Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](B1C2CCCC1CCC2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.FC(F)(F)S(O[C:28]1[CH:36]=[CH:35][C:31]2[CH:32]=[CH:33][O:34][C:30]=2[CH:29]=1)(=O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([C:28]1[CH:36]=[CH:35][C:31]2[CH:32]=[CH:33][O:34][C:30]=2[CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
Reactant: O=S(=O)(Oc1ccc2ccoc2c1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1CCOC1
Product: c1ccc(Cc2ccc3ccoc3c2)cc1
Temperature: 60 °C

Procedure:
To a purple mixture of benzofuran-6-ol (1.85 g, 13.8 mmol) and N,N-diisopropylethylamine 99% (7.21 mL, 41.4 mmol) in 50 mL DCM was added 1,1,1-trifluoro-n-phenyl-n-((trifluoromethyl)sulfonyl)methanesulfonamide (4.93 g, 13.8 mmol). The reaction became light blue. After 2 h, the reaction was light yellow. The reaction was quenched with saturated aq. sodium bicarbonate, and the aqueous layer was extracted with DCM. The combined organics were dried over anhyd sodium sulfate, filtered, and concentrated in vacuo. The resulting material was purified by silica gel chromatography, 0-15% EtOAc/hexanes, to give benzofuran-6-yl trifluoromethanesulfonate as a semi-solid. A portion of the unpurified material was carried on as follows. A mixture of 9-benzyl-9-bora-bicyclo[3.3.1]nonane 0.5M in THF (23 mL, 11 mmol), benzofuran-6-yl trifluoromethanesulfonate (1.50 g, 5.6 mmol), potassium phosphate (3.6 g, 17 mmol), benzofuran-6-yl trifluoromethanesulfonate (1.50 g, 5.6 mmol), S-Phos (0.19 g, 0.45 mmol), Pd(OAc)2 (0.051 g, 0.23 mmol) was flushed with argon, sealed, and heated to 60° C. overnight. The green/gray reaction was cooled and filtered through celite rinsing with Et2O. The filtrate was concentrated and adsorbed onto 15 g silica gel and dried. The material was purified by silica gel chromatography, ISCO, 80 g, 0-10% EtOAc/hexanes to give 6-benzylbenzofuran. A portion of this material was processed as follows. To a solution of 6-benzylbenzofuran (0.663 g, 3.18 mmol) in 30 mL THF at −78° C. was added 1-butyllithium 2.5 M in hexanes (1.53 mL, 3.82 mmol) slowly dropwise. The reaction was allowed to stir for 25 min, at which point triisopropyl borate (1.08 mL, 4.68 mmol) was added slowly dropwise. After 0.5 h, the bath was removed and the reaction was allowed to warm to ambient temperature. After 10 min, 50 mL 2N HCl was added. The mixture was diluted with MTBE, and the organics were washed with brine, dried over anhyd. MgSO4, filtered, and concentrated in vacuo to give an oil. The oil was treated with hexanes to give a solid, and the material was filtered and rinsed with hexanes and dried in vacuo to give 6-benzylbenzofuran-2-ylboronic acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47 (s, 2H), 7.57 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.39 (s, 1H), 7.24-7.33 (m, 4H), 7.15-7.22 (m, 1H), 7.10 (d, J=8.0 Hz, 1H), 4.06 (s, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:2]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)#[CH:19]>CCCCCCC.CCOC(C)=O>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]#[C:19][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:21][CH:22]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccnc2)cc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C#Cc2cccnc2)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid pyridin-3-yl ester and 1-ethynyl-4-methoxy-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 8:2; yield (83 mg, 80%); 1H NMR δ (CDCl3): 8.76-8.74 (m, 1H), 8.50-8.53 (m, 1H), 7.76-7.73 (m, 1H), 7.49-8.46 (m, 2H), 7.24-7.20 (m, 1H), 6.88-6.85 (m, 2H), 3.78 (s, 3H); LCMS m/z: 209.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:24]Br>>[F:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:24][N:7]1[C:8]([S:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Reactant: Fc1cc(F)cc(CBr)c1
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2cc(F)cc(F)c2)c(=O)[nH]c1=O
Yield: 48.7 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3,5-difluorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (196 mg, yield: 48.7%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:27][O:28][CH2:29][CH3:30])[N:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)=[CH:5][C:4]=2[N:3]=1>Cl>[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][C:6]([C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH2:27][O:28][CH2:29][CH3:30]
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Agent: Cl
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCCCN
Reaction time: 0.5 h
Yield: 113.6 %

