Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:5].[C:13]([O:17][C:18]([NH:20][C:21]1([C:24](O)=[O:25])[CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:13]([O:17][C:18](=[O:19])[NH:20][C:21]1([C:24](=[O:25])[NH:2][CH2:3][C:4]([C:6]2[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=2)=[O:5])[CH2:22][CH2:23]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C(=O)NCC(=O)c2ccc(Br)cc2)CC1
Reaction time: 18 h
Yield: 89.6 %

Procedure:
2-Amino-1-(4-bromo-phenyl)-ethanone HCl (2.5 g, 10 mmol) in DMF (30 mL) was treated with 1-tert-butoxycarbonylamino-cyclopropanecarboxylic acid (1.97 g, 9.8 mmol), HATU (4.02 g, 10.5 mmol), and DIPEA (5.6 mL, 31.1 mmol). The mixture was stirred for 18 hours and concentrated. The mixture was diluted with EtOAc (25 mL), and washed with saturated NaHCO3 (3 10 mL), H2O (10 mL), and brine (10 mL). The solution was dried over MgSO4 and subjected to a 80 g SiO2 COMBIFLASH column (0-100% EtOAc-hexanes gradient) to afford {1-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-cyclopropyl}-carbamic acid tert-butyl ester (3.49 g, 90%). This material (3.49 g, 8.8 mmol) in xylenes (20 mL) was treated with ammonium acetate (3.4 g, 44 mmol). The reaction was stirred at 130° C. in a sealed tube for 18 hours. The mixture was concentrated and suspended in dicholormethane (100 mL) and washed with saturated NaHCO3 (50 mL). The solution was dried over MgSO4 to afford crude {1-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester, which was used without further purification: MS (ESI) m/z 379 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@:8]([CH2:19][OH:20])([CH3:18])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:28](OS(C)(=O)=O)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].Cl>C(O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:21])[NH:7][C@:8]([CH2:19][OH:20])([CH3:18])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CO)CCc1ccc(O)cc1
Reactant: CCCCCCCOS(C)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(CC[C@](C)(CO)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of [(R)-1-hydroxymethyl-3-(4-hydroxy-phenyl)-1-methyl-propyl]-carbamic acid tert-butyl ester (2.06 g, 6.98 mMol) in ethanol (100 ml) is added potassium carbonate (2.90 g, 20.8 mMol) and methanesulfonic acid heptyl ester (2.04 g, 10.5 mMol). The mixture is heated to reflux temperature and stirred at that temperature for 6 hours. The mixture is then cooled to RT and stirred at RT overnight. The reaction mixture is then poured onto a biphasic mixture of AcOEt and HCl (aqueous, 1 M). The aqueous phase is extracted twice with AcOEt. The combined organic layers are washed with NaHCO3 (saturated aqueous solution), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography eluting with 8% AcOEt in toluene gives the title compound as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:16][N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]#[N:23]>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:21]2[N:17]([CH3:16])[C:18]([C:22]#[N:23])=[CH:19][CH:20]=2)=[CH:3][CH:4]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cn1cccc1C#N
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Product: Cn1c(C#N)ccc1-c1ccc(C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared from (4-bromophenyl)-phenyl-methanone and 1-methyl-2-cyanopyrrole according to the coupling procedure as described in example 1. MS (ES) m/z 287.1; HRMS: calcd for C19H14N2O+H+, 287.11789; found (ESI, [M+H]+), 287.1185.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.N1C=CC=CC=1C(O)=O.C(=O)(O)[O-].[K+]>CN(C)C=O.Cl.[Cu]I>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:3]1[C:4](=[O:15])[C:5]2[C@@H:6]3[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]3)[C:10]=2[N:2]1[CH3:1]
Reactant: Brc1ccccn1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Agent: [Cu]I
Agent: Cl
Agent: O=C(O)c1ccccn1
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1-c1ccccn1)[C@H]1CC[C@]2(C)C1(C)C
Yield: 25.9 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 412 mg, 2 mmol), 2-bromo-pyridine (175 μL, 1.8 mmol), copper(I) iodide (19 mg, 0.1 mmol), picolinic acid (49 mg, 0.4 mmol), and potassium bicarbonate (280 mg, 2.8 mmol) in N,N-dimethylformamide (10 mL) was irradiated in a microwave oven at 220° C. for 30 min. The reaction mixture was diluted with 0.1 M HCl (200 mL) and then extracted with ethyl acetate (200 mL). The organic layer was washed with 0.1 M HCl, 0.25 M NaOH, and brine, then dried (magnesium sulfate), filtered, evaporated and purified using an ISCO system, eluting with 5-60% ethyl acetate/dichloromethane to give (4S,7R)-2-(pyridin-2-yl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (132 mg, 23%) as a white solid. ES(+)-MS (M+H) 284.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([OH:10])=[CH:4][C:3]=1[F:11].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>ClCCl.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>[Br:1][C:2]1[C:7]([CH2:8][O:9][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][O:12]2)=[CH:6][C:5]([O:10][CH:17]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:4][C:3]=1[F:11]
Reactant: OCc1cc(O)cc(F)c1Br
Reactant: C1=COCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: Fc1cc(OC2CCCCO2)cc(COC2CCCCO2)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
A mixture of 4-bromo-3-fluoro-5-(hydroxymethyl)phenol (5.64 g, 25.5 mmol), 3,4-dihydro-2H-pyran (5.8 mL, 64 mmol), and dl-camphorsulfonic acid (118 mg, 2 mol %) in dichloromethane (150 mL) was stirred at room temperature for overnight. The mixture was washed with saturated aqueous sodium bicarbonate and brine, and dried on anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (9:1 hexane/ethyl acetate) to give 2-(4-bromo-3-fluoro-5-((tetrahydro-2H-pyran-2-yloxy)methyl)phenoxy)tetrahydro-2H-pyran (9.14 g, 92%).
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:26][OH:27]>C(O)C.O.CO>[OH:27][N:26]=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: NO
Reactant: O=C(O)CCC(=O)c1ccc(-n2cccn2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCO
Solvent: O
Product: O=C(O)CCC(=NO)c1ccc(-n2cccn2)cc1
Reaction time: 24 h
Yield: 78.5 %

