Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[H-].[Na+].Cl[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[N:14]([CH2:27][CH3:28])[N:15]=[C:16]2[C:25]=1[C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:18]=[C:17]2[NH2:26].[I-].[Na+]>CN(C=O)C>[NH2:26][C:17]1[C:16]2=[N:15][N:14]([CH2:27][CH3:28])[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[C:25]2[C:24]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:18]=1
Reactant: CS(N)(=O)=O
Reactant: CCn1nc2c(N)nc3ccccc3c2c1CCCCCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nc2c(N)nc3ccccc3c2c1CCCCNS(C)(=O)=O
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 23.1 %

Procedure:
Methanesulfonamide (1.14 g, 12.0 mmol) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 480 mg, 12.0 mmol) in DMF (5 mL); the reaction was stirred for five minutes. 1-(4-Chlorobutyl)-2-ethyl-2H-pyrazolo[3,4-c]quinolin-4-amine (0.70 g, 2.4 mmol, prepared as described in Example 19) in DMF (2 mL) and sodium iodide (90 mg, 0.6 mmol) were sequentially added. The reaction was heated at 80° C. for one hour and 90° C. for three hours, allowed to cool to ambient temperature, and poured into ice water (70 mL). A precipitate was removed by filtration, and the filtrate was washed with diethyl ether. A precipitate formed in the aqueous layer over a period of 24 hours and was isolated by filtration and washed with water to provide 200 mg of N-[4-(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)butyl]methanesulfonamide as tan crystals, mp 192-194° C.
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([O:22][C:23]1[CH:27]=[CH:26][O:25][N:24]=1)[CH2:20]N)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl:28][CH2:29][CH2:30][CH2:31][S:32]([NH:35]CC(OC)CSCCCCCCCCCCCCCCCC)(=[O:34])=[O:33]>>[Cl:28][CH2:29][CH2:30][CH2:31][S:32]([NH:35][CH:18]([S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:19]([O:22][C:23]1[CH:27]=[CH:26][O:25][N:24]=1)[CH3:20])(=[O:34])=[O:33]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCSCC(CN)Oc1ccon1
Product: CCCCCCCCCCCCCCCCSC(NS(=O)(=O)CCCCl)C(C)Oc1ccon1

Procedure:
3-Hexadecylthio-2-(3-isoxazolyloxy)propylamine IVJ1 is allowed to react and worked up by the same procedure as described in (4). The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[C:7]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=[CH:10][C:3]1=2.[OH-].[Na+].[C:19]([O:23][CH2:24][CH3:25])(=[O:22])[CH:20]=[CH2:21]>>[S:2]1[CH:6]=[CH:5][C:4]2[C:7]([N:11]3[CH2:16][CH2:15][N:14]([CH2:21][CH2:20][C:19]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][CH2:12]3)=[CH:8][CH:9]=[CH:10][C:3]1=2
Reactant: c1cc(N2CCNCC2)c2ccsc2c1
Reactant: C=CC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)CCN1CCN(c2cccc3sccc23)CC1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
5.05 g (19.8 mmol) of 1-Benzo[b]thiophen-4-yl-piperazine hydrochloride was added to an aqueous solution of sodium hydroxide, and the mixture was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 50 ml of ethanol and ethyl acrylate (2.44 ml, 21.8 mmol) was added thereto, then the reaction mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Isopropyl ether was added to the residue to filter out insoluble matters. The insoluble matters were washed with isopropyl ether and dried to obtain ethyl 3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propionate (5.26 g) as white powder.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[C:13]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:18]=1[OH:27])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([C:2]1[CH:3]=[C:4]([C:21]2[CH:22]=[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:18]([OH:27])=[C:19]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=2)[CH:5]=[C:6]([C:19]([CH3:23])([CH3:20])[CH3:18])[C:1]=1[OH:7])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: Oc1ccccc1
Agent: O=S(=O)(O)O
Product: CC(C)(C)c1cc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Reaction time: 6 h