Procedure:
A solution of tert-butyl {4-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate (40.35 g, 82.24 mmol) in concentrated hydrochloric acid (400 mL) was stirred for one hour, filtered, and concentrated under reduced pressure. The residue was dissolved in a minimal amount of water, and 50% aqueous sodium hydroxide was added to adjust the solution to pH 14. Chloroform (1.2 L) and a mixture of saturated aqueous sodium bicarbonate and 1% aqueous sodium carbonate (600 mL) were added; the mixture was stirred for 30 minutes. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure to provide 36.48 g of 1-(4-aminobutyl)-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a light yellow solid.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=1>>[CH3:33][C:32]1[C:27]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Reactant: Cc1cccnc1Br
Product: Cc1cccnc1C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1

Procedure:
This compound is prepared by method C using compound 12d and 2-bromo-3-methylpyridine.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][CH:11]([F:34])[O:12][CH2:13][C@@H:14]([O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:20]([OH:22])=O)[CH3:15].[NH2:35][C:36]1[CH:40]=[CH:39][N:38]([CH3:41])[N:37]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[F:34][CH:11]([F:10])[O:12][CH2:13][C@@H:14]([O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=1)[C:20]([NH:35][C:36]1[CH:40]=[CH:39][N:38]([CH3:41])[N:37]=1)=[O:22])[CH3:15]
Reactant: C[C@@H](COC(F)F)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Reactant: Cn1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](COC(F)F)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.8 %

Procedure:
DIPEA (0.198 mL, 1.14 mmol) was added to a mixture of 3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-[(phenylmethyl)oxy]benzoic acid (0.1 g, 0.28 mmol), 3-amino-1-methylpyrazole (39 mg, 0.4 mmol) and HATU (0.227 g, 0.6 mmol) in DMF (3 mL) and stirred at RT for 20 hours. Ethyl acetate (30 mL) was added and the mixture washed with water (30 mL), brine (30 mL), dried (MgSO4), filtered and reduced in vacuo to give a yellow oil which was chromatographed on silica, eluting with a gradient of 0-100% ethyl acetate in isohexane, to give the desired compound (0.1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]([C:21]1[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:22]=1)([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:12][CH3:13].CN1CCOCC1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]([C:21]2[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:22]=2)([N:6]2[C:7]3[C:3](=[C:2]([NH:1][S:39]([CH3:38])(=[O:41])=[O:40])[CH:10]=[CH:9][CH:8]=3)[CH:4]=[N:5]2)[CH2:12][CH3:13])=[CH:19][CH:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1noc(C(CC)(c2ccc(Cl)cc2)n2ncc3c(N)cccc32)n1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)c1noc(C(CC)(c2ccc(Cl)cc2)n2ncc3c(NS(C)(=O)=O)cccc32)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product from Step D above (0.080 g, 0.17 mmol) and N-methylmorpholine (0.035 g, 0.35 mmol) in DCM (1.0 mL) was added methanesulfonyl chloride (0.019 g, 0.17 mmol) at 0° C. After stirring at RT for 30 min, the reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with dioxane/water, acidified with TFA, and purified directly on RP-HPLC to give the title compound. LC/MS m/z=504.1 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:41][CH2:42][CH3:43])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:44](#[N:47])[CH:45]=[CH2:46]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([O:40][CH2:46][CH2:45][C:44]#[N:47])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:41][CH2:42][CH3:43])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(O)CC1
Reactant: C=CC#N
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(OCCC#N)CC1

Procedure:
In a manner similar to the method described in example 177, [(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-(4-hydroxy-piperidin-1-yl)-methanone (example 101) was reacted with acrylonitrile (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C37H44Cl2N5O3 [(M+H)+] 676.2816, observed 676.2815.
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:18]O>>[NH2:2][C:3]1[C:11]([OH:12])=[CH:10][C:9]([CH3:13])=[CH:8][C:4]=1[C:5]([O:7][CH3:18])=[O:6]
Reactant: Cc1cc(O)c(N)c(C(=O)O)c1
Reactant: CO
Agent: Br
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(C)cc(O)c1N
Temperature: 25 °C
Yield: 72 %

