Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].O[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+](C(OCC)=O)(C(OCC)=O)=[N-]>O1CCCC1>[C:1]([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:26]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C(Nc1ccc(O)cc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(NC(=O)c3ccccc3)cc2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
2-{[4-(2-Hydroxyethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (1.0 g) synthesized in Example 4 and N-(4-hydroxyphenyl)benzamide (703 mg) were dissolved in tetrahydrofuran (10 mL), triphenylphosphine (866 mg) and diethyl diazodicarboxylate (575 mg) were added thereto under ice-cooling, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=2:1) to give the title compound (1.1 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=2[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:4][CH:3]=1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH2:38]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)[CH:39]([CH3:41])[CH3:40]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([N:45]3[CH2:46][CH2:47][N:42]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH2:43][CH2:44]3)=[O:14])=[CH:10][C:9]=2[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:21][CH:22]=1
Reactant: CC(C)Cc1cc(C(=O)O)ccc1OCc1ccc(F)cc1
Reactant: CC(C)CN1CCNCC1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)Cc1cc(C(=O)N2CCN(CC(C)C)CC2)ccc1OCc1ccc(F)cc1
Reaction time: 0.67 h
Yield: 84.2 %

Procedure:
4-(4-fluorobenzyloxy)-3-isobutylbenzoic acid (16.5 g) was dissolved in a mixture of chloroform (150 ml) and triethylamine (15.3 ml). To this mixture was added diphenylphosphinic chloride (11.5 ml) while being cooled with ice. After being stirred for 40 minutes, the mixture, with 1-isobutylpiperazine (7.83 g) added thereto, was stirred for 1.5 hours at room temperature. This reaction mixture was washed with saturated sodium hydrogencarbonate solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. Thus obtained residue was purified by silica gel column chromatography (chloroform: methanol=50:1) and the resulting solid was recrystallized (from n-hexane), thereby yielding 19.6 g of the aimed compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.C[O:16][B:17](OC)[O:18]C.[OH-].[Na+]>C1COCC1.CCCCCC>[CH3:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([B:17]([OH:18])[OH:16])=[CH:3][CH:4]=1
Reactant: CSc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
Under nitrogen, a stirred solution of 30 g (150 mmol) of 4-bromothioanisole (Aldrich) in 1500 mL of anhydrous THF at -78° C. was treated with 180 mmol of n-butyllithium in hexane. After 30 minutes, 51 mL (450 mmol) of trimethylborate was added neat and the reaction was allowed to warm to ambient temperature overnight. A solution of 300 mL of 10% NaOH was added and the mixture stirred vigorously for 1 h. The solvent was removed in vacuo, the pH adjusted to 4-5, and the product collected by filtration. Repeated washings with hexane and water provided 21 g (83%) of 4-methylthiophenylboronic acid (21 in Synthetic Scheme VII when R5 =SCH3 and R3, R4, R6, and R7 =H) as a colorless solid: NMR (DMSO-d6) d 2.47 (s, 3H) , 7.20 (d, J=8 Hz, 2H) , 7.71 (d, J=8 Hz, 2H) , 7.96 (br s, 2H) .
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[C:9]([C:24]#[N:25])[C:10]([NH:12][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1.CI.[C:28](=O)([O-])[O-].[K+].[K+].[C:34]([O:37][CH2:38][CH3:39])(=O)C>CC(C)=O>[Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](\[C:24]#[N:25])/[C:10]([NH:12][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:28])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1.[Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[C:9](/[C:24]#[N:25])\[C:10]([NH:12][CH:13]([C:17]2[CH:22]=[CH:39][C:38]([O:37][CH3:34])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: CCCC(NC(=O)C(C#N)=Cc1cccc(Br)n1)c1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCCC(NC(=O)/C(C#N)=C/c1cccc(Br)n1)c1ccc(OC)cc1
Product: CCCC(NC(=O)/C(C#N)=C\c1cccc(Br)n1)c1ccc(OC)cc1
Yield: 42 %
Yield: 20 %