Procedure:
A portion (10.0 g) of this reaction solution was used in the subsequent process. Phenol (20 g) and sulfuric acid (0.04 g) were added to 10.0 g of reaction solution (1) not only for neutralizing the base in the reaction system but also to render the reaction solution acidic (pH, 1). Thereafter, the following two reactions were performed in one step at 180° C. over a period of 6 hours: a redox reaction in which the unreacted 2,6-di-t-butylphenol and 3,3',5,5'-tetra-t-butyl-4,4'-diphenoquinone were reacted to produce 3,3',5,5'-tetra-t-butyl-4,4'-dihydroxybiphenyl; and a reaction in which 3,3',5,5'-tetra-t-butyl-4,4'-dihydroxybiphenyl was dealkylated into p,p'-biphenol.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]1[CH2:13][C:11](=[O:12])[N:10]([CH2:14][NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[C:8]1=[O:9].N1C=CC=CC=1>C1(C)C=CC=CC=1>[O:9]=[C:8]1[N:10]([CH2:14][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[C:3](=[O:4])[CH3:2])[C:11](=[O:12])[CH2:13][N:7]1[CH3:6]
Reactant: O=C(Cl)CCl
Reactant: COc1ccccc1NCN1C(=O)CN(C)C1=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccccc1N(CN1C(=O)CN(C)C1=O)C(C)=O
Reaction time: 1.5 h
Yield: 73.3 %

Procedure:
A solution of 4.5 g of chloroacetyl chloride in 10 ml of toluene was added dropwise to a solution of 7 g of the 1-methyl-3-(2-methoxyphenylaminomethyl)hydantoin and 2.8 g of pyridine in 40 ml of toluene at -10° C. The suspension was stirred on an ice-bath for 1.5 hrs. The resulting precipitate was filtered and thoroughly washed with 5% hydrochloric acid, water, and recrystallized from chloroformether to give 6.0 g of N-(2,4-dioxo-1-methylimidazolidin-3-ylmethyl)-N-(2-methoxyphenyl)acetamide, mp 169°-172° C; M+ = 325.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[C:7](=[N:18]/[O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])/[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:2]=1.[OH-].[Na+].Cl>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[C:7](=[N:18]/[O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])/[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:2]=1
Reactant: CCOC(=O)CCCCO/N=C(/c1cccnc1)c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCCO/N=C(/c1cccnc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 42.2 %

Procedure:
A mixture of 4.3 parts of ethyl (E)-5-[[[(3-pyridinyl)[3-(trifluoromethyl)phenyl]methylen]amino]oxy]pentanoate, 25 parts of a sodium hydroxide solution 1N and 20 parts of ethanol was stirred for 2.5 hours at room temperature. 25 Parts of a hydrochloric acid solution 1N were added and the ethanol layer was evaporated. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and hexane (2:1 by volume). The product was filtered off and dried, yielding 1.7 parts (42.2%) of (E)-5-[[[(3-pyridinyl)[3-(trifluoromethyl)phenyl]methylen]amino]oxy]pentanoic acid; mp. 70.3° C. (compound 63).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:4][CH:3]=1.ClCCl.Cl[S:38]([C:41]1[S:45][C:44]([C:46]([O:48][CH3:49])=[O:47])=[CH:43][CH:42]=1)(=[O:40])=[O:39]>C(N(CC)CC)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3[NH:20][CH:21]2[CH2:22][CH2:23][N:24]([S:38]([C:41]3[S:45][C:44]([C:46]([O:48][CH3:49])=[O:47])=[CH:43][CH:42]=3)(=[O:39])=[O:40])[CH2:25][CH2:26]2)=[CH:32][CH:31]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)s1
Reactant: Oc1cc(NC2CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)N2CCC(Nc3cc(O)nc4ccc(C(c5ccc(Cl)cc5)c5ccc(Cl)cc5)cc34)CC2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4-[(piperidin-4-yl)amino]quinolin-2-ol (150 mg, 0.31 mmol, 1.00 equip), dichloromethane (20 mL), triethylamine (0.5 mL), and methyl 5-(chlorosulfonyl)thiophene-2-carboxylate (76 mg, 0.32 mmol, 1.00 equip). The resulting solution was stirred for 1 h at 25° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) to yield methyl 5-[4-([6-[bis(4-chlorophenyl)methyl]-2-hydroxyquinolin-4-yl]amino)piperidine-1-sulfonyl]thiophene-2-carboxylate as a yellow solid. LCMS (ES, m/z) 682 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:46]=[CH:45][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:36][C@@H:37]([C:42]([OH:44])=[O:43])[CH2:38][CH2:39][CH2:40][NH2:41])=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:46]=[CH:45][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:36][C@@H:37]([C:42]([OH:44])=[O:43])[CH2:38][CH2:39][CH2:40][NH2:41])=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1
Reactant: NCCC[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: NCCC[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Yield: 85.7 %

