Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>>[CH2:33]([S:35]([N:16]1[CH2:15][CH2:14][N:13]([C:6]2[C:5]([CH3:19])=[C:4]([NH:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:26]=3)[C:3]3[C:8](=[CH:9][C:10]([F:12])=[CH:11][C:2]=3[F:1])[N:7]=2)[CH2:18][CH2:17]1)(=[O:37])=[O:36])[CH3:34]
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)N1CCN(c2nc3cc(F)cc(F)c3c(Nc3cncc(N4CCOCC4)c3)c2C)CC1

Procedure:
Prepared according to Procedure M using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (50 mg, 0.11 mmol) and ethylsulfonyl chloride to give 2-(4-(ethylsulfonyl)piperazin-1-yl)-5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (DMSO-d6) δ ppm 1.15 (t, J=7.2 Hz, 3H), 2.08 (s, 3H), 3.05-3.11 (br s, 4H), 3.13 (q, J=7.2 Hz, 2H), 3.33 (br s, 8H), 3.69 (m, 4H), 6.51 (br s, 1H), 7.10-7.15 (m, 1H), 7.28-7.31 (m, 1H), 7.46 (s, 1H), 7.74 (s, 1H), 8.39 (s, 1H). Mass Spectrum (ESI) m/e=533.4 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]3[CH2:27][CH2:28][NH:29][CH2:30][C:19]=23)=[O:17])[CH2:12][CH2:11]1.[CH2:31](N(CC)CC)C.C=O.C([BH3-])#N.[Na+]>CO>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]3[CH2:27][CH2:28][N:29]([CH3:31])[CH2:30][C:19]=23)=[O:17])[CH2:12][CH2:11]1
Reactant: COc1ccccc1C1CCN(C(=O)c2c3n(c4ccccc24)CCNC3)CC1
Reactant: CCN(CC)CC
Agent: C=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: COc1ccccc1C1CCN(C(=O)c2c3n(c4ccccc24)CCN(C)C3)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
A solution of 0.040 g (0.094 mmol) [4-(2-methoxy-phenyl)-piperidin-1-yl]-(1,2,3,4-tetrahydro-pyrazino[1,2-a]indol-10-yl)-methanone hydrochloride, 0.026 ml (0.19 mmol) triethylamine and 0.023 g (0.77 mmol) paraformaldehyde in 2 ml methanol was heated at reflux for 1 h. The reaction mixture was cooled to 0° C. on an ice-water bath and treated with 0.0089 g (0.14 mmol) sodium cyanoborohydride. After completed addition the mixture was allowed to warm to room temperature and stirred for 2 h. Quenching with water and dilution with 2 M aqueous sodium carbonate solution was followed by extraction with dichloromethane (2×50 ml). The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash-chromatography (aminopropyl-modified silica gel, n-heptane/ethyl acetate) to give the title compound (0.031 g, 82%) as an off-white solid.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[N:6][CH:7]=1.[F:19][C:20]1([F:39])[O:24][C:23]2[CH:25]=[C:26]([CH3:38])[C:27](B3OC(C)(C)C(C)(C)O3)=[CH:28][C:22]=2[O:21]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(#N)C.O>[F:39][C:20]1([F:19])[O:24][C:23]2[CH:25]=[C:26]([CH3:38])[C:27]([C:2]3[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]4[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=4[F:17])=[N:6][CH:7]=3)=[CH:28][C:22]=2[O:21]1
Reactant: O=C(Nc1cnc(Br)cn1)c1c(F)cccc1F
Reactant: Cc1cc2c(cc1B1OC(C)(C)C(C)(C)O1)OC(F)(F)O2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CC#N
Product: Cc1cc2c(cc1-c1cnc(NC(=O)c3c(F)cccc3F)cn1)OC(F)(F)O2
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 76486.1 %

Procedure:
Palladium tetrakis-triphenylphosphine (23 mg, 20 μmol) was added to a degassed solution of bromide 17 (129 mg, 0.4 mmol) and boronate 14 (117 mg, 0.4 mmol) in dioxane: acetonitrile:water (9:9:2, 2.0 mL) and potassium phosphate (125 mg, 0.6 mmol). The resulting mixture was heated under argon at 80° C. with stiffing for 1.5 hours. The mixture was then cooled, extracted with dichloromethane (3×7 mL), dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-30% ethyl acetate in hexane) provided 10 (124 g, 78%) as a crystalline solid: LRESIMS 406.1 [M+H]+, calcd. for C19H12F4N3O3 406.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[CH:12]([S:15]([C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20])(=[O:17])=[O:16])([CH3:14])[CH3:13].[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[S:15]([CH:12]([CH3:14])[CH3:13])(=[O:17])=[O:16])[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1
Reactant: Clc1cc(Cl)n2nccc2n1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Cl)nc2ccnn12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 5,7-dichloro-pyrazolo[1,5-a]pyrimidine (1.0 mmol) and 2-(isopropylsulfonyl)aniline(1.0 mmol) in 5 mL of DMF, was added carefully NaH (24 mg). The resulting suspension was stirred at 50° C. for 2 hours. After cooling at RT and careful quenching (ice), water was added and the mixture was extracted with EtOAc. The organic layers were collected, dried (Na2SO4), filtrated and concentrated. The residue was purified over SiO2 column chromatography (eluent: 9:1 Hexane:EtOAc), to give the desired 5-chloro-N-(2-(isopropylsulfonyl)phenyl)pyrazolo[1,5-a]pyrimidin-7-amine. MS (ES+): 351.06 (M+1)+.
Reaction SMILES: [C:1]([NH:11][C@@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.[NH2:26][CH2:27][C:28]([O:32][CH3:33])([O:30][CH3:31])C>C1COCC1>[CH3:31][O:30][CH:28]([O:32][CH3:33])[CH2:27][NH:26][C:16](=[O:18])[C@H:12]([NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH:13]([CH3:14])[CH3:15]
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(C)(CN)OC
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(CNC(=O)[C@H](NC(=O)OCc1ccccc1)C(C)C)OC
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
A solution of Cbz-D-Valine (500 g, 1.99 mol) and N-methylmorpholine (201.8 g, 1.99 mol) in anhydrous THF (8 L) was cooled to −15° C., i-butylchlorofomate (299 g, 2.19 mol) was added dropwise under stirring. After 30 min, a solution of 1-amino-2,2-dimethyoxypropane (209.5 g, 1.99 mol) in THF (1 L) was added slowly and the temperature was maintained at −15° C. for 2 h. The reaction mixture was washed with brine (2 L) and the organic phase was concentrated to remove the THF. The residue was diluted with EtOAc (4 L), washed with 1N aqueous HCl (2×2 L), washed with sat. NaHCO3 (2 L) and Na2CO3 (2 L), and washed with brine (1.5 L). After drying over Na2SO4, the organic solvent was removed under reduce pressure to afford (R)-benzyl (1-((2,2-dimethoxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate as a white solid (670 g, yield 99.5%), which was used for next step without further purification. LC-MS m/z 360.9 [M+Na]+. 1H NMR (CD3OD 300 MHz): δ 7.35-7.30 (m, 5H), 5.08 (s, 2H), 4.45-4.35 (m, 1H), 3.95-3.85 (m, 1H), 3.34-3.25 (m, 8H), 2.10-1.90 (m, 1H), 0.94-0.91 (m, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8]2[C:13]([CH:14]=O)=[CH:12][N:11]=[C:10]([S:16][CH3:17])[N:9]=2)=[CH:5][C:4]([CH3:18])=[N:3]1.Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])=[O:22].C(=O)([O-])[O-].[K+].[K+].N12CCCN=C1CCCCC2>CN(C=O)C.CCOC(C)=O.[NH4+].[Cl-]>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:21]([C:20]1[N:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([CH3:18])[CH:5]=2)[C:8]2[N:9]=[C:10]([S:16][CH3:17])[N:11]=[CH:12][C:13]=2[CH:14]=1)=[O:22]
Reactant: O=C(CBr)c1ccccc1Cl