Procedure:
To a stirred suspension of 4oxo-4(4-pyrazol-1-yl-phenyl)butyric acid (Sircar I., et al., Journal of Medicinal Chemistry, 1985;28:1405-13) (0.0277 g, 0.000113 mol) in absolute ethanol (0.55 mL) at room temperature was added potassium carbonate (0.010 g, 0.000072 mol) followed by a solution of hydroxylamine hydrochloride (0.010 g, 0.00014 mol) in water (0.25 mL), and the resulting mixture was stirred for 1 day. The volatiles were rotary evaporated. The residue was dissolved in methanol, silica gel (0.35 g, 230-400 mesh) was added, and the mixture was rotary evaporated to dryness. The residue was purified by chromatography on silica gel (6.0 g, 230-400 mesh) eluting with dichloromethane-methanol (12:1,25×5 mL) to give 0.0230 g of 4-hydroxyimino-4(4pyrazol-1-yl-phenyl)-butyric acid as an off-white solid; mp 128-130° C.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH2:13][CH2:12][O:11][N:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:22])C=1.O>C(Cl)Cl>[C:1]1([S:7]([C:9]2[CH2:13][CH2:12][O:11][N:10]=2)(=[O:22])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(C1=NOCC1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(C1=NOCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3-(phenylsulfonyl)-4,5-dihydroisoxazole I-250a and I-250b were prepared by the oxidation of racemic 3-(phenylsulfinyl)-4,5-dihydroisoxazole I-249. 3-(Phenylsulfinyl)-4,5-dihydroisoxazole I-249 is dissolved in methylene chloride (0.03 M). m-Chloroperbenzoic acid (77% by weight, 2.95 equiv) are added in two portions and the reaction is allowed to stir at room temperature for 14 h after which it is transferred to a separatory funnel with excess water and methylene chloride. The organic layer is washed with saturated sodium bicarbonate (2×), dried over magnesium sulfate, and concentrated to provide crude solid that is recrystallized from methylene chloride/hexanes to provide the desired racemic 3-(phenylsulfonyl)-4,5-dihydroisoxazole I-250. These compounds can be separated using chiral HPLC methods known in the art. For example, see chiral HPLC Method disclosed herein. [M+H]+=371.7 m/z. Activity: C
Reaction SMILES: [ClH:1].[CH2:2]([C:4]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH2:12][CH3:13])[C:5]=1N)[CH3:3].N(OCCC(C)C)=O>ClC1C=CC=CC=1Cl>[Cl:1][C:5]1[C:4]([CH2:2][CH3:3])=[CH:10][C:9]([CH3:11])=[CH:8][C:7]=1[CH2:12][CH3:13]
Reactant: CCc1cc(C)cc(CC)c1N
Reactant: Cl
Agent: CC(C)CCON=O
Solvent: Clc1ccccc1Cl
Product: CCc1cc(C)cc(CC)c1Cl
Temperature: 45 °C
Yield: 90 %

