.5 g) and 4-aminomethylpyridine (5.8 g) were dissolved in xylene (100 ml), and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-methylphenyl)-2-(4-pyridyl)imidazole-4-carboxylate (54.2 g), melting point 182-185° C.
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:8]2[CH2:11][CH:10]([NH:12][NH:13]C(OC(C)(C)C)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:27]>O1CCOCC1>[ClH:27].[ClH:27].[C:21]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:11][CH:10]([NH:12][NH2:13])[CH2:9]2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)NNC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: NNC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To a stirred suspension of tert-butyl 2-[1-(diphenylmethyl)azetidin-3-yl]hydrazinecarboxylate (Preparation 691, 19.3 g, 54.6 mmol) in 1,4-dioxane (64 ml) was added 4M hydrogen chloride in 1,4-dioxane (290 ml) at 0° C. and stirred at room temperature for 4 hours. Then the reaction mixture was concentrated in vacuo and the residue was triturated with diethyl ether to give 15 g (85%) of the title compound as a white solid.
Reaction SMILES: CN([CH:4]=[O:5])C.[CH3:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](O)=[O:10].IC>O>[CH3:6][C:7]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([O:5][CH3:4])=[O:10]
Reactant: Cc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1cccc([N+](=O)[O-])c1C
Temperature: 40 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
With reference to FIG. 4, DMF (130 mL) was added to a well mixed 2-methyl-3-nitrobenzoic acid 2 (50 g, 0.28 mol) and KHCO3 (84 g, 0.84 mol) solution. Since the mixture became highly viscous, it was heated to 40° C. with manual shaking. Iodomethane (79 g, 0.56 mol) was added via syringe after the gas evolution had ceased. The resulting orange colored solution was stirred for 12 hours at room temperature. The reaction mixture was poured into water (800 mL), and the resulting precipitate collected by filtration and dried over P2O5 to give pure methyl 2-methyl-3-nitrobenzoate 3 (56 g, 100%) as a white solid: mp. 64.2-65.5° C.; 1H-NMR (CDCl3) δ 8.00 (d, J=7.8 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.39 (t, J=8.0 Hz, 1H), 3.95 (s, 3H), 2.63 (s, 3H); IR (KBr, cm−1) 1724, 1548, 1279; MS (EI): 195 (M+).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:31](Br)(Br)([Br:33])[Br:32]>C(Cl)Cl>[Br:32][C:31]([Br:33])=[CH:7][C:6]1[CH:1]=[CH:2][C:3]2[O:11][CH2:10][O:9][C:4]=2[CH:5]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
To a solution of piperonal (4.5 g, 30 mmol) and triphenylphosphine (24 g, 90 mmol) in DCM (120 mL) in an ice-water bath was added a solution of carbontetrabromide (15 g, 45 mmol) over a 10 minutes period. After the addition completed, the ice-water bath was removed, the reaction stirred at ambient temperature for 2 h, and then quenched with saturated NaHCO3. Aqueous was separated, and extracted with dichloromethane (2 times). The organic layers were combined, dried over Na2SO4, filtered, and concentrated to give a redish colored residue, that was filtered through a short path silica gel plug, eluting with DCM/hexane (10% to 20%). Concentration of the filtrate gave the title compound (6.5 g, 74% yield) as a pale yellow liquid. 1H NMR (CDCl3) δ 7.36 (s, 1H), 7.18 (d, 1H, J=1.6 Hz), 6.95 (dd, 1H, J=1.5, 8.1 Hz), 6.79 (d, 1H, J=8.1 Hz), 5.99 (s, 2H).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].ClCCl.[OH:14]O>O.[O-2].[O-2].[Mn+4]>[CH2:1]1[O:14][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: OO
Reactant: C=CCCCCCCCC
Agent: [Mn+4]
Agent: [O-2]
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCC1CO1
Temperature: 25 °C
Reaction time: 14 h
Yield: 94 %

Procedure:
In a 25 mL scintillation vial equipped with a magnetic stirrer, 1-decene (1.41 g, 10 mmol) was placed followed by addition of 4 mL dichloromethane. To this solution was added BTSP (2.8 g, 15 mmol). The vial was immersed into ice/water bath. After 5 minutes Re2O7 (24 mg, 0.05 mmol)5 was added followed by 10 μL of water. The reaction turned bright yellow and was allowed to warm up to room temperature and stirred for 14 h. Upon completion, water (3 drops) was added followed by manganese dioxide (ca. 5 mg) in order to decompose the remaining H2O2. The destruction of H2O2 was evident by the disappearance of yellow color. The mixture was then dried over Na2SO4. Concentration afforded 1-decene oxide (1.48 g, 94% yield) of a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[N:3]=1.[CH3:23]N>O1CCOCC1.C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:23])[CH:5]=[C:4]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[N:3]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2cc([N+](=O)[O-])cc(Br)n2)cc1
Solvent: C1COCCO1
Solvent: CCO
Product: CNc1cc(Br)nc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
0.10 g (0.00026 mol) of 2-bromo-4-nitro-6-(4-nitrobenzenesulphonyl)-pyridine was dissolved in 3.2 ml of dioxane and treated with 3.2 ml of 8M methylamine in ethanol. The mixture was stirred at room temperature for 3 hrs., the solvents were removed and the residue was chromatographed on silica gel with ethyl acetate/hexane 1:4. There was obtained 0.065 g (68%) of [2-bromo-6-(4-nitrobenzenesulphonyl)-pyridin-4-yl]-methylamine as pale yellow crystals; m.p.: 191-192° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]1.C(N(CC)CC)C>C1COCC1>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:12]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccc(N)cn2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.8 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) in THF (30 mL) was added tert-butyl piperidin-3-ylcarbamate (700 mg, 3.5 mmol) and triethylamine (0.64 mL, 4.6 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to dryness, the residue was dissolved in dichloromethane and washed with 1 N HCl aq. and water. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness. The residue was dissolved in tetrahydrofuran (30 mL), degassed with nitrogen, charged with catalytic 10 wt. % Pd/C (0.3 g) and the reaction mixture was placed under an atmosphere of hydrogen (40 Psi) until the reduction was complete as indicated by LCMS analysis. The reaction mixture was filtered over diatomaceous earth and the filtrate was concentrated to provide the desired product (850 mg, 93%) as a purple solid: ESI MS m/z 293 [C15H24N4O2+H]+.
Reaction SMILES: [F:1][CH:2]([F:17])[O:3][C:4]1[N:8]([CH:9]([CH3:11])[CH3:10])[N:7]=[C:6]([C:12]([F:15])([F:14])[F:13])[C:5]=1[CH3:16].[Br:18]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:16][C:5]1[C:6]([C:12]([F:15])([F:14])[F:13])=[N:7][N:8]([CH:9]([CH3:10])[CH3:11])[C:4]=1[O:3][CH:2]([F:1])[F:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(C(F)(F)F)nn(C(C)C)c1OC(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)n1nc(C(F)(F)F)c(CBr)c1OC(F)F
Yield: 40.8 %

