Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH2:8][CH:9]([OH:11])[CH3:10])[N:6]=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1.[CH3:15][NH2:16]>ClCCl>[CH3:15][NH:16][CH2:2][C:3]1[N:7]([CH2:8][CH:9]([OH:11])[CH3:10])[N:6]=[C:5]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: CN
Reactant: CC(O)Cn1nc([N+](=O)[O-])cc1CBr
Solvent: ClCCl
Product: CNCc1cc([N+](=O)[O-])nn1CC(C)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
To a solution of 250b (3.0 g, 11.4 mmol) in dichloromethane (30 mL) was added the solution of CH3NH2 (3.0 g, 34.2 mmol, 35% in water). This reaction mixture was stirred at room temperature for 1 h. Then the organic layer was separated, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to afford 250c (1.9 g, 78%) as yellow solid. MS-ESI: [M+H]+ 215.3
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:8])=[N:6][CH:7]=1.[I:9]I>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[Br:8][C:5]1[N:6]=[C:7]([I:9])[C:2]([NH2:1])=[CH:3][CH:4]=1
Reactant: II
Reactant: Nc1ccc(Br)nc1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ccc(Br)nc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
5.0 g 5-Amino-2-bromopyridine were dissolved in 70 ml ethanol. 9.0 g silver sulfate and 7.33 g iodine were added. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue diluted with 500 ml ethyl acetate and filtered over a celite pad. The filtrate was washed with 200 ml saturated Na2S203 solution and water, dried over MgSO4 and then the solvent was removed in vacuo to obtain 7.7 g 6-Bromo-2-iodo-pyridin-3-ylamine.
Reaction SMILES: [CH3:1][N:2]1[C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3]1.[CH2:24]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:25][CH2:26][C:27]#[CH:28]>CCCCCCC.C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:28]#[C:27][CH2:26][CH2:25][CH2:24][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:5][C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:3]1
Reactant: C#CCCCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(-c3ccccc3)nn2C)cc1
Solvent: ClCCl
Solvent: CCCCCCC
Product: Cn1nc(-c2ccccc2)cc1C#CCCCc1ccccc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-methyl-5-phenyl-2H-pyrazol-3-yl ester and pent-4-ynyl-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/DCM 1:1; yield (80 mg, 53%); 1H NMR δ (CDCl3): 7.78 (d, J=8.21 Hz, 2H), 7.43-7.22 (m, 8H), 6.62 (s, 1H), 3.98 (s, 3H), 2.78 (t, J=7.30 Hz, 2H), 2.43 (t, J=7.19 Hz, 2H), 1.96 (p, J=7.33 Hz, 2H); LCMS m/z: 300.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:8][C:7]2=[O:18].C([Sn](CCCC)(CCCC)[C:28]([O:30]CC)=[CH2:29])CCC>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:28]([C:2]1[CH:3]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:8][C:7]2=[O:18])(=[O:30])[CH3:29]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(C(C)=O)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 90 °C
Yield: 69.9 %

Procedure:
To a stirred suspension of methyl 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylate (40 g, 108 mmol, as described in Example 1.00) in dioxane (300 mL) was added tributyl(1-ethoxyvinyl)stannane (38.5 mL, 114 mmol) and bis(triphenylphosphine) palladium (II) chloride (3.05 g, 4.35 mmol). The mixture was purged with nitrogen and heated at 90° C. overnight. More tributyl(1-ethoxyvinyl)stannane (20 mL) and bis(triphenylphosphine) palladium (II) chloride (1.5 g) were added and the reaction mixture heated for an additional 3 hrs. The mixture was cooled to room temperature, HC1-2N (81 mL, 163 mmol) was added and the dark suspension heated at 45° C. for 30 min. The dioxane was evaporated under vacuum, the residue was dissolved in DCM and a saturated solution of sodium bicarbonate was added until pH 4. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to afford a crude compound which was triturated in diethylether, filtered and dried to afford methyl 8-acetyl-2-morpholino-4-oxo-4H-chromene-6-carboxylate (25.0 g, 69.5%) as an off-white solid.
Reaction SMILES: [OH:1][C:2]([CH3:40])([CH3:39])[C:3]#[C:4][C:5]1[N:6]=[C:7]([N:10]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:11][C@@H:12]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[S:8][CH:9]=1.C1C(=O)N([Br:48])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:48][C:9]1[S:8][C:7]([N:10]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:11][C@@H:12]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)=[N:6][C:5]=1[C:4]#[C:3][C:2]([OH:1])([CH3:40])[CH3:39]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(O)C#Cc1csc(N(C[C@H](Cc2ccc(C(F)(F)F)cc2)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(O)C#Cc1nc(N(C[C@H](Cc2ccc(C(F)(F)F)cc2)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)sc1Br
Reaction time: 3 h
Yield: 24.3 %