Procedure:
Gaseous hydrogen chloride (1.05 equiv.) is fed into a solution of 2,6-diethyl-4-methylaniline (1.00 equiv.) in o-dichlorobenzene, allowing the pot temperature to rise to 70° C. The resulting salt suspension is cooled to 45° C. Isoamyl nitrite (1.05 equiv.) and additional gaseous hydrogen chloride (0.50 equiv.) are fed subsurface simultaneously at 45-50° C. over a 2-hour period to afford 1-chloro-2,6-diethyl-4-methylbenzene in 90-93% yield. 20% sodium hydroxide (0.50 equiv.) is added to adjust the pH to 10-12. The bottom aqueous phase is separated off. Isoamyl alcohol and o-dichlorobenzene are stripped off to produce the crude 1-chloro-2,6-diethyl-4-methylbenzene material. The product can be further purified by vacuum distillation at 85° C./5 mmHg to give an assay of 97-99%.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].[OH-].[Na+].[CH2:9]([O:13][C:14]1[C:17](=O)[C:16](=[O:19])[C:15]=1[O:20]CCCC)[CH2:10][CH2:11][CH3:12]>CO>[CH2:9]([O:13][C:14]1[C:15](=[O:20])[C:16](=[O:19])[C:17]=1[NH:6][CH2:5][CH2:4][CH2:3][Br:2])[CH2:10][CH2:11][CH3:12]
Reactant: NCCCBr
Reactant: CCCCOc1c(OCCCC)c(=O)c1=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1c(NCCCBr)c(=O)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Solid 3-bromopropylamine hydrobromide (31.0 g, 0.1416 mole) was added with stirring to a solution of sodium hydroxide (5.77 g, 0.140 mole) in methanol (152 mL) and stirred at ambient temperature for 15 minutes. The solution was cooled to 0°-5° C. and then added with stirring to the solution of Step A. The mixture was stirred at 22° C. for 1.5 hours then concentrated under reduced pressure (40° C.) to about 120 mL volume. Toluene (120 mL) was added and the mixture was washed with water (240 mL). The organic layer was dried (sodium sulfate), filtered, and the solvent was evaporated under reduced pressure to give 38.64 g (95.0 % yield) of the title compound as an off-white solid. The product was used without further purification in the subsequent reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=O)[NH:9]2)=[CH:4][CH:3]=1.[CH2:13]([N:15]([CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH:19]([NH2:21])[CH3:20])[CH3:14]>>[CH3:14][CH2:13][N:15]([CH2:16][CH2:17][CH2:18][CH:19]([NH:21][C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=12)[CH3:20])[CH2:22][CH3:23]
Reactant: CCN(CC)CCCC(C)N
Reactant: O=C1CCc2ccc(Cl)cc2N1
Product: CCN(CC)CCCC(C)Nc1ccnc2cc(Cl)ccc12
Yield: 90 %

Procedure:
3.665 millimols, i.e. a yield of 90% relative to the 7-chloro-1,2,3,4-tetrahydroquinolinone converted, and a yield of 91.2% relative to the 1-diethylamino-4-aminopentane converted, and
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:11])[CH:8]=2)[C:3]1=[O:12].[CH3:13][S-:14].[Na+]>C(O)C>[Cl:11][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3](=[O:12])[CH:2]([S:14][CH3:13])[CH2:10]2
Reactant: C[S-]
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Agent: [Na+]
Solvent: CCO
Product: CSC1Cc2cc(Cl)ccc2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.2 %

Procedure:
0.98 g (4 M-mol) of 2-bromo-5-chloroindan-1-one and 0.42 g (6 mmol) of sodium thiomethoxide are suspended in 5 ml of ethanol, treated in an ultrasonic bath for 30 minutes and then stirred at room temperature for 90 minutes. The reaction mixture is concentrated under reduced pressure and chromatographed on silica gel using toluene/ethyl acetate 10/1. The eluates are concentrated under reduced pressure, giving 0.63 g of 5-chloro-2-methylsulfanylindan-1-one of melting point 90° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)=[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[H-].[Na+].[CH3:24]I.Cl>O1CCCC1.O>[Cl:1][C:2]1[C:10]([N:11]2[CH2:12][CH2:13][CH:14]([O:17][CH3:24])[CH2:15][CH2:16]2)=[C:9]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1N1CCC(O)CC1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC1CCN(c2c(S(C)(=O)=O)ccc(C(=O)O)c2Cl)CC1
Reaction time: 24 h