Procedure:
To a solution of 3-(6-bromopyridin-2-yl)-2-cyano-N-(1-(4-hydroxyphenyl)butyl)acrylamide (21 mg, 0.05 mmol) in acetone was added MeI (32.6 μL, 0.52 mmol) and potassium carbonate powder (7.25 mg, 0.05 mmol). The resulting mixture was stirred at room temperature for 4 hours before the addition of ethyl acetate. The organic solution was then washed with water (1×), saturated brine (1×), dried over sodium sulfate and concentrated to give a yellow oil as the crude product. The crude material was purified with preparative TLC plate to afford (E)-3-(6-bromopyridin-2-yl)-2-cyano-N-(1-(4-methoxyphenyl)butyl)acrylamide (8) as a light yellow solid (9.2 mg, 42% yield) and (Z)-3-(6-bromopyridin-2-yl)-2-cyano-N-(1-(4-methoxyphenyl)butyl)acrylamide (9) as a white solid (4.4 mg, 20% yield). Mass spec ES+, m/z=414.0 (m+H+). E-isomer (8): 1H NMR (500 MHz, CDCl3/CD3OD) δ 7.59 (t, J=7.7, 1H), 7.52 (d, J=8.0, 1H), 7.27 (d, J=8.7, 2H), 7.22 (d, J=7.4, 1H), 6.83 (d, J=8.9, 2H), 6.81 (s, 1H), 3.89-3.83 (m, 2H), 3.81 (s, 3H), 1.65 (dd, J=15.4, 7.9, 2H), 1.39 (dd, J=15.1, 7.5, 2H), 0.94 (t, J=7.4, 3H). Z-isomer (9): 1H NMR (500 MHz, CDCl3) δ 7.83 (s, 1H), 7.79 (d, J=7.6, 1H), 7.61 (t, J=7.8, 1H), 7.52 (d, J=7.9, 1H), 7.15 (d, J=8.8, 2H), 6.93 (d, J=8.8, 2H), 3.84 (s, 3H), 3.84-3.79 (m, 2H), 1.57 (dd, J=14.8, 7.1, 5H), 1.37 (dq, J=15.0, 7.5, 2H), 0.94 (t, J=7.4, 3H).
Reaction SMILES: C(Cl)(Cl)Cl.[NH2:5][C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[O:8][CH:7]=1.C(N(CC)C(C)C)(C)C.[Br:26][CH2:27][C:28](Cl)=[O:29]>C1(C)C=CC=CC=1>[Br:26][CH2:27][C:28]([NH:5][C:6]1[C:15](=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:8][CH:7]=1)=[O:29]
Reactant: O=C(Cl)CBr
Reactant: Nc1coc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(CBr)Nc1coc2ccccc2c1=O
Temperature: 40 °C

Procedure:
The starting material can be prepared for example as follows: 10 ml of chloroform are added to 8 g of 3-aminochromone in 200 ml of toluene and the mixture is warmed to 40° C. After cooling to 20° C., 10 ml of N,N-diisopropylethylamine are added with stirring, followed by the addition of 4.8 ml of bromoacetyl chloride in 20 ml of toluene at 10° C. in the course of 5 minutes. When the addition is complete, the reaction mixture is stirred for 1 hour at room temperature. The crystalline precipitate which has formed is collected by suction, washed with water and recrystallised from ethanol/petroleum ether, yielding 11.8 g of 2-bromo-N-(4-oxo-1-benzopyran-3-yl)-acetamide with a melting point of 198° C.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9]1[N:10]=[C:11]([NH:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12][CH:13]=1)\[C:4]([O:6][CH2:7][CH3:8])=[O:5].CI.[C:36]([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:36][O:1]/[N:2]=[C:3](/[C:9]1[N:10]=[C:11]([NH:14][C:15]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12][CH:13]=1)\[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Solvent: O
Product: CCOC(=O)/C(=N\OC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
A mixture of ethyl (Z)-2-hydroxyimino-2-(2-tritylaminothiazol-4-yl)acetate (II) (5.00 g, 10.9 mmoles), CH3I (2.04 mL, 32.8 mmoles) and K2CO3 (4.54 g, 32.8 mmoles) in dry dimethylsulfoxide (DMSO) (100 mL) was stirred at room temperature overnight and then poured into water (250 mL). The precipitate which formed was collected by filtration, washed with water and dried to give the title compound (5.15 g, quantitative yield). Mp. 115° C. (dec.)
Reaction SMILES: C([O-])([O-])=O.[Ca+2].[CH3:6][C:7](=[CH:9][CH2:10][CH2:11][C@H:12]([CH2:14][CH2:15][OH:16])[CH3:13])[CH3:8]>>[CH3:6][C:7](=[CH:9][CH2:10][CH2:11][CH:12]([CH2:14][CH:15]=[O:16])[CH3:13])[CH3:8].[CH3:6][C:7](=[CH:9][CH2:10][CH2:11][C@H:12]([CH2:14][CH:15]=[O:16])[CH3:13])[CH3:8]
Reactant: CC(C)=CCC[C@@H](C)CCO
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Product: CC(C)=CCCC(C)CC=O
Product: CC(C)=CCC[C@@H](C)CC=O