Procedure:
(S)-tert-butyl 1-(N-(4-(3-hydroxy-3-methylbut-1-ynyl)thiazol-2-yl)-tert-butoxylcarbonylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.18 g, 0.31 mmol) was taken up in 5 mL of CCl4 and NBS (0.11 g, 0.62 mmol) was added. After 3 hours, the solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (5% to 40% EtOAc/hexanes) to afford (S)-tert-butyl 1-(N-(5-bromo-4-(3-hydroxy-3-methylbut-1-ynyl)thiazol-2-yl)-tert-butoxylcarbonylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.05 g, 24% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:9]([F:12])([F:11])[F:10])[C:6]=1[C:7]#[N:8].S(=O)(=O)(O)[OH:20].C(=O)(O)[O-].[Na+]>>[NH2:1][C:2]1[S:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:9]([F:10])([F:12])[F:11])[C:6]=1[C:7]([NH2:8])=[O:20]
Reactant: N#Cc1c(N)sc(-c2ccccc2)c1C(F)(F)F
Reactant: O=S(=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Product: NC(=O)c1c(N)sc(-c2ccccc2)c1C(F)(F)F
Temperature: 50 °C

Procedure:
A mixture of 2-amino-4-trifluoromethyl-5-phenyl-3-thiophenenitrile (0.12 g) and concentrated sulphuric acid (1.5 ml) was stirred and heated at 50° C. for 8 h. The reaction mixture was added to saturated aqueous sodium bicarbonate until a pH of 7 was obtained. The product was extracted into ethyl acetate (100 ml) and the organic layer was dried with anhydrous sodium sulfate (3 g), filtered and concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate/isohexane mixtures. The solvent was removed and the product collected (0.07 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][C:10]([C:12]([O:14]CC)=[O:13])=[CH:9][CH:8]=1.[OH-].[Na+]>CCO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1ccc(-c2ccccn2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(-c2ccccn2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
To a solution of ethyl 5-pyridin-2-yl-2-furoate (2.00 g, 9.21 mmol) in EtOH (10 mL) was added NaOH (0.74 g) in water. The reaction mixture was allowed to stir at rt for 1 h and then concentrated. The residue was diluted with 1M HCl to pH 3-4. A precipitate formed and was collected by filtration and identified as 5-pyridin-2-yl-2-furoic acid (0.41 g). The aqueous solution was extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated to give additional 5-pyridin-2-yl-2-furoic acid (0.57 g). LCMS: (FA) ES+ 190.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1>>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(Br)cc1
Reactant: c1cscn1
Product: COc1ccc(-c2nccs2)cc1
Yield: 67 %

Procedure:
The title compound was prepared from thiazole (2.0 g, 24 mmol) and 4-bromoanisole (3.0 g, 16 mmol) using the procedure of Example 146, step 1 with 67% yield (2.0 g).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:26]=1[C:27](Cl)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][C:26]=1[C:27]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)ccc2Cl)n1
Temperature: 150 °C
Yield: 9.5 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (3.0 mL) under N2, was added 2-chloro-5-(trifluoromethyl)benzoyl chloride (0.299 g, 1.23 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.015 g (16% yield) of pure product: MS (ES) m/z 512 (M+).
Reaction SMILES: [F:1][C:2]1[C:3]([CH:25]=[CH:26]OC)=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].CS(O)(=O)=O>ClCCl>[F:1][C:2]1[C:3]2[CH:25]=[CH:26][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH:16]4[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]4)[CH:14]=3)[C:4]=2[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: CCCC1CCC(c2ccc(-c3cc(F)c(F)c(F)c3C=COC)cc2)CC1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: CCCC1CCC(c2ccc3c(ccc4c(F)c(F)c(F)cc43)c2)CC1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
6.1 g of 3,4,5-trifluoro-2-(2-methoxyvinyl)-4′-(4-propylcyclohexyl)biphenyl are dissolved in 180 ml of dichloromethane, and 8.5 ml of methanesulfonic acid are added at 0° C. After the reaction mixture has been stirred at 0° C. for 2.5 hours, it is added to ice-water and subjected to conventional work-up. Chromatographic purification (silica gel, n-heptane) and recrystallisation from n-heptane gives 1,2,3-trifluoro-7-(4-propylcyclohexyl)phenanthrene in the form of colourless crystals. C: 124, N: 124.4, I; Δε=12.7; Δn=0.1843;
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: OCc1ccccc1
Reactant: CSc1nc(N)nc(Br)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: CSc1nc(N)nc(OCc2ccccc2)c1C#N