Procedure:
To a solution of 2-amino-3-hydroxy-5-methylbenzoic acid hydrobromide (2.65 g, 10.7 mmol) in anhydrous CH3OH (50 mL) was added thionyl chloride (3.9 mL, 53.4 mmol) at −78° C. The resulting reaction mixture was allowed to warm to room temperature and then heated to reflux for 17 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was treated with a saturated aqueous NaHCO3 solution to adjust pH to 7 and then extracted with EtOAc (4×100 mL). The combined organic phase was washed with H2O, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford methyl 2-amino-3-hydroxy-5-methylbenzoate (1.40 g, 72%): 1H NMR consistent.
Reaction SMILES: C1([NH2+]C2CCCCC2)CCCCC1.[C:14]([NH:24][C@H:25]([C:35]([O-:37])=[O:36])[CH2:26][CH:27]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O-:30])=[O:29])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C1([NH2+]C2CCCCC2)CCCCC1.C(OCC)(=O)C.[CH3:57][N:58]([CH2:60][CH2:61]Cl)[CH3:59]>C1C=CC=CC=1>[CH3:57][N:58]([CH2:60][CH2:61][O:36][C:35](=[O:37])[C@H:25]([CH2:26][CH:27]([C:31]([CH3:32])([CH3:33])[CH3:34])[C:28]([OH:30])=[O:29])[NH:24][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH3:59]
Reactant: CN(C)CCCl
Reactant: CC(C)(C)C(C[C@H](NC(=O)OCc1ccccc1)C(=O)[O-])C(=O)[O-]
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CN(C)CCOC(=O)[C@H](CC(C(=O)O)C(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 90 °C

Procedure:
To 1.88 g N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-dicyclohexyl ammonium salt, 24 ml ethyl acetate and 3.3 ml solution of dimethylaminoethylchloride in the amount of 0.78 g, stoichiometrically corresponds to two times the molar volume, in benzene were added to be subjected to reflux in oil bath at 90° C. for 16 hrs. After cooling down to a room temperature, precipitated dicyclohexyl ammonium chloride was filtered off and ethyl acetate phase in the filtrate was washed with diluted hydrochloride to remove excessive dimethylaminoethylchloride contained therein. The filtrate was further washed with 10% aqueous solution of hydrogen sodium bicarbonate so as to remove unreacted starting meterial, N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-dicyclohexyl-ammonium salt and then with saturated brine to be neutral, which was then treated with sulfuric sodium anhydride for dehydration and subjected to reduced pressure distillation so as to distill off ethyl acetate and obtain Intermediate I, N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-dimethylamino-ethyl ester in the amount of 1.43 g (yield; 96.6% by weight).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:16]C.O>CN(C=O)C>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:10][CH3:16])=[CH:4][CH:3]=1
Reactant: OCCCOc1ccc(Br)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In DMF (100 ml) was dissolved 3-(4-bromophenoxy)-1-propanol (10.0 g). To the mixture was added under ice-cooling 65% sodium hydride (2.4 g), and the mixture was stirred at room temperature for 2 hours. To the mixture was added dropwise iodoethane (3.8 ml), and the mixture was stirred for 3 hours. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=4/1) to give 1-bromo-4-(3-methoxypropoxy)benzene (8.6 g).
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[F:14][C:15]1[CH:16]=[CH:17][C:18]([CH:24]=O)=[C:19]2[C:23]=1[O:22][CH:21]=[CH:20]2.[Cl-].[NH4+]>COCCOC.C(OCC)(=O)C>[F:14][C:15]1[C:23]2[O:22][CH:21]=[CH:20][C:19]=2[C:18](/[CH:24]=[CH:3]/[C:1]#[N:2])=[CH:17][CH:16]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=Cc1ccc(F)c2occc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: N#C/C=C/c1ccc(F)c2occc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of diethyl cyanomethylphosphonate (5.35 g) in dry ethylene glycol dimethyl ether (DME; 20 ml) was added to a suspension of sodium hydride (60% oil dispersion; 1.32 g) in DME (20 ml) at 0° under nitrogen over 5 mins. After 15 min, a solution 7-fluoro-benzofuran-4-carbaldehyde (4.51 g) in DME (20 ml) was added and after 5 mins the solution was warmed up and stirred at room temperature for 2 h. Ammonium chloride solution (200 ml) and ethyl acetate (150 ml) were added, the phases separated and the aqueous extracted with ethyl acetate (2×150 ml). The extracts were dried (MgSO4) and evaporated and the residue triturated under ether (20 ml) and filtered to give the E isomer as a buff coloured solid (3.07 g)
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[F:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].O>C(O)(=O)C>[CH3:6][C:5]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([F:8])[CH:10]=1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(F)c1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1cccc(F)c1

