Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[NH2:29][C:30]1[N:31]=[CH:32][C:33]([C:38]([O:40][CH3:41])=[O:39])=[N:34][C:35]=1[O:36][CH3:37].O>C(O)C.ClCCl>[C:18]([O:17][C:16]([NH:15][C:11]1([C:8]2[CH:9]=[CH:10][C:5]([C:3]3[N:29]=[C:30]4[C:35]([O:36][CH3:37])=[N:34][C:33]([C:38]([O:40][CH3:41])=[O:39])=[CH:32][N:31]4[C:2]=3[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:6][CH:7]=2)[CH2:14][CH2:13][CH2:12]1)=[O:22])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)c1cnc(N)c(OC)n1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: COC(=O)c1cn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c(OC)n1

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [Int-1-A] (715 mg, 1.45 mmol, 1.0 eq), methyl 5-amino-6-methoxypyrazine-2-carboxylate (265 mg, 1.45 mmol, 1 eq.; see step 1) were dissolved in ethanol. The reaction vessel was equipped with a Dean-Stark trap containing 4 Å molsieves and then the reaction mixture refluxed for 17 h. The reaction mixture was diluted with 20 mL dichloromethane and treated with water. The organic phase was washed with 1 N hydrochloric acid and brine, filtered through a Whatman-filter and the solvent was removed by the use of a rotary evaporator. Finally purification was achieved via MPLC (Isolera, 50 g Snap-cartridge, eluent:hexane→hexane/ethyl acetate 9/1) to deliver 97 mg (12%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]=O.[OH:8][C:9]1[C:16]([OH:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:10]=1[CH:11]=[O:12]>C(O)C>[OH:8][C:9]1[C:16]([OH:17])=[C:15]([OH:18])[C:14]([CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:13][C:10]=1[CH:11]=[O:12]
Reactant: O=Cc1ccc(O)c(O)c1O
Reactant: C=O
Reactant: C1CCNC1
Solvent: CCO
Product: O=Cc1cc(CN2CCCC2)c(O)c(O)c1O

Procedure:
17.1 g (0.24 mol) of pyrrolidine were added to 19.2 g (0.24 mol) of a 37% aqueous formaldehyde solution in 140 ml of ethanol. Then 25.0 g (0.16 mol) of 2,3,4-trihydroxybenzaldehyde were added thereto. The reaction mixture was refluxed for one hour, developing a dark brown color. After cooling, a beige-brown solid precipitated out, which was filtered out and dried.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11][CH3:12].C([O-])([O-])=O.[K+].[K+].[Br:19][CH2:20][CH2:21][CH2:22]Br>C(#N)C>[Br:19][CH2:20][CH2:21][CH2:22][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11][CH3:12]
Reactant: CSc1cc(C(C)=O)ccc1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CSc1cc(C(C)=O)ccc1OCCCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[4-hydroxy-3-(methylmercapto)phenyl]ethanone (5.4 g; 0.03 mole), K2CO3 (4.2 g), 1,3-dibromopropane (8 g, 0.039 mole) in acetonitrile (150 ml) was heated at reflux for 3 hours and stirred at room temperature overnight. Acetonitrile was removed at reduced pressure and the residue was extracted into dichloromethane (250 ml). Insolubles were filtered off. The dichloromethane solution was concentrated. The crude product was purified on a silica gel column (SiO2, 100 g; eluted with 3:2 hexane:dichloromethane, 1.6 l). The compound crystallized upon concentration, and the product (3.5 g, 39%) was recrystallized from ethanol (40 ml) to yield 1-[4-(3-bromopropoxy)-3-(methylmercapto)phenyl]ethanone as white needles, 2.0 g; m.p.=120°-122° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N+:3]=1[O-:12].C(C(C)=O)C.[F:18][C:19]([F:26])([C:22]([F:25])([F:24])[F:23])[CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(=O)(N(C)C)N(C)C>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:21][CH2:20][C:19]([F:26])([F:18])[C:22]([F:25])([F:24])[F:23])[CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Reactant: OCC(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCC(C)=O
Product: Cc1c(OCC(F)(F)C(F)(F)F)cc[n+]([O-])c1C
Reaction time: 108 h