Procedure:
To a solution of 10.3 g (40.0 mmol) of 5-difluoromethoxy-4-methyl-1-iso-propyl-3-trifluoromethyl-1H-pyrazole in 40 ml of carbon tetrachloride were added 7.8 g (44.0 mmol) of N-bromosuccinimide and 0.3 (2.0 mmol) of α,α′-azobisisobutyronitrile, followed by heating and refluxing under stirring. The reaction solution was externally irradiated with a light for 1 hour. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with chloroform. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was purified by silica gel column chromatography to obtain 5.5 g (yield: 40.7%) of 4-bromomethyl-5-difluoromethoxy-1-iso-propyl-3-trifluoromethyl-1H-pyrazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([N:8]([CH2:12][C:13](O)=[O:14])[CH:9]([CH3:11])[CH3:10])[CH:7]=1>C(O)(=O)C.[Fe]>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:16][C:13](=[O:14])[CH2:12][N:8]2[CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)N(CC(=O)O)c1cc(Br)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(C)N1CC(=O)Nc2ccc(Br)cc21
Reaction time: 2 h
Yield: 73.4 %

Procedure:
To a solution of [(5-bromo-2-nitro-phenyl)-isopropyl-amino]acetic acid (27 g, 85 mmol) in acetic acid (400 ml) was added iron powder (15 g, 0.27 mol) and the mixture was stirred for 2 hrs. at 90° C. The reaction mixture was cooled, filtered, and the acetic acid was evaporated. The remaining slurry was extracted with CH2Cl2 (3×300 ml). The CH2Cl2 extracts were combined, dried (MgSO4) and evaporated to afford the subtitled compound (16.8 g, 73%): 1H-NMR (DMSO-d6) δ1.13 (d, J=6.54 Hz, 6H), 3.57 (s, 2H), 3.99 (septet, J=6.54 Hz, 1H), 6.82 (dd, J=8.23, 1.88 Hz, 1H), 6.72 (d, J=8.17 Hz, 1H), 6.90 (d, J=1.59 Hz, 1H), 10.50 (s, 1H): MS (EI) 267/269 (M)++1 bromine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][C:10]([C:19]([NH2:21])=[NH:20])=[N:9]2)=[CH:4][CH:3]=1.Cl.[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(#N)C>[F:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:20][C:19]([C:10]2[CH2:11][CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=2)=[NH:21])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: N=C(N)C1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N=C(NS(=O)(=O)c1ccc(F)cc1)C1=NN(c2ccc(Cl)cc2)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
Part B: To a stirred solution of 1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamidine.HCl (1.87 gram, 5 mmol) and 4-fluorophenylsulfonyl chloride (0.97 g, 5 mmol) in anhydrous acetonitrile (20 ml) is added triethylamine (2.1 ml, 15 mmol) and the resulting mixture is stirred at room temperature for 16 hours. After concentration in vacuo, the residue is dissolved in a mixture of Ethyl acetate and water. The Ethyl acetate layer is collected, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is recrystallised from methyl-t-butyl ether to give N-[(4-fluorophenyl)sulfonyl]-1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamidine (1.22 gram, 54% yield). Melting point: 200-203.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.O1CCOCC1>Cl[Pd]Cl.O>[N:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:11]([OH:13])=[O:12])=[CH:5]3)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C(O)c1cc2cc(Br)ccc2[nH]1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc2cc(-c3ccncc3)ccc2[nH]1

Procedure:
A solution of 5-bromo-1H-indole-2-carboxylic acid (25 mg), PdCl2 HPNor2 (5 mg), K3PO4 (45 mg), 4-pyridylboronic acid (26 mg), dioxane (1 mL) and H2O (1 mL) was heated to 170° C. in a microwave for 2 h. The solution was passed thru a C18-SPE cartridge eluting with 3, 20, 60, and finally 95% CH3CN in H2O to yield the crude product. LCMS (m/z): 239.1 (M+H).