Procedure:
A solution of acetic anhydride (30.30 g, 0.297 mol) in glacial acetic acid (30 ml) is added to stirred 3-fluoroaniline (30.0 g, 0.27 mol). The resulting stirred mixture is heated under reflux for 20 minutes and poured into cold water (500 ml). the product is extracted into ether (×2) and the combined ethereal extracts are washed with water and dried (MgSO4). The solvent is removed in vacuo and the residue is recrystallized from aqueous acetic acid to yield colourless crystals with a yield of 28.90 g (70%).
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>O>[C:9]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)OOC(=O)c1ccccc1
Yield: 95.3 %

Procedure:
Before the start of the reaction, the loop reactor is filled with a solution of 19.6% by weight of tert-butyl hydroperoxide and 9.0% by weight of sodium hydroxide. Initially 18.4 kg/h of a solution of 70% by weight of tert-butyl hydroperoxide in water, 11.8 kg/h of a solution of 50% by weight of sodium hydroxide in water, 35.2 kg/h of water and 18.0 kg/h of benzoyl chloride are then fed to the loop reactor. Cooling with cooling water keeps the internal temperature at 12° C. in the loop reactor and at 11° C. in the stirred cell reactor. The partial neutralization is effected with 2.2 kg/h of 31% by weight hydrochloric acid with addition of 6.0 kg/h of water at a temperature of 16° C. The organic phase is extracted with 17.2 kg/h of a 15% by weight aqueous solution of sodium hydroxide. This affords 18.4 kg/h of aqueous extract comprising 6.3% by weight of tert-butyl hydroperoxide and 14.1% by weight of sodium hydroxide, which are feeded into the loop reactor. From the time at which aqueous extract is recycled into the loop reactor, the metered addition of the feedstocks is changed to 16.8 kg/h of a solution of 70% by weight of tert-butyl hydroperoxide in water, 6.6 kg/h of a solution of 50% by weight of sodium hydroxide in water and 23.0 kg/h of water. After the extraction, the organic phase is washed with 36 kg/h of a solution of 1% by weight of sodium sulphite and 0.4% by weight of sulphuric acid, and dried by stripping at 35° C. and 43 mbar. 23.8 kg/h of tert-butyl peroxybenzoate with a purity of 99.7% are obtained (95.3% yield based on benzoyl chloride).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:21][C@@H:20]2[C@:15]([CH3:23])([CH2:16][CH2:17][C:18](=[O:22])[NH:19]2)[C@@H:14]2[C@@H:3]1[C@H:4]1[C@:11]([CH3:24])([CH2:12][CH2:13]2)[C@@H:7]([C:8](=[O:10])[CH3:9])[CH2:6][CH2:5]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C[Si](N([Si](C)(C)C)C(=O)C(F)(F)F)(C)C.OS(C(F)(F)F)(=O)=O.C(OC)(=O)CC(C)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])=O.[Na+].[Na+]>O>[CH3:1][C@H:2]1[CH2:21][C@@H:20]2[C@:15]([CH3:23])([CH:16]=[CH:17][C:18](=[O:22])[NH:19]2)[C@@H:14]2[C@@H:3]1[C@H:4]1[C@:11]([CH3:24])([CH2:12][CH2:13]2)[C@@H:7]([C:8](=[O:10])[CH3:9])[CH2:6][CH2:5]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: COC(=O)CC(C)=O
Agent: C[Si](C)(C)N(C(=O)C(F)(F)F)[Si](C)(C)C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)C[C@H]4NC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 4 h

Procedure:
To a solution of 7β-methyl-5α-4-azapregnane-3,20-dione (5.5 gm, 16.6 mmol) in dry toulene (100 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 4.52 gm, 19.92 mmol) followed by bis(trimethylsilyl)trifluoroacetamide (17.6 mL, 66.4 mmol) and triflic acid (0.11 mL, 1.3 mmol). The mixture was stirred under nitrogen for 24 hr at room temperature after which methyl acetoacetate (1.8 mL, 1.66 mmol) was added and stirring continued for 4 hr followed refluxing for 48 hr. The reaction mixture was poured into water (500 mL) containing sodium bicarbonate (8 gm) and sodium sulfite (3 gm). The solution was extracted with methylene chloride (3×250 mL), washed with water, saturated salt solution, and dried over anhydrous sodium sulfate. The solvent was removed by rotoevaporation and the product purified by flash column chromatography on silica gel eluted with 10% isopropanol in hexane as eluent to the title compound (2.47 gm).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5](=[O:8])[CH2:6][NH2:7].O[CH:15]=[CH:16][C:17]#[N:18].[Na]>C(O)C>[Cl:2][C:3]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5](=[O:8])[CH2:6][NH:7][CH:15]=[CH:16][C:17]#[N:18]
Reactant: NCC(=O)c1cccc(Cl)c1Cl
Reactant: N#CC=CO
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: N#CC=CNCC(=O)c1cccc(Cl)c1Cl