Procedure:
A mixture of 2,3-dimethyl-4-nitropyridine-1-oxide (2.0 g), methyl ethyl ketone (30 ml), 2,2,3,3,3-pentafluoropropanol (3.05 ml), anhydrous potassium carbonate (3.29 g) and hexamethylphosphoric acid triamide (2.07 g) was heated at 70°-80° C. with stirring for 4.5 days. Then, the insoluble matter was filtered off and the filtrate was concentrated. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract layer was dried over magnesium sulfate, then the solvent was distilled off, and the residue was applied to a silica gel column (50 g). Elution with chloroform-methanol (10:1) and recrystallization from ethyl acetate-hexane gave 2.4 g of 2,3-dimethyl-4-(2,2,3,3,3-pentafluoropropoxy)pyridine-1-oxide as colorless needles. Melting point 148°-149° C.
Reaction SMILES: [C:1]1(=[C:6]2[CH2:10][CH2:9][CH2:8][C:7]2=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.N.[CH3:13][N:14]([CH3:18])CC[Cl:17].Cl.[C:20]1(C)C=CC=C[CH:21]=1>>[ClH:17].[C:4]1([CH:5]([N:14]([CH3:18])[CH3:13])[CH2:1][CH:6]2[CH2:10][CH2:9][CH2:8][C:7]2=[O:11])[CH2:3][CH2:2][CH2:21][CH:20]=1
Reactant: O=C1CCCC1=C1CCCC1
Reactant: Cc1ccccc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: N
Product: CN(C)C(CC1CCCC1=O)C1=CCCC1
Temperature: 100 °C

Procedure:
To a suspension of 1.90 g (41 mmole) of NaNH2 in 60 ml of dry toluene, 5.50 g (35 mmole) of 2-cyclopentylidene cyclopentanone was added dropwise below about 30° C. under stirring. The resulting mixture was stirred at about room temperature until no NH3 was evolved and then 3.8 g (32 mmole) of 2-dimethylaminoethyl chloride was added dropwise. The mixture was heated for about 2 hours at about 100° C. under stirring. On cooling, the mixture was acidified with 2N HCl. The aqueous layer was separated and the organic layer was extracted with 2N HCl. The combined aqueous layer was basified with 10% NaOH and extracted with ether. The ether extracts were dried over anhydrous MgSO4. The ether solution was treated with ethanolic hydrogen chloride to give 2-(1-cyclopenten-1-yl)-2-dimethylamino-ethyl cyclopentanone hydrochloride.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.[F:23][C:24]1[C:25]([CH:34]=O)=[CH:26][C:27]2[O:32][CH2:31][CH2:30][O:29][C:28]=2[CH:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+].[Cl:55]CCl>CO.C(Cl)(Cl)Cl>[ClH:55].[F:23][C:24]1[C:25]([CH2:34][NH:1][CH:2]2[CH2:7][CH2:6][N:5]([CH2:8][C@H:9]3[N:19]4[C:20]5[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=5[N:16]=[CH:17][C:18]4=[O:21])[CH2:10]3)[CH2:4][CH2:3]2)=[CH:26][C:27]2[O:32][CH2:31][CH2:30][O:29][C:28]=2[CH:33]=1
Reactant: ClCCl
Reactant: O=Cc1cc2c(cc1F)OCCO2
Reactant: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cl
Product: O=c1ccc2ncc(=O)n3c2n1C[C@H]3CN1CCC(NCc2cc3c(cc2F)OCCO3)CC1

Procedure:
(2R)-2-[(4-Amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (50 mg, 0.166 mmol) (for a preparation see Example 16(j)) and 7-fluoro-2,3-dihydro-benzo[1,4]dioxin-6-carboxaldehyde (28 mg, 0.926 eq.) (for a synthesis see WO2002056882, Example 23(a)) were stirred in 9:1 v:v chloroform:methanol (1 ml) for 2.5 hours. Sodium triacetoxyborohydride (105 mg, 3.000 eq.) was then added in one portion and the mixture was stirred vigorously at room temperature for 30 min. Saturated aqueous sodium hydrogen carbonate (0.5 ml) was then added, followed by dichloromethane (10 ml) and the mixture was stirred vigorously at room temperature for 10 min and the phases were separated (hydrophobic frit). The organic phase was evaporated under reduced pressure and the crude product was purified by column chromatography on silica (eluted with 0-12% (2M NH3 in MeOH) in DCM. Appropriate fractions were combined and evaporated under reduced pressure to give the free base of the title compound as a white solid (48 mg).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]#[CH:22])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]#[C:22][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Ic1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
Iodobenzene (135 μl, 1.2 mmols), 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (209 mg, 1 mmols) and triethylamine (167 μl, 1.2 mmols) were dissolved in acetonitrile (6 ml). Dichlorobis(triphenylphosphine)palladium(II) (35 mg, 0.05 mmols) and CuI (10 mg, 0.05 mmols) were added, and reaction mixture was stirred at room temperature overnight and continued to stir at 50 C for two more hours before partitioning between ethyl acetate and water. Organic layer was isolated, washed with 1 N HCl, brine and dried (MgSO4). Solvents were removed and residue was purified by column chromatography on silica gel using solutions of ethyl acetate in hexanes (1:4; 1:2) to yield the title compound (74 mg). LCMS m/e (230, M-t-Bu+2H)
Reaction SMILES: [F:1][C:2]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([O:11]CC2C=CC=CC=2)[CH2:7][CH2:6]1)([F:4])[CH3:3].[H][H]>CO.[Pd]>[F:1][C:2]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1)([F:4])[CH3:3]
Reactant: CC(F)(F)[C@H]1CC[C@@H](OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(F)(F)[C@H]1CC[C@@H](O)CC1

