Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][NH:29][CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:14][CH2:13]1.C(N(CC)CC)C.[CH3:44][CH:45]([S:47](Cl)(=[O:49])=[O:48])[CH3:46]>C(Cl)Cl>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:19]=[C:20]3[CH2:31][CH2:30][N:29]([S:47]([CH:45]([CH3:46])[CH3:44])(=[O:49])=[O:48])[CH2:28][C:21]3=[N:22][C:23]=2[NH:24][CH:25]([CH3:27])[CH3:26])[CH2:16][CH2:17]1
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCNC2
Reactant: CC(C)S(=O)(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CCN(S(=O)(=O)C(C)C)C2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of 2-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (47 mg, 0.091 mmol) in DCM (908 μL) at 0° C. was treated with triethylamine (38.0 μL, 0.272 mmol), followed by propane-2-sulfonyl chloride (15.3 μL, 0.136 mmol). The reaction mixture was allowed to stir for 45 min, gradually warming to room temperature. The reaction mixture was concentrated under reduced pressure and was purified by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 60% to 95% ACN gradient to give the title compound, as a TFA salt, as a yellow oil (16.4 mg, 29.0%). 1H NMR (400 MHz, methanol-d4) δ ppm 1.29 (d, J=6.6 Hz, 6H), 1.35 (d, J=6.8 Hz, 6H), 1.95 (m, 2H), 2.13 (m, 2H), 2.82 (t, J=5.9 Hz, 2H), 3.07 (m, 2H), 3.42 (m, 3H), 3.67 (t, J=5.8 Hz, 2H), 4.12 (septet, J=6.5 Hz, 1H), 4.41 (s, 2H), 4.48 (dt, J=7.5, 3.6 Hz, 1H) 6.87 (m, 1H), 6.98 (ddd, J=11.3, 8.5, 2.9 Hz, 1H), 7.17 (td, J=9.2, 5.6 Hz, 1H); ESI-MS m/z [M+H]+ 510.5.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[Li+].[CH3:15][CH:16]([N-]C(C)C)C.C(I)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:15][CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
To a solution of ethyl 2-(4-bromophenyl)acetate (972 mg, 4 mmol) in 10 mL dry THF at −78° C. was added LDA (2 M, 2 mL, 4 mmol). The solution was warmed to rt and stirred 2 h, then was recooled to −78° C. EtI (0.52 mL) was added, then the reaction was stirred rt for 16 h. The reaction was quenched with sat. NH4Cl, then extracted with EtOAc (3×20 mL). The organic layer washed with brine, then dried (Na2SO4). Purification via flash chromatography (0-20% EtOAc in hexanes) gives 75A (228 mg, 21%). MS (ESI) m/z 271.0 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:10]([NH:12][OH:13])=[N:9][CH:8]=[N:7][C:6]=2[N:5]([CH:14]2[C:18]([CH3:20])([OH:19])[CH:17]([OH:21])[CH:16]([CH2:22][OH:23])[O:15]2)[CH:4]=1)#[CH:2].[H][H]>C1COCC1.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[OH:13][NH:12][C:10]1[C:11]2[C:3]([CH:1]=[CH2:2])=[CH:4][N:5]([CH:14]3[C:18]([CH3:20])([OH:19])[CH:17]([OH:21])[CH:16]([CH2:22][OH:23])[O:15]3)[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: C#Cc1cn(C2OC(CO)C(O)C2(C)O)c2ncnc(NO)c12
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: C1CCOC1
Product: C=Cc1cn(C2OC(CO)C(O)C2(C)O)c2ncnc(NO)c12

Procedure:
The title compound from Example 29 is dissolved in THF and placed under hydrogen (1 atm) in the presence of Lindlar's catalyst until one mole of hydrogen is consumed.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 5-Methyl-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (14, 0.160 g, 0.55 mmol) in tetrahydrofuran (3.0 mL) was added tetra-n-butylammonium fluoride (0.145 g, 0.55 mmol). The reaction was stirred for 1 hour at room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 3% methanol in dichloromethane to provide light yellow solid (15, 0.07 g, 95%). MS (ESI)[M+H+]+=133.2.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH:11]=[CH:12][C:13]=2[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]2[CH:26]=[CH:27][N:28](S(C3C=CC(C)=CC=3)(=O)=O)[C:4]=2[C:3]1=[O:39].[C:40](=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:40][N:21]([C:10]1[CH:11]=[CH:12][C:13]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]([C:6]2[C:5]3[CH:26]=[CH:27][NH:28][C:4]=3[C:3](=[O:39])[N:2]([CH3:1])[CH:7]=2)[CH:9]=1)[S:22]([CH3:25])(=[O:23])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cc(NS(C)(=O)=O)ccc4Oc4ccccc4)cn(C)c(=O)c32)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CN(c1ccc(Oc2ccccc2)c(-c2cn(C)c(=O)c3[nH]ccc23)c1)S(C)(=O)=O
Yield: 14.2 %