Reactant: CSc1ncc(C=O)c(Nc2cc(C)nn2C)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ncc2cc(C(=O)c3ccccc3Cl)n(-c3cc(C)nn3C)c2n1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
To a solution of 4-(2,5-dimethyl-2H-pyrazol-3-ylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde, 18, (0.25 g, 0.95 mmol) in DMF (4 mL) is added 2-bromo-1-(2-chloro-phenyl)-ethanone (0.33 g, 1.42 mmol) and potassium carbonate (0.26 g, 1.90 mmol). The reaction mixture is stirred at room temp for 21 hours after which the reaction solution is diluted with EtOAc and washed three times with aqueous saturated NH4Cl. The organic phase is washed with brine, dried (MgSO4), filtered, concentrated in vacuo and the resulting residue is dissolved in DMF (6 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL, 1.90 mmol) is added to the reaction. After stirring the reaction at room temp for 3 hours, the mixture is diluted with aqueous saturated NH4Cl solution and extracted with EtOAc. The organic phase is washed with brine, dried (MgSO4), filtered, concentrated in vacuo, and the resulting residue is purified over silica (33% EtOAc//hexanes) to afford 0.14 g of the desired product: 1H NMR (300 MHz, CDCl3) δ 8.92 (s, 1H), 7.52-7.35 (m, 4H), 7.00 (s, 1H), 6.14 (s, 1H), 3.67 (s, 3H), 2.55 (s, 3H), 2.37 (s, 3H); ESI+ MS: m/z (rel intensity) 398.0 (100, M++H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([S:11](Cl)(=[O:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CCCCCC>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([S:11]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)(=[O:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: C1CCNCC1
Reactant: Cc1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: Cc1nc2ccc(S(=O)(=O)N3CCCCC3)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
A solution of Compound 2 (2.5 g, 10 mmol) in chloroform (15 ml) was added drop wise to a solution of piperidine (1.7 g, 20.0 mmol) in chloroform (10 ml). The combined mixture was stirred at room temperature for 1 hour. The reaction mixture was then washed with water (2×, 50 ml) and brine (1×, 50 ml). The organic layer was dried with sodium sulfate and evaporated. The sticky white solid thus obtained was dissolved in ca. 5 ml of hot ethyl acetate and this solution was then slowly added to 40 ml hexane. The white solid that precipitated was collected, washed with hexane and dried to yield 2.2 g (74%) of Compound 3, Rf=0.28 (30% ethyl acetate in hexane). The structure of Compound 3 is given below:
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:19](Cl)(=[O:21])[CH3:20].Cl>C(Cl)Cl>[C:19]([C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:13][CH2:12][C:11]=2[CH:10]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: c1ccc2c(c1)CCc1ccccc1-2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCc1ccccc1-2
Reaction time: 2 h

Procedure:
To a solution of 18 g (0.1 mole) 9,10-dihydrophenanthrene in 200 mL of dry CH2Cl2, cooled in ice, 20 g (0.15 mole) of anh. AlCl3 was added. To this solution 9.42 g (0.12 mmole) of acetyl chloride in 50 mL of dry CH2Cl2 was added in 17 mins. Stirring was continued for 30 mins in ice and 2 h at room temperature. The solution was poured on ice and 25 mL of concentrated HCl and stirred for 15 mins. The yellow organic layer was separated, washed with NaHCO3 solution, and dried. The solvent was removed and the residue distilled at 0.15 mm pressure. The distillate, 15.28 g, crystallized from ethanol-hexane, m.p. 58°-60° .