Procedure:
Compounds ((cis-4-(1,1-difluoroethyl)cyclohexyloxy)methyl)benzene (480 mg, 1.89 mmol) and Pd—C (2.0 g, 0.38 mmol, 0.2 eq.) were dissolved in CH3OH (20 mL). Then the mixture was stirred at 50° C. under 40 atm. of hydrogen atmosphere for 6 h. When the reaction completed by TLC, the mixture was filtrated and the filtrate was concentrated and purified by silica gel column chromatography using petroleum ether/ethyl acetate (10/1) as eluent to give product (140 mg, 45%) as a slight yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.07-4.05 (m, 1H), 1.86-1.83 (m, 2H), 1.75-1.72 (m, 2H), 1.63-1.48 (m, 8H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:13][C:14](=[O:28])[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[BH4-].[Na+].O.Cl>CO.O1CCCC1>[OH:3][CH2:4][CH2:5][N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:13][C:14]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)=[O:28]
Reactant: CCOC(=O)CN(CC(=O)Nc1ccc(-c2ccncc2)cc1)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(CN(CCO)c1ccccc1)Nc1ccc(-c2ccncc2)cc1
Yield: 48 %

Procedure:
Ethyl[(2-oxo-2-{[4-(4-pyridinyl)phenyl]amino}ethyl) (phenyl)amino]acetate (50.0 mg) was dissolved in methanol/tetrahydrofuran (1:1, 1.0 mL) and sodium borohydride (14.6 mg) was added portionwise to the mixture cooled with ice bath stirring. The mixture was stirred at 0° C. for 5 hours and water (2.0 mL) was added to the resulting mixture. The mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate (3.0 mL). The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography (2 g, 10% methanol in chloroform) to afford 2-[(2-hydroxyethyl) (phenyl)amino]-N-[4-(4-pyridinyl)phenyl]acetamide (21.4 mg) as white crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=[N:3]1.[NH:13]1[CH2:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(OCC)(=O)C>[N:13]1([C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]=2[N+:10]([O-:12])=[O:11])=[O:9])[CH2:16][CH2:15][CH2:14]1
Reactant: Cn1ncc([N+](=O)[O-])c1C(=O)O
Reactant: C1CNC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc([N+](=O)[O-])c1C(=O)N1CCC1
Temperature: 25 °C
Reaction time: 40 h
Yield: 73.1 %

Procedure:
To a suspension of 2-methyl-4-nitro-2H-pyrazole-3-carboxylic acid (300 mg, 1.75 mmol), azetidine (354 μl, 5.25 mmol) and diisopropylethylamine (920 μl, 5.26 mmol) in ethyl acetate (7.5 ml) was added 1-propanephosphonic acid cyclic anhydride (3.68 ml, 6.13 mmol; 50% in ethyl acetate) at 0° C. The ice bath was removed and stirring at r.t. was continued for 40 h. The reaction mixture was poured into ethyl acetate (100 ml) and extracted with sodium bicarbonate (saturated aqueous solution) water and brine. The aqueous layer was back-extracted with ethyl acetate, the combined organic phases were dried, evaporated, and the product was purified by silica gel chromatography using an amine phase and a heptane/ethyl acetate gradient to yield a white solid (269 mg, 73%).
Reaction SMILES: [C-:1]#[C-:2].[Li+].[Li+].[C:5]1([C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.O>O1CCCC1>[CH:5]1([C:11]([OH:12])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:1]#[CH:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: [C-]#[C-]
Reactant: O=C(c1ccccc1)C1CCCCC1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C#CC(O)(c1ccccc1)C1CCCCC1
Temperature: 0 °C