Procedure:
A mixture of Example 7d (0.113 g, 0.2 mmol) and potassium carbonate (0.111 g, 0.800 mmol) in methanol (0.9 mL) and water (0.1 mL) was heated at 100° C. for 1 hour. The reaction was partitioned between ethyl acetate and water adjusting the pH to 7. The organic layer was separated, dried (Na2SO4), filtered and concentrated. The residue was purified by reverse phase HPLC (C18, 10-100% CH3CN/water (0.1% TFA)) to afford the title compound (0.012 g, 14%). 1H NMR (300 MHz, DMSO-d6) δ 2.99 (s, 3H) 3.27 (s, 3H) 3.51 (s, 3H) 6.27-6.32 (m, 1H) 6.93 (d, J=7.80 Hz, 2H) 6.99 (d, J=8.82 Hz, 1H) 7.03-7.10 (m, 1H) 7.25-7.34 (m, 4H) 7.40 (dd, J=8.65, 2.88 Hz, 1H) 7.55 (d, J=2.71 Hz, 1H) 12.01 (s, 1H). MS (ESI+) m/z 424 [M+H]+.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][CH2:8][NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:41])([CH3:40])[CH2:37][CH2:38][NH2:39])[NH:13]2)=[O:11])[CH2:4][O:3]1.C(N(CC)CC)C.[CH3:50][S:51](Cl)(=[O:53])=[O:52].Cl>ClCCl.O1CCCC1>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][CH2:8][NH:9][C:10]([CH:12]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=2[F:24])[C:15]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:41])([CH3:40])[CH2:37][CH2:38][NH:39][S:51]([CH3:50])(=[O:53])=[O:52])[NH:13]1)=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CCN)CC1NC(C(=O)NCC[C@H]2COC(C)(C)O2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(CCNS(C)(=O)=O)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F

Procedure:
In a manner similar to the method described in Examples 122a and 122b, rac-(2R,3S,4R,5S)-5-(4-amino-2,2-dimethyl-butyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid [2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethyl]-amide (60 mg, 0.096 mmol) prepared in Example 121a was reacted with triethylamine and methanesulfonyl chloride (13 mg, 0.11 mmol) in dichloromethane, followed by the reaction with aqueous HCl solution in tetrahydrofuran to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(4-methanesulfonylamino-2,2-dimethyl-butyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a off white solid (57 mg, 90%)
Reaction SMILES: [CH2:1]=[C:2]1[S:6][C:5](=[NH:7])[N:4]([C:8]2[CH:21]=[CH:20][C:11]3[O:12][C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[O:15][C:10]=3[CH:9]=2)[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:31][CH:32]([CH3:37])[CH2:33][C:34](Cl)=[O:35]>C(#N)C.C(Cl)Cl>[CH3:31][CH:32]([CH3:37])[CH2:33][C:34](/[N:7]=[C:5]1\[S:6][C:2]([CH3:1])=[CH:3][N:4]\1[C:8]1[CH:21]=[CH:20][C:11]2[O:12][C:13]([F:19])([F:18])[C:14]([F:16])([F:17])[O:15][C:10]=2[CH:9]=1)=[O:35]
Reactant: C=C1CN(c2ccc3c(c2)OC(F)(F)C(F)(F)O3)C(=N)S1
Reactant: CC(C)CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cn(-c2ccc3c(c2)OC(F)(F)C(F)(F)O3)/c(=N/C(=O)CC(C)C)s1
Temperature: 65 °C