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[N:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[CH:13]=[CH:12]1.CN(C)[CH:24]=[O:25]>>[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[N:15][C:16]([O:20][CH3:21])=[CH:17][CH:18]=2)[C:13]([CH:24]=[O:25])=[CH:12]1
Reactant: COc1ccc2c(ccn2CCCCBr)n1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(n1)c(C=O)cn2CCCCBr
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under argon and in an anhydrous medium, 730 μl (7.95 mmol) of phosphorus oxychloride are added dropwise to 12.5 ml of N,N-dimethylformamide maintained at 0° C.: after 30 minutes' stirring, 1.50 g (5.3 mmol) of the compound obtained in Step A dissolved in 25 ml of N,N-dimethylformamide are added by transfer. The reaction mixture is stirred for 30 minutes at 0° C. and then for 3 hours at room temperature. The reaction mixture is evaporated to dryness and then taken up in water, the aqueous phase is rendered alkaline with a 6N sodium hydroxide solution and extracted several times with ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and then evaporated. After washing with a petroleum ether/diethyl ether mixture, the title compound is obtained in the form of a yellow oil.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].CN(C)C1C=CC=CC=1.[CH3:15][O:16][C:17]1[CH:39]=[CH:38][C:20]([CH2:21][N:22]2[C:31]3[C:26](=[CH:27][C:28]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:30]=3)[NH:25][C:24](=O)[C:23]2=[O:37])=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Cl:3][C:24]1[C:23](=[O:37])[N:22]([CH2:21][C:20]2[CH:38]=[CH:39][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[C:31]2[C:26]([N:25]=1)=[CH:27][C:28]([C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:30]=2
Reactant: COC(=O)c1ccc2c(c1)[nH]c(=O)c(=O)n2Cc1ccc(OC)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)nc(Cl)c(=O)n2Cc1ccc(OC)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
POCl3 (2 g, 13.25 mmol) and N,N-dimethylbenzenamine (2.13 g, 17.60 mmol,) were added to a solution of methyl 1-(4-methoxybenzyl)-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (3 g, 8.81 mmol) in toluene (100 ml). The resulting reaction was stirred overnight at 110° C. and concentrated in vacuo. The residue was triturated with methanol (50 ml) and collected by filtration to afford methyl 3-chloro-1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a green solid (2.27 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[F:12][CH:13]([F:16])[CH2:14][NH2:15]>C(Cl)Cl.O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:15][CH2:14][CH:13]([F:16])[F:12])[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2occc2n1
Reactant: NCC(F)F
Solvent: ClCCl
Solvent: C1COCCO1
Product: FC(F)CNc1nc(Cl)nc2ccoc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a flask was added 2,4-dichlorofuro[3,2-d]pyrimidine (2 g, 10.58 mmol, Arkpharm), DCM (20 mL) and TEA (2.95 mL, 21.16 mmol). A solution of 2,2-difluoroethanamine (0.858 g, 10.6 mmol, Matrix) in DCM (5 mL) was added drop-wise and the mixture was stirred at rt overnight. The mixture was concentrated under reduced pressure. To the residue was added 1,4-dioxane (20 mL), TEA (2.95 mL, 21.2 mmol) and a solution of 2,2-difluoroethanamine (0.858 g, 10.58 mmol, Matrix) in 1,4-dioxane (5 mL). The mixture was stirred at rt for about 4 h, and then at about 55° C. overnight. The mixture was concentrated under reduced pressure, and the residue was taken up in EtOAc (120 mL) and water (25 mL). The organic layer was isolated and washed with water (2×25 mL). The combined aqueous layers were washed with EtOAc (2×25 mL). The combined organic layers were washed with brine (25 mL), dried with MgSO4, filtered, concentrated under reduced pressure, and dried in a vacuum oven at about 70° C. over 2 days to give 2-chloro-N-(2,2-difluoroethyl)furo[3,2-d]pyrimidin-4-amine (2.20 g, 89%): LC/MS (Table 2, Method c) Rt=1.69 min.; MS m/z: 234 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH2:16][C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[C:7]([NH:16][C:17]1[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[CH:19][N:18]=1)=[O:8])([O-:3])=[O:2]
Reactant: Nc1cc(C(F)(F)F)ccn1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Product: O=C(Nc1cc(C(F)(F)F)ccn1)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1

Procedure:
Prepared analogously to example 303a from 3,4-dinitro-benzoyl chloride and 2-amino-4-trifluoromethyl-pyridine.