Procedure:
From 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile, benzyl alcohol and DBU in DME. ES-MS m/e (%): 273 (M+H+, 100).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:23])=[C:17]([CH:22]=1)[C:18]([O:20][CH3:21])=[O:19].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:23])=[C:17]([CH:22]=2)[C:18]([O:20][CH3:21])=[O:19])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1cc(N)ccc1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(NC(=O)c2ccc(C#N)cc2)ccc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
4-Cyanobenzoyl chloride (4.50 g) was added to a stirred suspension of methyl 5-amino-2-methylbenzoate (J. Med. Chem., 1991, 34, 2176-2186; 3 g), triethylamine (2.54 ml) and methylene chloride (100 ml) and the resultant mixture was stirred at ambient temperature for 16 hours. The mixture was acidified by the addition of 1N aqueous hydrochloric acid solution and the mixture was stirred at ambient temperature for 30 minutes. The resultant solid was isolated and dried under vacuum at 40° C. to give methyl 5-(4-cyanobenzamido)-2-methylbenzoate (5.32 g); NMR Spectrum: (DMSOd6) 2.47 (s, 3H), 3.83 (s, 3H), 7.31 (d, 1H), 7.88 (d, 1H), 8.0 (d, 2H), 8.1 (d, 2H), 8.27 (s,1H), 10.57 (s, 1H); Mass Spectrum: M+H+ 295.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25].C(N(CC)CC)C.Br[C:37]1[CH:38]=[C:39]([C:43]2[O:44][C:45]3[CH:51]=[CH:50][C:49]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[CH:48][C:46]=3[N:47]=2)[CH:40]=[CH:41][CH:42]=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:28][O:27][C:23](=[O:26])[CH:24]=[CH:25][C:41]1[CH:42]=[CH:37][CH:38]=[C:39]([C:43]2[O:44][C:45]3[CH:51]=[CH:50][C:49]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[CH:48][C:46]=3[N:47]=2)[CH:40]=1
Reactant: Brc1cccc(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C=Cc1cccc(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Reaction time: 0.03 h

Procedure:
Tri(o-toly)phosphine (9 mg, 0.030 mmol), palladium(II) acetate (6 mg, 0.027 mmol), methyl acrylate (31 mg, 0.34 mmol), triethylamine (116 mg, 1.14 mmol) and aryl bromide (32) (100 mg, 0.29 mmol) in acetonitrile (3 mL) were heated in a CEM Discover microwave for 90 minutes at 90° C. The solvent was removed under a stream of nitrogen gas, water was added and the organics extracted with EtOAc. The organic layer was dried (Na2SO4) and the solvent concentrated in vacuo. The crude product was purified by column chromatography eluting with 20% EtOAc in heptane. Yield: 41 mg, 40%; LC-MS tr 1.86 min; HPLC Purity: 67%; MS (ES+) m/z 356 (M+H)
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:14][CH:13]([OH:15])[CH:12]([OH:16])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[O:15]([C@H:13]1[CH2:14][N:10]([CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:11][C@H:12]1[OH:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OC1CN(Cc2ccccc2)CC1O
Reactant: Fc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O[C@@H]1CN(Cc2ccccc2)C[C@@H]1Oc1ccccc1
Temperature: 50 °C