Procedure:
2-Chloro-3-(4-hydroxypiperidin-1-yl)-4-methylsulfonylbenzoic acid (0.70 g, 2.1 mmol) was added with stirring to a suspension of 0.25 g (6.3 mmol) of sodium hydride in a mixture of 0.40 mL (6.4 mmol) of methyl iodide and 10 mL of dry tetrahydrofuran. The mixture was heated to reflux and stirred for 24 hr. The resulting mixture was treated with water, acidified with 1N aqueous hydrochloric acid and extracted several times with dichloromethane. The organic layers were combined and dried over magnesium sulfate, the solvent was removed by concentration under reduced pressure, and the residue was rinsed with petroleum ether to obtain 0.70 g (96 percent of theory) of the title compound.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH:18]1[CH2:30]O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.[OH-].[Na+]>ClCCl>[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH:18]1[CH2:30][F:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: FCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.2 %

Procedure:
To a solution of diethylaminosulfur trifluoride (1.5 ml, 12.16 mmol) in dichloromethane (10 ml) at −72° C. was added 1,4-dibenzyl-2-(hydroxymethyl)piperazine (3 g, 10.1 mmol) in dichloromethane (20 ml) over 10 minutes. The mixture was stirred for 16 h whilst warming to room temperature and treated with water (20 ml). The aqueous phase was basified to pH 9 using 4 M sodium hydroxide and the organic phase separated. The aqueous phase was extracted with dichloromethane (2×30 ml) and the combined organic layers dried with sodium sulfate and evaporated. The residue was purified by flash chromatography eluting with 20% (v/v) ethyl acetate in hexane to afford 1,4-dibenzyl-2-(fluoromethyl)piperazine (0.94 g) as a colourless oil.
Reaction SMILES: [O-2].[Zn+2:2].[C:3]([OH:7])(=[O:6])[CH:4]=[CH2:5]>CCCCCCC>[C:3]([O-:7])(=[O:6])[CH:4]=[CH2:5].[Zn+2:2].[C:3]([O-:7])(=[O:6])[CH:4]=[CH2:5]
Reactant: C=CC(=O)O
Agent: [O-2]
Agent: [Zn+2]
Solvent: CCCCCCC
Product: C=CC(=O)[O-]
Temperature: 50 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
In a jacketed kneader having an inner volume of 10 L and made of SUS-316, 1,140 g of heptane was placed as a solvent and 407 g of zinc oxide was added and they were stirred together till they formed a suspension. While the inner temperature of the kneader holding the suspension was retained at a temperature in the range of 5–30° C., 739 g of acrylic acid was gradually added to the suspension over a period of three hours till the temperature reached 40° C. At 40° C., the ensuant reaction was continued for four hours. Then, while the inner pressure of the kneader was gradually lowered and the inner temperature was raised to 50° C. till the pressure reached 20 Torrs, the reaction solution was distilled for five hours to expel the reaction product and the heptane. Consequently, 1,037 g of zinc acrylate was obtained.
Reaction SMILES: [CH2:1]([C:3]12[CH2:17][C:16](=[O:18])[CH:15]=[C:4]1[C:5]1[C:10]([CH2:11][CH2:12]2)=[CH:9][C:8]([O:13][CH3:14])=[CH:7][CH:6]=1)[CH3:2].C([O-])(O)=O.[Na+].[Br:24]Br>>[Br:24][C:15]1[C:16](=[O:18])[CH2:17][C:3]2([CH2:1][CH3:2])[CH2:12][CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=3)[C:4]=12
Reactant: CCC12CCc3cc(OC)ccc3C1=CC(=O)C2
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC12CCc3cc(OC)ccc3C1=C(Br)C(=O)C2
Reaction time: 0.03 h