Procedure:
N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-D-ornithine (0.021 g, 0.032 mmole) was dissolved in methanol (1.5 mL). NaBH4 (0.0032 g, 0.085 mmole) was added and after about 15 min the reaction was complete according to LC-MS. A few drops of acetic acid was added. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on a Kromasil C8-column using 37% MeCN in 0.1M ammonium acetate buffer as eluent. After freeze-drying, 0.018 g (85%) of the desired product was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13]C)=[CH:4][C:5]2[CH:9]=[C:8]([CH3:10])[S:7][C:6]=2[C:11]=1[Cl:12].Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([OH:13])=[CH:4][C:5]2[CH:9]=[C:8]([CH3:10])[S:7][C:6]=2[C:11]=1[Cl:12]
Reactant: COc1cc2cc(C)sc2c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc2cc(O)c(Cl)c(Cl)c2s1
Reaction time: 3 h

Procedure:
A mixture of 4.8 g of 6,7-dichloro-5-methoxy-2-methylbenzo[b]thiophene and 40 g of pyridine hydrochloride is stirred at 190° for 3 hours. The cooled mixture is diluted with 500 ml of water. The solid is collected and air-dried. Recrystallization from ether-hexane mixture gives 6,7-dichloro-5-hydroxy 2-methylbenzo[b]thiophene as off-white crystals, mp 93°-95° C.
Reaction SMILES: [CH3:1][N:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=[N:3]1.C([O-])([O-])=O.[K+].[K+].Br[C:23]1[CH:24]=[N:25][C:26]([C:29]([OH:31])=[O:30])=[N:27][CH:28]=1>O1CCOCC1.O.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>[CH3:1][N:2]1[C:6]([C:23]2[CH:24]=[N:25][C:26]([C:29]([OH:31])=[O:30])=[N:27][CH:28]=2)=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(O)c1ncc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1cnc(C(=O)O)nc1
Temperature: 80 °C
Yield: 74.7 %

Procedure:
To a solution of 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.35 g, 6.5 mmol) in dioxane/H2O (5:1, 59 mL) was added K2CO3 (2.8 g, 20.3 mmol), tetrakistriphenylphosphine Pd(0) (340 mg, 0.3 mmol), and 5-bromo-2-pyrimidinecarboxylic acid (1.2 g, 5.9 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h. The reaction solution was poured onto H2O (100 mL) and extracted with DCM. The organics were dried (Na2SO4), concentrated under vacuum to give the title compound (0.9 g, 36%) as a tan solid: LC-MS (ES) m/z=437 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Cl[CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1>>[CH3:21][N:18]1[CH2:19][CH2:20][CH:15]([N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][N:7]=3)[N:3]=[CH:2]2)[CH2:16][CH2:17]1
Reactant: N#Cc1ccnc(-c2c[nH]cn2)c1
Reactant: CN1CCC(Cl)CC1
Product: CN1CCC(n2cnc(-c3cc(C#N)ccn3)c2)CC1

Procedure:
The title compound was prepared from 2-(1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-chloro-1-methylpiperidine according to the procedure for the preparation of Example 43, part A. [M+H] Calc'd for C15H17N5, 268. Found, 268.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8](=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:21])[C:9](O)=[O:10].[Cl:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25]>>[Cl:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][C:9](=[O:10])[C:8]([C:3]1[NH:4][C:5]([CH3:7])=[CH:6][C:2]=1[CH3:1])=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C:13]1=[O:21]
Reactant: Nc1ccccc1Cl
Reactant: Cc1cc(C)c(C(C(=O)O)=C2C(=O)Nc3ccccc32)[nH]1
Product: Cc1cc(C)c(C(C(=O)Nc2ccccc2Cl)=C2C(=O)Nc3ccccc32)[nH]1
Yield: 22.4 %

Procedure:
(3,5-Dimethyl-1H-pyrrol-2-yl)-(2-oxo-1,2-dihydro-indol-3-ylidene)-acetic acid (90 mg) was reacted with 2-chloroaniline (80 mg) using method B to give 28 mg (22%) of the title compound.
Reaction SMILES: [NH2:1][OH:2].[F:3][C:4]([F:23])([F:22])[C:5]1[N:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][CH:17]([C:20]#[N:21])[CH2:16][CH2:15]3)[CH:12]=[CH:13][C:8]2=[N:7][N:6]=1>C(O)C>[OH:2][NH:1][C:20]([CH:17]1[CH2:18][CH2:19][N:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:9]([C:5]([C:4]([F:23])([F:3])[F:22])=[N:6][N:7]=3)[N:10]=2)[CH2:15][CH2:16]1)=[NH:21]
Reactant: NO
Reactant: N#CC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Solvent: CCO
Product: N=C(NO)C1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.6 %