Procedure:
A tubular reactor heatable by means of a salt melt was charged with 10.8 g of a catalyst consisting of 55% by weight of ZnO and 45% by weight of CaCO3 in the calcite modification (determined in each case in the form of the oxides of the calcined catalyst mass). At a temperature of 400° C., a mixture of 46 Nl/h of nitrogen and 3.44 g/h of (R)-citronellol with an enantiomeric excess of 95% ee was passed over the bed. Citronellal was obtained with an enantiomeric excess of (R)-citronellal of 95% ee, the conversion being 50.2% and the selectivity 75.5%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([B:9]2[O:17][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:10]2)[CH:6]=[CH:7][CH:8]=1.[CH3:18][NH:19][CH3:20].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:18][N:19]([CH3:20])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([B:9]2[O:17][C:14]([CH3:16])([CH3:15])[C:11]([CH3:13])([CH3:12])[O:10]2)[CH:4]=1
Reactant: CNC
Reactant: CC1(C)OB(c2cccc(CBr)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
To a solution of 3-bromomethylphenyl boronic acid pinacol ester (Combi Block Inc., 297 mg, 1.0 mmol) in acetonitrile (5 mL) was added dimethylamine (2M solution in methanol, 2.0 mmol) followed by the addition of K2CO3 (691 mg, 5.0 mmol). The reaction mixture was stirred at room temperature for 16 h. Acetonitrile was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated NaHCO3, dried (MgSO4), filtered and the filtrate concentrated in vacuo to give dimethyl-[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]amine (INTERMEDIATE XI.1) as a viscous oil (200 mg, 0.77 mmol, 77%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([Sn](CCCC)(CCCC)CCCC)[CH:30]=1>>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:11]=1[C:10]([NH2:18])=[N:9][C:8]2([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:31]2[CH:30]=[C:29]([O:28][CH3:27])[CH:34]=[CH:33][N:32]=2)[CH:3]=1)[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH3:26])[CH:20]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(OC)ccn1
Reactant: COc1cc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)ccn1
Product: COc1ccnc(-c2cccc(C3(c4ccnc(OC)c4)N=C(N)c4c(F)cccc43)c2)c1
Yield: 13 %

Procedure:
The title compound was synthesized as described in Example 29 in 13% yield starting from 1-(3-bromophenyl)-4-fluoro-1-(2-methoxypyridin-4-yl)-1H-isoindol-3-amine (0.150 g, 0.36 mmol) and 4-methoxy-2-(tributylstannyl)pyridine (0.188 g, 0.47 mmol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:21](N1CCOCC1)(=[O:24])[CH2:22][CH3:23].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[C:13]([C:21](=[O:24])[CH2:22][CH3:23])=[CH:12][CH:11]=[C:10]([Cl:14])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC(=O)N1CCOCC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cl)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(=O)c1ccc(Cl)nc1NC(=O)OC(C)(C)C
Temperature: -50 °C
Reaction time: 1 h

Procedure:
Under argon, 7.00 g (30.6 mmol) of tert-butyl(6-chloropyridin-2-yl)carbamate (Example 3A) were initially charged in 90 ml of THF and cooled to −50° C. 47.8 ml (76.5 mmol) of butyllithium (1.6 M in hexane) were added dropwise. After the dropwise addition had ended, the reaction was slowly warmed to 0° C. and kept at 0° C. for 1 h. The mixture was then cooled again to −40° C., and 9.85 g (61.2 mmol) of N-propionylmorpholine dissolved in 10 ml of THF were added. The reaction solution was stirred at −40° C. for another 1 h and then, at −40° C., poured into 1 l of ethyl acetate and 350 ml of ammonium chloride solution, and the organic phase was separated off and washed with water and saturated aqueous sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and concentrated on a rotary evaporator. The crude product was chromatographed on silica gel (mobile phase cyclohexane/ethyl acetate 10:1 to 1:1). This gave 2800 mg (32% of theory) of the product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)[NH:13][CH:14]=2)=[CH:6][CH:5]=1.F[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=3)[N:13]([C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)[CH:14]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(-c2c[nH]c(Cc3ccc(Br)cc3)n2)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: COC(=O)c1ccc(-c2cn(-c3ccc([N+](=O)[O-])cc3)c(Cc3ccc(Br)cc3)n2)cc1