Procedure:
A solution of 3a-ethyl-7-methoxy-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one (415 mg, 1.7 mol) in CCL4 (5.1 mL) was treated with NaHCO3 (714 mg, 8.5 mmol). The mixture was cooled in an ice bath, purged with N2, stirred, and treated with Br2 (0.088 mL, 1.7 mmol) to give an unstirrable orange gum. The mixture was sonicated for one minute, swirled in an ice bath for two minutes, and then stirred at 0-5° C. for 75 minutes. The mixture was then partitioned between CH2Cl2 and water (50 mL each). The organic phase was washed with saturated aqueous Na2S2O3 and brine, dried over MgSO4, filtered, and evaporated under vacuum. The crude product was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 40M (4×15 cm) silica gel column, eluting with 5:1 hexane-EtOAc, to provide 1-bromo-3a-ethyl-7-methoxy-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one as a white foam.
Reaction SMILES: C([N:4]([CH:7]([CH3:9])[CH3:8])CC)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Br:32][C:33]1[C:34]([C:40]2[S:44][C:43]3[CH:45]=[CH:46][CH:47]=[C:48]([C:49]([OH:51])=O)[C:42]=3[CH:41]=2)=[N:35][C:36]([Cl:39])=[N:37][CH:38]=1.C1(N)CC1>ClCCl>[CH:7]1([NH:4][C:49]([C:48]2[C:42]3[CH:41]=[C:40]([C:34]4[C:33]([Br:32])=[CH:38][N:37]=[C:36]([Cl:39])[N:35]=4)[S:44][C:43]=3[CH:45]=[CH:46][CH:47]=2)=[O:51])[CH2:9][CH2:8]1
Reactant: O=C(O)c1cccc2sc(-c3nc(Cl)ncc3Br)cc12
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NC1CC1
Solvent: ClCCl
Product: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Br)cc12
Reaction time: 5 h
Yield: 82.8 %

Procedure:
Diisopropylethylamine (1.19 mL, 6.82 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.650 g, 3.41 mmol) and 1-hydroxybenzotriazole (0.460 g, 3.41 mmol) are sequentially added to a stirred suspension of 2-(5-bromo-2-chloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid (1.20 g, 3.25 mmol) in anhydrous dichloromethane (25 mL) at ambient temperature under nitrogen. The resultant light suspension is treated with cyclopropylamine (0.190 g, 3.41 mmol), then the reaction mixture is allowed to stir for 5 hours. The reaction mixture is diluted with dichloromethane (50 mL) before it is washed with water (100 mL). The aqueous layer is extracted with dichloromethane (100 mL×2) to ensure no precipitation is present in the aqueous layer. The combined organic layers are concentrated and then resuspended in dichloromethane (1 mL)/diethyl ether (9 mL). After sonication and subsequent filtration, the solid is washed with additional dichloromethane (1 mL)/diethyl ether (9 mL) and dried to provide the title compound (1.10 g, 97% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].Cl.[NH:34]1[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]1.O>CN(C=O)C.CO.C(Cl)Cl>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([N:34]2[CH2:39][CH2:38][C:37](=[O:40])[CH2:36][CH2:35]2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2cc(N3CCC(=O)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 80 °C
Yield: 28.8 %

Procedure:
To a solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.1 g, 0.239 mmol) in DMF (2 mL), K2CO3 (0.198 g, 1.434 mmol) and piperidin-4-one HCl salt (0.186 g, 0.94 mmol) were added. The reaction mixture was heated at 80° C. for 16 h. Reaction was monitored by LCMS & TLC. On completion, reaction mass was poured into water and extraction was carried out using 5% MeOH/DCM. The combined organic layers were dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was purified by prep HPLC to provide the desired compound (0.03 g 28.8%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH2:20].C(N(CC)CC)C>>[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19][NH:20][S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13]
Reactant: CN(C)CCN
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Solvent: CCN(CC)CC
Product: CN(C)CCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 101.6 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (400 mg, 1.38 mmol), N,N-dimethylethylenediamine (121 mg, 1.38 mmol) and triethylamine(0.39mL, 2.76 mmol) were reacted to form the crude product (480 mg) which was carried on to the hydrolysis without purification.. EI-MS (m/z) 341.88 (M−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:15][N:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[C:21]([O:23][CH3:24])=[O:22]>ClCCCl>[CH3:15][N:16]1[CH:20]=[C:19]([C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[CH:18]=[C:17]1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1cccn1C
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COC(=O)c1cc(C(=O)c2cccc(Cl)c2)cn1C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To 100 ml 1,2-dichloroethane are added 5 g 3-chloro-benzoyl chloride followed by 8.4 g aluminium chloride. The mixture is cooled to 5° C. and 4 g methyl 1-methylpyrrole-2-carboxylate dissolved in 15 ml 1,2-dichloroethane are added thereto. The resulting mixture is stirred 0.5 hour at said temperature and then 1 hour at room temperature, after which the solution is hydrolyzed over ice, the organic phase is decanted and the solvent is evaporated off. Recrystallization of the solid residue from methanol give 7.5 g methyl 1-methyl-4-(3-chlorobenzoyl)pyrrole-2-carboxylate, m.p.=126° C.