Procedure:
A slurry of 2.4 g. (0.1 mole) of sodium hydride (4.2 g. of 57% oil dispersion, washed with ether to remove the oil) in 30 ml. of dimethylformamide was stirred while a solution of 19.3 g. (0.1 mole) of 1-benzyl-3,4-dihydroxypyrrolidine, cis isomer, (I) in 30 ml. of dimethylformamide was added dropwise. The mixture was heated at 50° C. for 1 hr., then a solution of 19.2 g. (0.2 mole) of fluorobenzene in 30 ml. of dimethylformamide was added in one portion. The mixture was heated at 90° C. for 18 hr., then cooled and concentrated under vacuum. The residue was dissolved in benzene and washed with water. The semicrystalline residue from the concentrated organic fraction was dissolved in cyclohexane and the solution was decanted from an insoluble oil (mostly I). The cyclohexane solution was treated with charcoal to remove residual I and then crystallized as fluffy, off-white needles (m.p. 88.5°-90° d.) which weighed 1.2 g. (4.5%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:8]=[C:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[NH:10][CH:11]=2)[CH2:3][CH2:2]1.[OH-].[K+].Br[CH2:28][CH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1>CS(C)=O>[O:32]1[CH2:33][CH2:34][CH2:35][CH2:36][CH:31]1[O:30][CH2:29][CH2:28][N:10]1[CH:11]=[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[N:8]=[C:9]1[CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]1
Reactant: BrCCOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)c[nH]2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)cn2CCOC2CCCCO2)CC1
Temperature: 45 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
Combine tert-butyl 4-(4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate (5.84 g, 17.40 mmol) and potassium hydroxide (5.91 g, 6.0 eq) (freshly powdered) in dimethyl sulfoxide (30 mL). Heat the reaction mixture to 45° C. under nitrogen. After 15 minutes, add 2-(2-bromoethoxy)tetrahydro-2H-pyran (2.90 mL, 1.1 eq). Continue to heat the reaction overnight. Add water and extract with ethyl acetate. Wash the organics with saturated aqueous sodium chloride. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with hexanes to 50% ethyl acetate in hexanes to ethyl acetate to 10% methanol in ethyl acetate, to give the title compound as a thick yellow oil (6.94 g, 86%). MS (ES) m/z=464 [M]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[CH:4][C:3]=1[CH2:16][OH:17].[O:18]1[CH:23]=[CH:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[Br:1][C:2]1[C:3]([CH2:16][O:17][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][O:18]2)=[CH:4][C:5]([O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[CH:6][C:7]=1[CH3:8]
Reactant: C1=COCCC1
Reactant: Cc1cc(OC2CCCCO2)cc(CO)c1Br
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Product: Cc1cc(OC2CCCCO2)cc(COC2CCCCO2)c1Br
Temperature: 25 °C
Reaction time: 21 h
Yield: 90.2 %

Procedure:
To a solution of (2-bromo-3-methyl-5-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanol (2.54 g, 8.43 mmol) and 3,4 dihydro-2H-pyran (0.92 mL, 10.12 mmol) in CH2Cl2 (8 mL) was added camphorsulfonic acid (40 mg, 0.17 mmol), and the mixture was stirred at room temperature for 21 h. The reaction mixture was then quenched with equal volumes of 0.2 M NaOH and EtOAc (1:1, 20 mL) before the layers were separated. The water phase was further extracted with equal volume of EtOAc before the organic layers were combined and dried over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column using Combiflash to give 2-(4-bromo-3-methyl-5-((tetrahydro-2H-pyran-2-yloxy)methyl)phenoxy)tetrahydro-2H-pyran (2.93 g, 90%).
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH3:4].[Br:7][CH2:8][CH2:9][CH2:10][Sn:11](Br)(Br)[CH3:12].[NH4+].[Cl-]>C(OCC)C>[Br:7][CH2:8][CH2:9][CH2:10][Sn:11]([CH3:12])([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](Br)(Br)CCCBr
Reactant: CCCC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCC[Sn](C)(CCCC)CCCBr
Yield: 88 %