Procedure:
Lithium acetylide (47.84 g, 0.52 mol) was added to 70 ml of dry tetrahydrofuran (THF). The solution was cooled to 0° C. and a solution of cyclohexyl phenyl ketone in 100 ml of dry THF was added over a period of 15 minutes with stirring. The solution was allowed to warm to room temperature and stirred for 16 hours. The solution was then cooled to 0° C. and 50 ml of a 5N HCl solution was added with. The solution was then warmed to room temperature and 200 ml of water was added. The solution was transferred to a separatory funnel and washed with ether. The ether washes were combined and dried over sodium sulfate. Upon removal of the ether under vacuum and vacuum distillation of the crude product a pale yellow oil was isolated (60.33 g, 82.9%). Bp 111°-14° C. (0.8 mm). 1H NMR (CDCl3) δ7.7-7.2(m, 5H), 2.6(s, 1H), 2.3(s, 1H), 2.1-0.9(m, 11H). IR (neat) 3433, 3304, 2111, 1448, 1016 cm-1 .
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:13])=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([I:13])=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)c(I)cc1O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)c(I)c([N+](=O)[O-])c1O
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 88 %

Procedure:
To a mixture of methyl 5-chloro-2-hydroxy-4-iodobenzoate (5.1 g, 16 mmol) in acetic acid (50 mL) was added nitric acid (6.8 mL) at room temperature. The reaction was stirred at 60° C. for 90 min and then cooled and poured into ice water. The precipitate was collected by filtration, washed with water and air dried to give the desired product (5.15 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)[O:8][C:7](=[O:27])[C:6]=2[CH:28]=1.O.[NH2:31][NH2:32].O1CCCC1.O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]([NH:10][C:9]([C:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=2)=[O:8])=[C:6]([C:7]([NH:31][NH2:32])=[O:27])[CH:28]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: NN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)cc(C(=O)NN)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.2 %

Procedure:
A mixture of 0.44 g of 6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazine-4-one, 0.05 g of hydrazine monohydrate and 10 ml of tetrahydrofuran was stirred at room temperature for 2 hours. After the reaction mixture was mixed with water and ethyl acetate, layers were separated. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.10 g of N-[4-chloro-2-(hydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-3-trifluoromethyl-1H-pyrazole-5-carboxamide of the formula:
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:10]([C:11](=[O:14])[CH2:12]Br)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.O>CN(C)C=O>[N:17]1([CH2:12][C:11]([C:10]2[CH:15]=[CH:16][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=2)=[O:14])[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: c1c[nH]cn1
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cn1ccnc1)c1ccc(-c2ccccc2)cc1
Yield: 65.4 %

Procedure:
39 g (0.14 mol) of 4-phenylphenacyl bromide are introduced in portions into a solution of 48.2 g (0.7 mol) of imidazole in 140 ml of dimethylformamide, whilst cooling. The mixture is allowed to subsequently react for 15 hours and the solution is poured into water. The crystal mass which has separated out is recrystallised from ethanol. 24 g (65% of theory) of 4-biphenylyl imidazol-1-yl-methyl ketone of melting point 198° C. are obtained.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][S:15]2(=[O:24])=[O:23])=[CH:10][CH:9]=1.[Br:25][CH2:26][CH2:27][CH2:28][CH2:29]Br>CN(C=O)C.C(OCC)C>[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][N:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:14]([C:11]2[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=2)[S:15]1(=[O:23])=[O:24]
Reactant: O=S1(=O)Nc2ccccc2N1c1ccc(Cl)cc1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=S1(=O)N(CCCCBr)c2ccccc2N1c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 59 %