Procedure:
4-[2-(4-Bromo-benzyl)-1H-imidazol-4-yl]-benzoic acid methyl ester (12.3 g, 33 mmol) was treated as described in general procedure B using 1-fluoro-4-nitrobenzene to give 4-[2-(4-bromo-benzyl)-1-(4-Nitro-phenyl)-1H-imidazol-4-yl]-benzoic acid methyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5]([NH:28]C=O)[CH:6]=[C:7]([CH:19]1[CH2:24][CH2:23][N:22]([C:25](=[O:27])[CH3:26])[CH2:21][CH2:20]1)[CH2:8][P:9]([O:15]C(C)C)([O:11]C(C)C)=[O:10])[CH3:2].C[Si](C)(C)Br.C(O)C>ClCCl>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([NH2:28])[CH:6]=[C:7]([CH:19]1[CH2:20][CH2:21][N:22]([C:25](=[O:27])[CH3:26])[CH2:23][CH2:24]1)[CH2:8][P:9]([OH:15])([OH:11])=[O:10])[CH3:2]
Reactant: CCOC(=O)C(C=C(CP(=O)(OC(C)C)OC(C)C)C1CCN(C(C)=O)CC1)NC=O
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(N)C=C(CP(=O)(O)O)C1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3.15 g (6.84 mmol) of 4-(1-acetylpiperidin-4-yl)-5-diisopropylphosphono-2-formylamino-pent-3-enoic acid ethyl ester are dissolved in 17 ml of dichloromethane, and 3.54 ml (27.3 mmol) of trimethylbromosilane are added dropwise at room temperature. The mixture is left to stand at room temperature for 16 hours, 17 ml of ethanol are added dropwise, the mixture is left to stand for a further 18 hours and is concentrated by evaporation in a rotary evaporator, the residue is dissolved in 12 ml of ethanol, and a mixture of 3 ml of propylene oxide and 3 ml of ethanol is added. A suspension forms, which is stirred for a further 2 hours at room temperature and for 2 hours with ice cooling and is then filtered with suction. 2-amino-4-(1-acetylpiperidin-4-yl)-5-phosphono-pent-3-enoic acid ethyl ester having a melting point of 225° (decomp.) is obtained.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].COCCOC.Cl[CH2:30][C:31]1[CH:32]=[CH:33][C:34]([CH3:37])=[N:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>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.C(OCC)(=O)C.O>[OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9]([CH2:30][C:31]2[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][CH:32]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)c(C)c1O
Reactant: Cc1ccc(CCl)cn1
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: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(Cc2ccc(C)nc2)c(C)c(C)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
To a solution of methyl 2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.80 g) in a mixed solvent of DME (12.0 mL)-water (4.00 mL) were added 5-(chloromethyl)-2-methylpyridine (0.41 g), tetrakis(triphenylphosphine)palladium(0) (0.15 g) and sodium carbonate (0.55 g), and the mixture was stirred overnight at 80° C. under argon atmosphere. The reaction mixture was allowed to be cooled to room temperature, water and ethyl acetate were added thereto, and the mixture was partitioned. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.48 g).
Reaction SMILES: [F:1][C@H:2]1[C@H:7]([OH:8])[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.CC([O-])(C)C.[K+].C1COCC1.[N:30]1[N:31]=[C:32]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[C:42](F)[CH:43]=[CH:44][CH:45]=3)[N:40]=2)[N:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=12>CN(C=O)C>[N:30]1[N:31]=[C:32]([C:39]2[CH:48]=[CH:47][C:46]3[C:41](=[C:42]([O:8][C@@H:7]4[CH2:6][CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)=[O:10])[CH2:3][C@H:2]4[F:1])[CH:43]=[CH:44][CH:45]=3)[N:40]=2)[N:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=12
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](O)[C@H](F)C1
Reactant: Fc1cccc2ccc(-c3nnc4ccccn34)nc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC[C@@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)[C@H](F)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Non-racemic (trans)-benzyl 3-fluoro-4-hydroxypiperidine-1-carboxylate (0.192 g, 0.757 mmol) was treated with 1.0 M KOtBu in THF (0.757 mL, 0.757 mmol) and stirred at ambient temperature for 15 minutes. 2-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)-8-fluoroquinoline (0.200 g, 0.757 mmol) was added along with DMF (2.25 mL) and the mixture was stirred at 50° C. for 15 hours. The reaction was cooled and chromatographed on SiO2, eluting with a gradient of 2% NH4OH in isopropanol/methylene chloride. After concentration in vacuo, the desired product was isolated as a beige solid (0.306 g). MS APCI (+) m/z 498.1 (M+1) detected.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1([CH3:15])[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([OH:14])[C:7]=2[O:6]1.[H][H].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)P(N(C)C)(N(C)C)=O.C(O)(=O)C>[CH3:3][O:4][C:5]1([CH3:15])[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:7]=2[O:6]1
Reactant: [H][H]
Reactant: ClCc1ccccc1
Reactant: COC1(C)Oc2cccc(O)c2O1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC1(C)Oc2cccc(OCc3ccccc3)c2O1