Procedure:
To a solution of 5-methylene-3-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)thiazolidin-2-imine (Example 22C, 0.14 g, 0.44 mmol) in acetonitrile (3 mL) was added Hunig's base (0.062 g, 0.48 mmol) followed by 3-methylbutanoyl chloride (0.08 g, 0.66 mmol). The mixture was heated for 12 hours at 65° C. The reaction mixture was cooled down and more 3-methylbutanoyl chloride (0.08 g, 0.66 mmol) was added. The mixture was heated again at 65° C. for 12 hours. After cooling off, the mixture was diluted with CH2Cl2 (50 mL) and washed with water and brine. The organic phase was dried over sodium sulfate, filtered and dried. After evaporation under reduced pressure the residue was chromatographed over silica using CH2Cl2 100%-5% MeOH/CH2Cl2 to supply the titled compound. 1H NMR (CDCl3) δ ppm 0.95 (6 H), 2.20 (1 H), 2.35 (3 H), 2.40 (2 H), 6.75 (1 H), 7.20 (1 H), 7.30 (1 H), 7.40 (1 H); MS (ESI) m/z 405(M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[O:52][CH2:53][CH2:54][CH3:55].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:31][N:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:8]2[CH2:9][CH2:10][S:11](=[O:13])(=[O:12])[C:5]3[CH:4]=[CH:3][C:2]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=4[O:52][CH2:53][CH2:54][CH3:55])=[CH:32][C:6]=3[CH:7]=2)=[O:15])=[CH:18][CH:19]=1)[CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CCCOc1ccccc1OB([O-])[O-]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCOc1ccccc1-c1ccc2c(c1)C=C(C(=O)Nc1ccc(CN(C)C3CCOCC3)cc1)CCS2(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.9 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg) was added toluene/ethanol/water (20/1/1, 13.8 ml) and then were added 2-propoxyphenyl borate (125 mg) and potassium carbonate (175 mg), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (27 mg), and the mixture was refluxed at 100° C. for 8 hours and cooled to room temperature. The 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 (ethyl acetate/ethanol=3/1) and recrystallized from ethanol to give N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-7-(2-propoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 113) (46 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[ClH:8].[Cl:9]Cl>>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Cl
Reactant: Nc1ccccn1
Reactant: ClCl
Product: Nc1ncc(Cl)cc1Cl
Yield: 90 %

Procedure:
To produce 2-amino-3,5-dichloropyridine, 30 parts of chlorine are introduced in the course of 30 minutes, with slight cooling, into a solution of 37.6 parts of 2-aminopyridine in 160 parts of concentrated hydrochloric acid. The temperature is then raised to 50° to 60° C. and a further 60 parts of chlorine are introduced during 6 hours. After completion of the chlorine addition, the solution is poured onto ice, and the chlorine still present is removed with sodium bisulphite. There is then added a solution of 95 parts of sodium hydroxide in 150 parts of water, whereupon 2-amino-3,5-dichloropyridine precipitates. It is filtered off, washed with ice-water and dried at room temperature in water-jet vacuum. There are obtained 58.5 parts (90% of theory) of 2-amino-3,5-dichloropyridine, m.p. 77°-79° C.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[C:17](O)[CH:16]=[C:15](O)[C:3]=1[C:4](=[O:14])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1.Cl.C[OH:23]>>[O:1]1[C:2]2[C:3](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:4](=[O:14])[C:5]([OH:23])=[C:6]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CO
Reactant: O=C(C=Cc1ccc(O)cc1)c1c(O)cc(O)cc1O
Agent: Cl
Product: O=c1c(O)c(-c2ccccc2)oc2ccccc12

Procedure:
Determination of flavonoid glycosides and narichalcone (2′,4′,6′,4-tetrahydroxychalcone) in tomato fruit is carried out using a non-hydrolysing method as follows: 40 mg of freeze-dried tomato tissue is weighed and transferred to a 10 ml Pyrex glass tube. To each tube 4 ml of 75% aqueous methanol acidified with HCl to pH 2 is added. The tubes are closed with screw tops containing a Teflon inlay and incubated at room temperature (20-25° C.) for 1 hr with continuous mixing on a roller band.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:14]([CH2:22][C:23](OCC)=O)(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([CH:14]2[CH2:22][CH2:23][C:3]3[C:2](=[CH:7][CH:6]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=3)[NH:1]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Product: CCOC(=O)Cc1ccc2c(c1)CCC(c1ccccc1)N2

Procedure:
Using ethyl p-aminophenylacetate and ethyl benzoylacetate as starting materials, treatment was made similarly to Example 1 to obtain aimed product.
Reaction SMILES: C([N:8]1[CH:14]([CH3:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[Cl:16]C(OCCCl)=O>ClCCCl>[ClH:16].[CH3:15][CH:14]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9][NH:8]1
Reactant: O=C(Cl)OCCCl
Reactant: CC1CCOCCN1Cc1ccccc1
Solvent: ClCCCl
Product: CC1CCOCCN1
Product: Cl
Yield: 78.6 %