Procedure:
Hydroxylamine (50% w/v aqueous solution) (0.669 mL, 10.13 mmol) was added to a stirred suspension of 1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidine-4-carbonitrile (2.5 g, 8.44 mmol) in ethanol (16.88 mL) and the suspension was stirred at ambient temperature. Additional hydroxylamine (50% w/v aqueous solution) (3 mL) was added and stirring was continued for 18 hours. The mixture was then heated for 1 hour. The precipitate was collected by filtration, washed with EtOH and ether and dried under vacuum to afford N-hydroxy-1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidine-4-carboximidamide (2.380 g, 86%) as a colourless crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Br:24])[CH:23]=1)[C:5]([N:7]([CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:11][CH:12]=C)[CH3:8])=[O:6].FC1C=CC([C@H](CC=C)CN(C)C(=[O:50])C2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([Br:24])[CH:23]=1)[C:5]([N:7]([CH2:9][C@H:10]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:11][CH:12]=[O:50])[CH3:8])=[O:6]
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(Br)cc(Br)c1)c1ccc(F)cc1
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(F)cc1
Product: CN(C[C@@H](CC=O)c1ccc(F)cc1)C(=O)c1cc(Br)cc(Br)c1

Procedure:
The compound was synthesized in an analogous way to that of Method 20b but using 3,5-dibromo-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methylbenzamide rather than N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-3,5-bis(trifluoromethyl)benzamide (yield, 96%). 1H NMR (400 MHz, CDCl3): 2.6-3.9 (cm, 8H), 6.8-8.2 (cm, 7H), 9.8 (s, 1H).
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=2)[CH:4]=1.[NH2:29][C:30]1[CH:31]=[C:32]([S:36]([NH:39][C:40]([CH3:44])([CH3:43])[CH2:41][OH:42])(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>>[OH:42][CH2:41][C:40]([NH:39][S:36]([C:32]1[CH:31]=[C:30]([NH:29][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:28])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[C:17]([O:25][CH2:26][CH3:27])[CH:16]=4)=[N:6][C:7]=23)=[O:14])[CH:35]=[CH:34][CH:33]=1)(=[O:38])=[O:37])([CH3:44])[CH3:43]
Reactant: CCOc1cc(-c2cc(C(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Product: CCOc1cc(-c2cc(C(F)F)n3ncc(C(=O)Nc4cccc(S(=O)(=O)NC(C)(C)CO)c4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(3-ethoxy-4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.12) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Light yellow solid. MS (ISP) 626.6 [(M−H−]; mp 250° C.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26](O)=[O:27])[CH:24]=3)[N:19]([CH3:29])[CH:18]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C([O:46][N:47]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.NO>CN(C=O)C>[OH:46][NH:47][C:26]([C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH3:29])[CH:18]=[C:17]2[CH2:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:11][CH:12]=1)=[O:27]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cn1cc(Cc2ccc(NC(=O)c3ccccc3)cc2)c2cc(C(=O)O)ccc21
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Cc2ccc(NC(=O)c3ccccc3)cc2)c2cc(C(=O)NO)ccc21
Yield: 34.4 %

Procedure:
A solution of 3-(4-benzoylamino-phenylmethyl)-1-methyl-1H-indole-5-carboxylic acid (64 mg, 0.16 mmol), DIPEA (0.14 mL, 0.8 mmol), HATU (68 mg, 0.18 mmol), hydroxylamine hydrochloride (56 mg, 0.8 mmol) and DMF (4 mL) was stirred for 19 hr at room temperature. The reaction mixture was then subjected to HPLC purification to provide 3-(4-benzoylamino-phenylmethyl)-1-methyl-1H-indole-5-carboxylic acid hydroxyamide (22 mg, 34% yield). 1H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 10.18 (s, 1H), 7.99 (s, 1H), 7.93 (d, 2H, J=7.2 Hz), 7.67 (d, 2H, J=8.7 Hz), 7.57 (m, 2H), 7.53 (d, 2H, J=7.7 Hz), 7.43 (d, 1H, J=8.2 Hz), 7.27 (d, 2H, J=8.2 Hz), 7.19 (s, 1H), 4.03 (s, 2H), 3.76 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][O:6][C:5](=[O:8])[N:4]1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:11][N:10]=1.[CH3:32]I>>[CH3:32][O:1][CH2:2][C@@H:3]1[CH2:7][O:6][C:5](=[O:8])[N:4]1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([CH3:30])=[C:25]([CH3:31])[N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:11][N:10]=1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)nc3)CC2)nc1C
Reactant: CI
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3nc(C)c(C)cc3C)CC2)cn1