Reaction SMILES: C(N(N=O)[C:9](=[O:37])[CH:10]([N:19]1[C:23]2[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=2[N:21]=[C:20]1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[CH:11]1[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]1)C1C=CC=CC=1.O.[OH-].[Li+].OO.C(O)(=[O:47])C>O1CCCC1.O>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:20]2[N:19]([CH:10]([CH:11]3[CH2:12][CH2:13][C:14]([F:17])([F:18])[CH2:15][CH2:16]3)[C:9]([OH:47])=[O:37])[C:23]3[CH:24]=[C:25]([F:29])[C:26]([F:28])=[CH:27][C:22]=3[N:21]=2)=[CH:35][CH:34]=1
Reactant: CC(=O)O
Reactant: O=NN(Cc1ccccc1)C(=O)C(C1CCC(F)(F)CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(C1CCC(F)(F)CC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reaction time: 2 h
Yield: 49 %

Procedure:
To a suspension of 3.05 g (5.46 mmol) N-benzyl-N-nitroso-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-(4,4-difluoro-cyclohexyl)-acetamide in 15 ml tetrahydrofuran and 10 ml water were added dropwise over 5 min. a solution of 2.29 g (54.57 mmol) lithium hydroxide monohydrate in 11.14 ml (109 mmol) 30% hydrogen peroxide solution and 10 ml water. The reaction mixture turned into a turbid solution and became slightly warm (cooled temporarily using an ice-bath). After stirring for 2 h the pH was adjusted to pH 4 using 12.48 ml (218 mmol) acetic acid. The resulting light yellow solution was extracted three times with ethyl acetate. The combined organic layers were washed twice with saturated aqueous sodium bicarbonate solution, brine, dried over magnesium sulfate, filtered and evaporated. The remaining yellow foam was treated with 100 ml tert-butyl methylether and the resulting light yellow suspension was filtered, washed with tert-butyl methyl ether and dried under high vacuum to give a first batch of compound (yellow solid). The mother liquor was purified on a preparative HPLC system (Phenomenex Gemini column) eluting with a gradient of acetonitrile and water. to give another batch of compound (colorless solid). Overall yield 49%. MS (Turbo Spray): m/z=441.3 [M+H].
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[O:4][CH2:5][C:6]#[N:7].C(COC1C=C(N[S:24]([CH3:27])(=[O:26])=[O:25])C=CC=1)#N.NC1C=C(C=CC=1)OCC#N>>[C:6]([CH2:5][O:4][C:3]1[C:2]([CH3:1])=[C:11]([NH:12][S:24]([CH3:27])(=[O:26])=[O:25])[CH:10]=[CH:9][CH:8]=1)#[N:7]
Reactant: CS(=O)(=O)Nc1cccc(OCC#N)c1
Reactant: Cc1c(N)cccc1OCC#N
Agent: N#CCOc1cccc(N)c1
Product: Cc1c(NS(C)(=O)=O)cccc1OCC#N

Procedure:
N-(3-cyanomethoxy-2-methylphenyl)-methanesulfonamide was prepared from (2-methyl-3-aminophenoxy)acetonitrile in a manner similar to that described in Example 1 for the preparation of N-(3-cyanomethoxyphenyl)-methanesulfonamide from (3-aminophenoxy)-acetonitrile.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C:22](=[O:23])[CH2:21][CH2:20][C@@:19]2([CH3:24])[C:6]1=[CH:7][CH2:8][C@@H:9]1[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]1[CH2:11][CH2:12][C:13]2=[O:25])(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:4][C@@H:5]1[CH:22]([OH:23])[CH2:21][CH2:20][C@@:19]2([CH3:24])[C:6]1=[CH:7][CH2:8][C@@H:9]1[C@@H:18]2[CH2:17][CH2:16][C@@:14]2([CH3:15])[C@H:10]1[CH2:11][CH2:12][C@@H:13]2[OH:25])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C(=O)CC[C@@]2(C)C1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)O[C@H]1C2=CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CCC1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a suspension of 4α-acetoxyandrost-5-ene-3,17-dione (600 mg) in MeOH (20 ml) at 0° C., NaBH4 (70 mg) was added. The mixture was warmed and stirred for 1 h at RT. The solution was neutralized by addition of 5% NaH2PO4 and the organic solvent was evaporated. The residue was taken up in H2O and extracted with DCM. The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated to dryness. The resulting 4α-acetoxyandrost-5-ene-3,17β-diol (600 mg) was obtained as a 3α:3β mixture and used without purification in the next step.