Procedure:
2 g of 2,3-dichlorophenacylamine hydrochloride, 1 g of 3-hydroxyacrylonitrile, sodium salt, and 20 ml of ethanol are heated for 2 hours under reflux. The reaction mixture is concentrated by evaporation and the oily residue is purified by column chromatography (silica gel; elution with a 4:1 mixture of toluene/ethyl acetate), affording 3-(2,3-dichlorophenacylamino)acrylonitrile in the cis/trans ratio of 5:1. Melting point: 122°-125° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[S:10][C:9]([NH:11][C:12](=[O:15])[CH2:13][NH2:14])=[N:8][CH:7]=1)[CH3:2].[CH2:17]([C:19]1[CH:62]=[CH:61][C:22]2[CH:23]([C:33]3[C:34](=[O:60])[NH:35][C:36](=[O:59])[N:37]([C:39]4[CH:44]=[CH:43][N:42]=[C:41](NCC(NC5SC=C(CC(O)=O)N=5)=O)[N:40]=4)[CH:38]=3)[C:24]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:25]=3[CH:26]=[CH:27][C:21]=2[CH:20]=1)[CH3:18]>>[CH2:17]([C:19]1[CH:62]=[CH:61][C:22]2[CH:23]([C:33]3[C:34](=[O:60])[NH:35][C:36](=[O:59])[N:37]([C:39]4[CH:44]=[CH:43][N:42]=[C:41]([NH:14][CH2:13][C:12]([NH:11][C:9]5[S:10][C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:16])=[CH:7][N:8]=5)=[O:15])[N:40]=4)[CH:38]=3)[C:24]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:25]=3[CH:26]=[CH:27][C:21]=2[CH:20]=1)[CH3:18]
Reactant: CCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(NCC(=O)Nc3nc(CC(=O)O)cs3)n2)c(=O)[nH]c1=O
Reactant: CCOC(=O)Cc1cnc(NC(=O)CN)s1
Product: CCOC(=O)Cc1cnc(NC(=O)CNc2nccc(-n3cc(C4c5ccc(C)cc5C=Cc5cc(CC)ccc54)c(=O)[nH]c3=O)n2)s1

Procedure:
The subtitle compound was prepared from the product of step (iv) (1.05 g) and the product from example 15 step (viii) (0.5 g) by the method of example 10 step (ii). Purification was by chromatography eluting with 66-100% ethyl acetate in toluene. Yield 0.27 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:23])[C:10]([C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:24][O:25][C:26](=[O:29])[CH2:27]Br>C1(C)C=CC=CC=1>[CH3:24][O:25][C:26](=[O:29])[CH2:27][O:22][C:18]1[CH:17]=[C:16]([C:10]([OH:15])([C:11]([F:14])([F:13])[F:12])[CH:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH3:23])[CH:21]=[CH:20][N:19]=1
Reactant: CC(c1ccc(Cl)cc1Cl)C(O)(c1cc[nH]c(=O)c1)C(F)(F)F
Reactant: COC(=O)CBr
Solvent: Cc1ccccc1
Product: COC(=O)COc1cc(C(O)(C(C)c2ccc(Cl)cc2Cl)C(F)(F)F)ccn1
Temperature: 145 °C
Reaction time: 3.5 h
Yield: 45.1 %

Procedure:
To a solution of 4-[2-(2,4-dichloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1H-pyridin-2-one (100 mg) in toluene (5 mL) was added bromoacetic acid methyl ester (50 mg, 0.03 mL) and Ag2CO3 (53 mg) and the mixture was allowed to stir for 3.5 hours at 145° C. The mixture was cooled to room temperature, filtered and the residue was purified by flash chromatography (10 silica gel cartridge, using ethyl acetate/heptane 1:9 as an eluent) to provide the title compound as a colorless oil (54 mg). MS (m/e): 438.1 (MH+).