Procedure:
By reaction and treatment in the same manner as in Example 73 and using (R)-4-hydroxymethyl-3-{5-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}oxazolidin-2-one (200 mg) described in Example 254 and methyl iodide (35 μL), the title compound (158 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][C:6]1[O:7][CH:8]=[CH:9][CH:10]=1.[F:14][CH:15]([F:25])[O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[CH:19][CH:18]=1>C(N(CC)CC)C.[Cu](I)I.[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>[F:14][CH:15]([F:25])[O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[C:24][C:2]2[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=2)[CH2:5][C:6]2[O:7][CH:8]=[CH:9][CH:10]=2)=[CH:19][CH:18]=1
Reactant: Brc1cccc(Cc2ccco2)c1
Reactant: C#Cc1ccc(OC(F)F)cc1
Agent: I[Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: FC(F)Oc1ccc(C#Cc2cccc(Cc3ccco3)c2)cc1
Yield: 61.1 %

Procedure:
To a CEM snap top microwave vial (10 ml) equipped with a magnetic stir bar (3×10 mm) was added 2-(3-bromobenzyl)furan (385 mg, 1.62 mmol) in triethylamine (1.5 mL). Copper iodide (80 mg, 0.40 mmol), Tetrakis(triphenylphosphine) palladium (140 mg, 0.121 mmol) and 1-(difluoromethoxy)-4-ethynylbenzene (0.270 mg, 1.60 mmol) were added at room temperature. The reaction was capped and irradiated in a CEM Explorer microwave at 80° C. for 30 minutes then forced air-cooled. The crude material was loaded onto silica gel. Purification by chromatography (2% EtOAc in hexanes) afforded 0.317 gm of an oil (61%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.99 (s, 2H) 6.16 (dd, J=3.1, 0.8 Hz, 1H) 6.37 (dd, J=3.1, 2.0 Hz, 1H) 7.21 (d, J=8.8 Hz, 2H) 7.28 (ddd, J=7.5, 1.6, 1.6 Hz, 1H) 7.31 (t, J=73.7 Hz, 1H) 7.34-7.42 (m, 3H) 7.53 (dd, J=1.9, 0.7 Hz, 1H) 7.61 (d, J=9.0 Hz, 2H); MS (EI) m/z 324.0 [M+·].
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:3]=1[NH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].CI.[C:20]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:3]=1[N:4]([CH3:20])[C:5](=[O:10])[C:6]([F:7])([F:8])[F:9]
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1cc([N+](=O)[O-])ccc1F)C(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C(=O)C(F)(F)F)c1cc([N+](=O)[O-])ccc1F
Temperature: 90 °C
Reaction time: 24 h
Yield: 83 %

Procedure:
To a solution of compound 32-NO2—H (13.9 g, 55.2 mmol) and MeI (14.8 g, 0.104 mol) in DMF (80 mL), K2CO3 (12.5 g, 90.6 mmol) was added. After vigorous stirring for 24 h at 90° C., volatile materials were evaporated in vacuum. The residue was diluted with water (200 mL), the organic layer was separated, and the aqueous layer was extracted with ether (3×100 mL). Combined organic solutions were dried, and the solvent was evaporated at an ambient pressure (bath temperature 50° C.). The title compound was isolated by chromatography on SiO2 (600 g) with hexane/EtOAc mixture (1:0→1:1) as an eluent; yellowish oil (13.6 g, purity ca. 90%, yield 83%). 1H NMR (CDCl3, 300 MHz, ppm): δ=3.36 (s, 3 H, CH3), 7.39 (t, 3JHH=JHF=8.8, 1H, H-3), 8.25 (dd, 4JHH=2.6, 4JHF=6.5, 1H, H-6), 8.32-8.38 (m, 1H, H-4); EI-MS: m/z (rel. int., %)=266 (100) [M], 197 (57) [M-CF3], 184 (32), 170 (23), 123 (37), 110 (18).