Procedure:
Cesium carbonate (0.29 g, 0.9 mmol) was added to a solution of 1-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (Made analogously as in general procedure I, 0.25 g, 0.9 mmol), and 1,4-dibromobutane (0.42 mL, 3.6 mmol) in dry DMF (5.0 mL) under nitrogen. After 3 h, the reaction mixture was diluted with diethyl ether and washed with water and brine. The ether layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give 0.41 g of crude product. The crude product was pre-adsorbed onto Celite and purified via Isco chromatography (Redisep, silica, gradient 5-30% ethyl acetate in hexane) to afford 0.22 g (59%) of 1-(4-bromobutyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:5][C:4]=1[N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23](O)=[O:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15]1)#[N:2].C(N(CC)CC)C.C(Cl)(=O)C(Cl)=O.[Cl:39][C:40]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:41]=1[CH2:47][CH2:48][NH2:49]>C(Cl)Cl.CN(C=O)C>[Cl:39][C:40]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:41]=1[CH2:47][CH2:48][NH:49][C:23]([C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[N:14]([C:4]1[CH:5]=[CH:6][C:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:3]=1[C:1]#[N:2])[CH:15]=[CH:16]2)=[O:24]
Reactant: COC(=O)Cc1ccc(-n2ccc3cc(C(=O)O)ccc32)c(C#N)c1
Reactant: NCCc1ccc(Cl)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(-n2ccc3cc(C(=O)NCCc4ccc(Cl)cc4Cl)ccc32)c(C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(2-cyano-4-(2-methoxy-2-oxoethyl)phenyl)-1H-indole-5-carboxylic acid (0.020 g, 0.078 mmol, triethylamine (0.013 mL, 0.090 mmol) and oxalyl chloride (0.010 g, 0.079 mmol) was combined in 1 mL of DCM and 1 drop of DMF was added. The reaction mixture was stirred at ambient temperature for 30 minutes. To the reaction mixture was added 2-(2,4-dichlorophenyl)ethanamine.The reaction mixture was stirred for 1 hour then loaded onto a silica gel column. The product was eluted with solvent system of 5% EtOAc/Hexanes to 100% EtOAc to provide methyl 2-(4-(5-((2,4-dichlorophenethyl)carbamoyl)-1H-indol-1-yl)-3-cyanophenyl)acetate (0.170 g, 0.034 mmol). MS(APCI)=506.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[NH2:14][CH2:15][CH2:16][CH2:17][OH:18].C(N(CC)CC)C.[O:26]1[CH:31]=[CH:30][CH2:29][CH2:28][CH2:27]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>ClCCl.O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:14][CH2:15][CH2:16][CH2:17][O:18][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][O:26]1)(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: NCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
2-Nitrobenzenesulfonyl chloride (22.1 g, 0.10 mol) was added to a dichloromethane solution (400 ml) of 3-aminopropanol (8.2 g, 0.11 mol) and triethylamine (21 ml, 0.15 mol) at 0° C., and stirred at room temperature overnight. Water was added to the reaction mixture and extraction with dichloromethane was performed. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (400 ml), and 3,4-dihydro-2H-pyrane (9.3 g, 0.11 mol) and p-toluenesulfonic acid (1.9 g, 0.01 mol) were added thereto. Stirring was conducted at room temperature overnight. A 1N-sodium hydroxide aqueous solution was added to the reaction mixture, and extraction with dichloromethane was performed. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:2). The purified product was concentrated under reduced pressure to thereby obtain 27.56 g (yield: 80%) of 2-nitro-N-[3-(tetrahydropyran-2-yloxy)propyl]benzenesulfonamide as a pale brown oil.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:13]=1)[C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCN(CC)CC.[CH3:33][C:34](OC(C)=O)=[O:35].CO>CCOC(C)=O>[CH:21]1([O:20][C:14]2[CH:13]=[C:12]([CH:3]([C:4]#[C:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:2][NH:1][C:34](=[O:35])[CH3:33])[CH:17]=[CH:16][C:15]=2[O:18][CH3:19])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C(C#Cc2ccccc2)CN)cc1OC1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(C(C#Cc2ccccc2)CNC(C)=O)cc1OC1CCCC1
Reaction time: 0.08 h

Procedure:
A solution of (+/-)-4-amino-3-(3 cyclopentyloxy-4-methoxyphenyl)-1-phenyl-1-butyne (50 mg, 0.15 mmol) and Et3N (0.2 ml) in EtOAc (30 ml) at 5° was treated with Ac2O (0.2 ml). After 5 minutes, the reaction was treated with MeOH, to decompose excess Ac2O. The reaction was washed with H2O and 0.05 N HCl, dried, and the solvent was evaporated. The residue was purified by flash chromatography (alumina, neutral, activity 1, 5% MeOH/CHCl3), and then by recrystallization from a mixture of cyclohexane and Et2O, and gave the titled compound, 37 mg (65%). mp 114-117°. 1H NMR (400 MHz, CDCl3) δ 7.42 (m, 2 H), 7.32 (m, 3 H), 6.92 (m, 2 H), 6.84 (d, 1 H), 5.78 (broad s, 1 H), 4.76 (m, lH), 4.02 (t, 1 H), 3.82 (s, 3 H), 3.64 (m, 1 H), 3.50 (m, 1 H), 2.06 (s, 3 H), 1.78-2.00 (m, 6 H), 1.62 (m, 2 H).