Procedure:
To a solution of 4-benzyl-5-methyl-[1,4]oxazepane (0.30 g, 1.4 mmol) in 1,2-dichloroethane (3 mL) was added chloroethyl chloroformate (0.56 mL, 7 mmol) at room temperature. The mixture was refluxed for 10 hours and concentrated. The resulting residue was dissolved in methanol (5 mL) and the solution was refluxed for one hour. After concentration, the residual material was triturated, washed with ethyl acetate and collected by filtration to afford 5-methyl-[1,4]oxazepane hydrochloride (0.16 g, 1.1 mmol, 76%) as a white solid.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[N:9]=[C:8]2[CH2:10][O:11][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:7]2=[CH:6][CH:5]=1.[C:20]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:23])([CH3:22])[CH3:21].OC(C1N=CC=CC=1)CN(CC1C=CC=CC=1)C(C)(C)C.NO>CO>[OH:1][CH:2]([C:4]1[N:9]=[C:8]2[CH2:10][O:11][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:7]2=[CH:6][CH:5]=1)[CH2:3][N:24]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]([CH3:23])([CH3:21])[CH3:22]
Reactant: c1ccc(C2OCc3nc(C4CO4)ccc3O2)cc1
Reactant: CC(C)(C)NCc1ccccc1
Agent: CC(C)(C)N(Cc1ccccc1)CC(O)c1ccccn1
Agent: NO
Solvent: CO
Product: CC(C)(C)N(Cc1ccccc1)CC(O)c1ccc2c(n1)COC(c1ccccc1)O2

Procedure:
A solution of 33.0 g. (0.13 mole) 6-(1,2-epoxyethyl)-2-phenyl-4H-1,3-dioxino[5,4-b]pyridine and 22.0 g. (0.135 mole) of N-tert-butylbenzylamine in 200 ml. of methanol was heated to the reflux temperature overnight. Upon cooling there deposited 6-[1-hydroxy-2-(N-tert-butylbenzylamino)ethyl]pyridine which was recrystallized from isopropanol to give 29.4 g. (54%) of the amino alcohol m.p. 126°-130° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH2:10][C:11]([OH:13])=[O:12].[CH3:14]O>Cl>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: CO
Reactant: Cc1cc(C)c(CC(=O)O)c(C)c1
Agent: Cl
Product: COC(=O)Cc1c(C)cc(C)cc1C

Procedure:
173 g (2,4,6-trimethylphenyl)acetic acid is refluxed in 131 mL of concentrated hydrochloric acid and 1.1 L of methanol for 3 hours with stirring. The solvent is distilled off under reduced pressure and the aqueous phase extracted twice with diethyl ether. The combined organic phases are extracted twice with a saturated aqueous sodium hydrogen carbonate solution and dried with sodium sulfate and the solvent is distilled off under reduced pressure. The residue is fractionally distilled. Yield: 116 g (57%); bp15: 140° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[CH2:9][OH:10])(C)(C)C.Cl>CO.O1CCOCC1>[NH2:7][C@H:8]([C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1ccc(Br)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@@H](CO)c1ccc(Br)cc1
Yield: 116.5 %

Procedure:
A solution of [(R)-1-(4-bromo-phenyl)-2-hydroxy-ethyl]-carbamic acid t-butyl ester (946 mg, 3 mmol) in MeOH (15 ml) was treated with HCl in dioxane (4 M, 15 ml) for 1.5 h. The mixture was concentrated to give the titled compound (755 mg, 100%) as a white solid.
Reaction SMILES: [C:1]([C@:4]1(O)[C:9](=[CH2:10])[CH2:8][C@H:7]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:5]12[CH3:6])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]1)[C:13](=[CH2:25])[CH2:12]3)(=[O:3])[CH3:2].CN(C)C.[C:31]1([S:37](Cl)(=[O:39])=O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>C(Cl)Cl>[CH2:25]=[C:13]1[C:14]2[C@:19]([CH3:20])([CH2:18][CH2:17][C:16](=[O:24])[CH:15]=2)[C@@H:21]2[C@H:11]([C@H:7]3[C@:5]([CH3:6])([CH2:23][CH2:22]2)[C:4]([C:1](=[O:3])[CH3:2])=[C:9]([CH2:10][S:37]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:39])[CH2:8]3)[CH2:12]1
Reactant: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC(=C)[C@@]3(O)C(C)=O)[C@@]2(C)CCC(=O)C=C12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)C
Agent: Cl
Solvent: ClCCl
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(C(C)=O)=C(CS(=O)c4ccccc4)C[C@@H]23)[C@@]2(C)CCC(=O)C=C12
Reaction time: 0.17 h