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([OH:20])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C:7]1=[CH:6][CH2:5][C@@H:4]2[OH:21])[CH3:2].C.[H][H]>C1C=CC=CC=1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([OH:20])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:21])[CH3:2]
Reactant: CC[C@]12CCC3=C(CCc4cc(O)ccc43)C1=CC[C@@H]2O
Reactant: [H][H]
Solvent: c1ccccc1
Product: CC[C@]12CCC3=C(CCc4cc(O)ccc43)[C@@H]1CC[C@@H]2O

Procedure:
Shake 13β-ethylgona-1,3,5-(10),8,14-pentaene-3,17β-diol (0.28 g.) in benzene (35 cc.) with 10% palladised charcoal (300 mg.) in an atmosphere of hydrogen until 25 cc. of hydrogen has been absorbed. Filter off the catalyst, evaporate the solvent and recrystallize the residue from methanol to obtain the title product, m.p. 234°-8°; ultraviolet absorption peak at 280 mμ (ε 41,200).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([CH2:15]O)([CH2:13]O)[CH2:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][C:11]([CH2:15][S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:9])=[CH:18][CH:19]=3)(=[O:25])=[O:24])([CH2:13][S:33]([C:30]3[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=3)(=[O:35])=[O:34])[CH2:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(C2=C(c3ccc(F)cc3)CC(CO)(CO)C2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)CC2(CS(=O)(=O)c3ccc(C)cc3)CC(c3ccc(F)cc3)=C(c3ccc(S(C)(=O)=O)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 138.8 %

Procedure:
Under nitrogen, a solution of 2.34 mmol of the crude 1-[2-(4-fluorophenyl)-4,4-di(hydroxymethyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene (prepared in Step 9) in 8 mL of pyridine at ambient temperature was treated with 1.2 g (6.3 mmol) of p-toluenesulfonyl chloride (tosyl chloride). The resulting solution was stirred at room temperature for 17 hours, concentrated in vacuo, and chromatographed on silca gel to give 1.06 g (66% overall yield from Step 9) of 1-[2-(4-fluorophenyl)-4,4-di(tosylmethyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene as a colorless solid: NMR (CDCl3) δ2.46 (s, 6H), 2.73 (s, 3H), 3.04 (s, 3H), 4.05
Reaction SMILES: [O-]CC.[Na+].[CH3:5][C:6]([CH3:16])=[CH:7][C@H:8]1[C:10]([CH3:12])([CH3:11])[C@H:9]1[C:13]([OH:15])=[O:14]>>[CH3:5][C:6]([CH3:16])=[CH:7][C@H:8]1[C:10]([CH3:11])([CH3:12])[C@@H:9]1[C:13]([OH:15])=[O:14]
Reactant: CC(C)=C[C@@H]1[C@H](C(=O)O)C1(C)C
Agent: CC[O-]
Agent: [Na+]
Product: CC(C)=C[C@@H]1[C@@H](C(=O)O)C1(C)C

Procedure:
As in Example 1, n-butyl cis-chryanthemate (25.0 g) was treated with sodium ethoxide (2.0 g) at 150°C for 60 minutes while stirring. By gas chromatographic analysis, the product was confirmed to be a mixture of the cis-isomer and the trans-isomer in a weight ratio of 25 : 75. The product was hydrolyzed by a conventional procedure and cis-chrysanthemic acid was removed as dihydro-chrysanthemolactone to give trans-chrysanthemic acid (15.1 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH:10]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)([CH3:12])[CH3:11]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:17][C:16]2[CH:18]=[CH:19][C:13]([CH:10]([CH3:12])[CH3:11])=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(NCc2ccc(F)cc2)cc1
Yield: 93.5 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 4-fluorobenzaldehyde (1.2 g) and 4-isopropylaniline (1.4 g) as starting materials, [(4-fluorophenyl)methyl](4-isopropylphenyl)amine (2.2 g) was obtained.