Procedure:
A solution of 115 ml of 2.7 N butylmagnesium bromide in diethyl ether was added in about one hour to a solution of 62.5 g (0.15 mol) of (3-bromopropyl)methyltin dibromide in 200 ml of diethyl ether. After reflux for 1 h the mixture was treated with a saturated aqueous solution of NH4Cl and distilled to give 48.79 g (88%) of (3-bromopropyl)methyldibutyltin; b.p. 88°-90° C./0.1 mm Hg, nD20 =1.5001.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:21](O)=[O:22])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Na+].[Al].O>COCCOCCOC>[CH:1]1([CH2:7][O:8][C:9]([NH:11][C@H:12]([CH2:21][OH:22])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCC1CCCCC1
Agent: [Al]
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: O
Product: O=C(N[C@H](CO)Cc1ccc(O)cc1)OCC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 15 ml of diglyme (bis (2-methoxy) ether) was dissolved 1.0 g of N-(cyclohexylmethoxycarbonyl)-tyrosine. To the solution were added 570 mg of sodium borohydride and 50 ml of diglyme solution containing 7 g of anhydrous aluminium chyloride. The mixture was stirred at room temperature for 2 hours. After addition of 150 ml of water, the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was crystallized from ethyl acetate-petroleum ether to give N-(cyclohexylmethoxycarbonyl)-tyrosinol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:5]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)=[N:6][CH:7]=[N:8][C:9]=1Cl.C(N(CC)C(C)C)(C)C>O1CCOCC1>[C@@H:12]1([NH:11][C:5]2[C:4]3[CH2:3][CH2:2][NH:1][C:9]=3[N:8]=[CH:7][N:6]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: NCCc1c(Cl)ncnc1N[C@H]1CCc2ccccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc2c(c1)CC[C@@H]2Nc1ncnc2c1CCN2
Temperature: 160 °C
Yield: 92.8 %

Procedure:
5-(2-aminoethyl)-6-chloro-N-[(1S)-2,3-dihydro-1H-inden-1-yl]pyrimidin-4-amine (1.00 g, 3.46 mmol) and N,N-diisopropylethylamine (1.21 mL, 6.92 mmol) were dissolved in 1,4-dioxane (19 mL) and the solution was heated in a pressure tube at 160° C. for 48 hours. At that time, LCMS indicated complete conversion. Solvent was removed in vacuo and the residue was purified using chromatography on silica gel using gradient 0 to 20% MeOH in methylene chloride to afford the title compound (0.81 g, 93%). LC/MS: Rt=1.55 min, ES+ 253 (AA standard).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11](=[O:17])(=[O:16])[NH:12][CH2:13][CH2:14][CH3:15].[Br:18]Br>>[Br:18][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([S:11](=[O:17])(=[O:16])[NH:12][CH2:13][CH2:14][CH3:15])[CH:4]=1)=[O:10]
Reactant: BrBr
Reactant: CCCNS(=O)(=O)c1cc(C(C)=O)ccc1Cl
Product: CCCNS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl

Procedure:
13.8 g of 4'-chloro-3'-propylsulfamoylacetophenone were reacted as described in Example 1(a) with 8 g of bromine to give the 2-bromo-4'-chloro-3'-propylsulfamoylacetophenone, melting point: 96° C., from isopropanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].I[CH2:22][CH3:23].C(O)(=O)/C=C/C(O)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH3:23])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCI
Reactant: OC1(c2cc(Cl)cc(Cl)c2)CCNC1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCN1CCC(O)(c2cc(Cl)cc(Cl)c2)C1

Procedure:
Preparation according to Example 8: 3-(3,5-dichlorophenyl)pyrrolidin-3-ol (0.34 g, 1.46 mmol), acetonitrile (24 mL), sodium carbonate (0.20 g, 3.65 mmol), iodoethane (0.23 g, 1.46 mmol). Heated at reflux for 15 minutes. Yield: 0.24 g. The amine was converted to the fumaric acid salt and evaporated to a solid residue. MS m/z (relative intensity, 70 eV) 259 (M+, 5), 244 (5), 173 (4), 145 (44), 71 (bp).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C:5](=O)[C:6]([OH:8])=[O:7].CC1[N:18]=CC(COP(O)(O)=O)=C(C=O)C=1O>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C@@H:5]([NH2:18])[C:6]([OH:8])=[O:7]
Reactant: O=C(O)C(=O)CCC(F)(F)F
Reactant: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: N[C@H](CCC(F)(F)F)C(=O)O

Procedure:
A solution containing 5,5,5-trifluoro-2-oxopentanoic acid (100 mg, 0.588 mmoles), R,S-alanine (200 mg, 2.244 mmoles), and 0.02 mM pyridoxal phosphate, in 0.1 M potassium phosphate buffer, pH 7.5, was incubated with R-transaminase AT-103 from Biocatalytics (5 mg, 44units) or cloned R-transaminase from Bacillus thuringiensis SC 16569 (0.5 mL, 10 units, BMS transaminase) at 30° C. in a total volume of 5 mL in 15 mL tubes for 44 h. Reaction yields of (R)-5,5,5-trifluoro-2-aminopentanoic acid of 49% and 48% were obtained with AT-103 and BMS transaminases, respectively. Ee was 100% in both cases.