Procedure:
To a suspension of sodium hydride (2.4 g., 0.1 mole) in freshly distilled hexamethyl-phosphoramide (24 ml.) is added dropwise with stirring under dry nitrogen a solution of 2-methoxy-2-methyl-4-hydroxy-1,3-benzodioxole (18.2 g., 0.1 mole) in hexamethylphosphoramide (36 ml.) and stirring is continued at ambient temperature until hydrogen evolution essentially ceases. Benzyl chloride (12.65 g., 0.1 mole) is added and the mixture stirred at 75°-80° C. for 5 hours. The mixture then is poured onto ice and adjusted to ca. pH 6 with acetic acid. The product is extracted with ether, and the ethereal solution washed with 2% sodium carbonate solution (50 ml.) and then with saturated sodium chloride solution. After drying over magnesium sulphate and then calcium sulfate, the ethereal solution is evaporated to give 2-methoxy-2-methyl-4-benzyloxy-1,3-benzodioxole which can be crystallized from di-isopropyl ether.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:22][C:18]([CH:23]=O)([CH2:19][CH2:20][CH2:21]3)[CH2:17][CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH2:33].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C(O)(=O)C.C(OCC)(=O)C>[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][NH:33][CH2:23][C:18]12[CH2:22][C:14]([C:7]3[NH:6][C:5]4[C:4](=[O:25])[N:3]([CH2:26][CH2:27][CH3:28])[C:2](=[O:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9]=4[N:8]=3)([CH2:21][CH2:20][CH2:19]1)[CH2:15][CH2:16][CH2:17]2
Reactant: CCCn1c(=O)c2[nH]c(C34CCCC(C=O)(CCC3)C4)nc2n(CCC)c1=O
Reactant: CN(C)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCn1c(=O)c2[nH]c(C34CCCC(CNCCN(C)C)(CCC3)C4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.3.1]nonane-1-carbaldehyde (40 mg) taken in 5 ml of CH2Cl2. N1,N1-Dimethyl-ethane-1,2-diamine (40 mg), Na(OAc)3BH (100 mg), 2 drops of Acetic acid were added and stirred at rt overnight. Next day the reaction mixture was diluted with ethyl acetate, washed with sat. NAHCO3, brine and dried over MgSO4. The solvent was removed under reduced pressure. The crude product was purified by Preparative HPLC. Mass (ES+ 459)
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:23]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH:15]C(=O)OC(C)(C)C)[CH2:9]2)=[N:6][CH:7]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:15][CH2:14][CH:10]1[O:11][CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[C:3]([CH:23]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[F:31])[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)NCC1CN(c2cc(C(c3cc(F)ccc3F)S(=O)(=O)c3ccc(Cl)cc3)c(Cl)cn2)CCO1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC1CN(c2cc(C(c3cc(F)ccc3F)S(=O)(=O)c3ccc(Cl)cc3)c(Cl)cn2)CCO1
Reaction time: 1 h
Yield: 64.3 %

Procedure:
In methylene chloride (1.5 ml) was dissolved t-butyl [4-[5-chloro-4-[(4-chlorophenylsulfonyl)-(2,5-difluorophenyl)methyl]pyridin-2-yl]morpholin-2-yl]methylcarbamate (30 mg, 0.05 mmol). To the resulting solution were added anisole (30 μl) and trifluoroacetic acid (150 μl) at room temperature. The resulting mixture was stirred for 1 hour. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel chromatography (3% methanol/chloroform→3% methanol, 3% t-butylamine/chloroform) to give the title compound (17 mg, 67%) as an oil.