Procedure:
17α-Acetyl-17β-hydroxy-6,16-dimethyleneandrosta-4-en-3-one (Example 5, 8.0 g) is dissolved in methylene chloride (66 ml) and cooled to -20°. Trimethylamine (2.56 ml) at -20° and methylene chloride (5 ml) are mixed and the trimethylamine mixture transferred by syringe to the steroid solution. To the cold steroid solution was added phenylsulfonylchloride (1.0 equivalent) by a syringe pump over 1 hr. TLC shows the reaction approximately 80-85% complete. Phenylsulfonylchloride (0.25 equivalent) was added over approximately 10 min., TLC showing the reaction to be approximately 95% complete. Phenylsulfonylchloride (0.10 equivalent) was then added for a total of 1.35 equivalence, at which time TLC shows the reaction to be complete. Hydrochloric acid (10%, 40 ml) was added all at once, the temperature now being 7°, and the mixture stirred for about 10 min. The phases are separated. The aqueous portion is back-extracted with methylene chloride (10 ml). The organic extracts are washed with phosphate buffer (25 ml) and back-extracted with methylene chloride (10 ml). The organic extracts are combined, dired over sodium sulfate overnight at 20°-25°. This mixture is filtered and the filtrate concentrated under reduced pressure to an oil, which is the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH:8]1([Mg]Br)[CH2:10][CH2:9]1.O.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>CCOCC.C1COCC1>[Br:1][C:2]1[C:3]([CH:8]2[CH2:10][CH2:9]2)=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: Br[Mg]C1CC1
Reactant: Brc1cncnc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Brc1cncnc1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
To a solution of 5-bromopyrimidine (3 g, 18.87 mmol) in Et2O (120 mL) and THF (20 ml) was added cyclopropylmagnesium bromide (39.6 mL, 19.81 mmol) at 0° C. The resulting white suspension was stirred at room temperature for 1 h and quenched with water (0.340 mL, 18.87 mmol) followed by addition of DDQ (4.28 g, 18.87 mmol) in THF (10 ml). The resulting black mixture was stirred at room temperature overnight. The reaction mixture was extracted with EtOAc. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with NaOH (1N) and brine. The crude product was purified by BIOTAGE® (0-15% EtOAc/hexanes, 1.2 L) to afford the title compound (700 mg, 20%) as a yellow solid. 1H NMR (500 MHz, chloroform-d) δ ppm 8.87 (1 hr, s), 8.66 (1 hr, s), 2.40-2.56 (1 hr, m), 1.13-1.32 (4 hr, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:11]=[C:12]([F:17])[C:13](OC)=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH:11]=[C:12]([F:17])[CH2:13][OH:14])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(F)=CC1(c2ccc(Cl)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCC(F)=CC1(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 86 %

Procedure:
1-(4-Chlorophenyl)-1-(2-fluoro-2-(methoxycarbonyl)ethenyl)cyclopropane prepared as described In Example 1 (0.73 g) in dry diethyl ether (10 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (0.18 g) in dry diethyl ether at 0° C. Stirring was continued during 40 min, while the mixture warmed to room temperature. Water (20 ml) was added, and the mixture was extracted with diethyl ether (3×20 ml). The combined organic layers were washed with water (3×10 ml), dried and evaporated under reduced pressure. The residue was chromatographed on silica using diethyl ether/hexane (1:2) to yield 1-(4-chlorophenyl)-1-(2-fluoro-3-hydroxyprop-1-enyl) cyclopropane (0.56 g, 86%).
Reaction SMILES: CO[C:3](=[O:14])[CH:4]=[C:5]1[CH2:11][CH:10]2[N:12]([CH3:13])[CH:7]([CH2:8][CH2:9]2)[CH2:6]1.[C:15]1([Mg]Cl)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:13][N:12]1[CH:7]2[CH2:8][CH2:9][CH:10]1[CH2:11][C:5](=[CH:4][C:3]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:14])[CH2:6]2
Reactant: Cl[Mg]c1ccccc1
Reactant: COC(=O)C=C1CC2CCC(C1)N2C
Product: CN1C2CCC1CC(=CC(O)(c1ccccc1)c1ccccc1)C2

Procedure:
The title compound was prepared from (8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-acetic acid methyl ester and phenylmagnesium chloride by following the experimental procedures in Example 1 (44% yield): LCMS (ES) m/z 320 (M+H)+; 1H-NMR(CDCl3) δ 1.20 (m, 1H), 1.54 (m, 1H), 1.70 (m, 1H), 1.77 (m, 1H), 1.93 (m, 1H), 2.04 (m, 1H), 2.26 (s, 3H), 2.35 (m, 1H), 2.71 (m, 1H), 2.97 (m, 1H), 3.19 (m, 1H), 6.14 (s, 1H), 7.21 (m, 2H), 7.30 (m, 4H), 7.45 (m, 2H), 7.53 (m, 2H).