Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:7][CH:8]([CH2:11][CH3:12])[CH:9]=O>>[CH:1](=[O:6])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:12][CH2:11][CH:8]([CH3:9])[CH3:7]
Reactant: CCC(C)C=O
Reactant: CCCCC=O
Product: CC(C)CCCCC=CC=O

Procedure:
This example describes the process of the invention for the co-aldol condensation of n-pentanal and 2-methylbutanal (2-MBA) to give an isodecenal consisting of the isomers 2-propyl-4-methylhexenal (1+2) and 2-propylheptenal (1+1). 400 kg/h of catalyst were passed through the reactor (as described in Example 3) at a temperature of 110° C. at the autogenous pressure of the reactants.
Reaction SMILES: [F:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[N:5][C:4]=1[CH2:18][O:19]C1CCCCO1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CO>[F:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[N:5][C:4]=1[CH2:18][OH:19]
Reactant: FCc1sc(-c2cccc(C(F)(F)F)c2)nc1COC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1nc(-c2cccc(C(F)(F)F)c2)sc1CF
Temperature: 70 °C
Reaction time: 4 h
Yield: 55.4 %

Procedure:
To a solution (10 mL) of the compound (350 mg, 0.93 mmol) obtained in Example 89d in methanol was added p-toluenesulfonic acid monohydrate (530 mg, 2.8 mmol), and the mixture was stirred at 70° C. for 4 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=75/25) to give the title compound (150 mg, 56%) as a colorless oil.
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:26])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=3)[CH:13]=[CH:14][CH:15]=2)=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2].[N-:33]=[N+:34]=[N-:35].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:26])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]4[N:33]=[N:34][NH:35][N:25]=4)[CH:19]=3)[CH:13]=[CH:14][CH:15]=2)=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2cccc(NC(=O)c3cccc(C#N)c3)c2)ccc(C(C)=O)c1O
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCc2cccc(NC(=O)c3cccc(-c4nn[nH]n4)c3)c2)ccc(C(C)=O)c1O
Yield: 32.7 %

Procedure:
Heat a mixture of N-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-3-cyano-benzamide (876 mg, 2.04 mmol), sodium azide (1.32 g, 20.4 mmol), and ammonium chloride (1.09 g, 20.4 mmol) in dimethylformamide (10 mL) at 110° C. overnight. Cool. Dilute with water (120 mL). Filter, and wash several times with water. Dry. Dissolve the residue in hot acetone (20 mL) and purify via chromatography, eluting with 1:1 hexanes:acetone with 1% acetic acid to afford the title compound as a light yellow powder (315 mg, 33%): 1H NMR (DMSO-d6) δ 0.89 (t, 3H), 1.51 (sextet, 2H), 2.50 (s, 3H), 2.63 (t, 2H), 5.29 (s, 2H), 6.74 (d, 1H), 7.21 (d, 1H), 7.42 (t, 1H), 7.71 (d, 1H), 7.74 (t, 1H), 7.78 (d, 1H), 7.98 (s, 1H), 8.15 (d, 1H), 8.24 (d, 1H), 8.62 (s, 1H), 10.55 (s, 1H), 12.85 (s, 1H); MS (APCI-neg mode) m/z (rel intensity) 470 (100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][CH2:28][CH:29]=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:31]OS([O-])=O.[K+].Cl.C(OC(C)C)(=O)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:11]([CH3:25])[C:10]=1[CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C)c(OCc2ccccc2)c(CCCC=O)c(C)c1OCc1ccccc1
Reactant: O=S([O-])OO
Agent: Cl
Agent: [K+]
Solvent: CC(=O)OC(C)C
Solvent: CN(C)C=O
Product: Cc1c(C)c(OCc2ccccc2)c(CCCC(=O)O)c(C)c1OCc1ccccc1
Reaction time: 8 h
Yield: 92.8 %

Procedure:
To a solution of 4-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)butanal (450 mg, 1.12 mmol) in DMF (11.5 mL) was added Oxone (350 mg, 1.12 mmol) giving a cloudy white solution. The suspension was stirred vigorously overnight and poured over 10 mL 2.5 M HCl and stirred until the solution clarified. Isopropyl acetate (iPrOAc) (25 mL) was added after the exotherm subsided. The organics were washed 2×10 mL 2.5 M HCl, 1×10 mL saturated aqueous NaCl and dried over Na2SO4. Concentration gave 435 mg of 4-(2,5-bis(benzyloxy)-3,4,6-trimethylphenyl)butanoic acid as a white solid. MS M++H at 419 m/z; 1H NMR (400 MHz, CDCl3) δ=7.50 (m, 4H), 7.43-7.34 (m, 6H), 4.75 (s, 2H), 4.74 (s, 2H), 2.71 (t, 2H), 2.37 (t, 2H), 2.26 (s, 3H), 2.26 (s, 6H), 1.85 (s, 2H) ppm.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3]1=[O:14].C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH2:23][CH3:24]>CN(C=O)C>[O:9]=[C:8]1[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[NH:4][C:3](=[O:14])[CH:2]1[NH:1][C:22](=[O:25])[CH2:23][CH3:24]
Reactant: CCC(=O)Cl
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)NC1C(=O)Nc2ccccc2NC1=O
Reaction time: 8 h

Procedure:
Combine 3-amino-1H-1,5-benzodiazepine-2,4-(3H, 5H)-dione (5.7 g, 30.0 mmol) and triethyl amine(3.33 g, 33.0 mmol) in 120 mL DMF and add propionyl chloride (3.05 g, 33.0 mmol) dropwise at RT. After stirring overnight, remove DMF under reduced pressure, suspend the residue in a mixed solvent (CHCl3/i-PrOH=3/1, 400 mL). Collect an off-white solid via suction filtration to give the title compound. Wash the filtrate with NaHCO3 (sat.2×100 mL) and dry with Na2SO4. Concentrate the organic solvent down to a residue, treat with ether, collect the solid as title compound: mass spectrum (APCI) (m/e): 248.1 (M+1). 1H NMR (400 MHz, DMSO-d6): 10.70 (s, 2H), 8.19 (d, 1H, J=7.2 Hz), 7.23–7.15 (m, 4H), 4.73 (d, 1H, J=8.0 Hz), 2.27 (q, 2H, J=8.0 Hz), 0.94 (t, 3H, J=8.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:14])[CH3:13])[C@:7]([CH2:16][CH2:17][NH:18][CH3:19])([OH:15])[CH2:6][CH2:5]2.[CH3:20][O:21][CH2:22][C:23]([CH2:32][O:33][CH3:34])([CH3:31])[C:24]([NH:26][CH2:27][CH2:28][CH:29]=O)=[O:25].C([BH3-])#N.[Na+]>C(Cl)Cl.CC(O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:13])[CH3:14])[C@:7]([CH2:16][CH2:17][N:18]([CH3:19])[CH2:29][CH2:28][CH2:27][NH:26][C:24](=[O:25])[C:23]([CH2:32][O:33][CH3:34])([CH3:31])[CH2:22][O:21][CH3:20])([OH:15])[CH2:6][CH2:5]2
Reactant: CNCC[C@@]1(O)CCc2cc(F)ccc2[C@@H]1C(C)C
Reactant: COCC(C)(COC)C(=O)NCCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COCC(C)(COC)C(=O)NCCCN(C)CC[C@@]1(O)CCc2cc(F)ccc2[C@@H]1C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
6.55 g of (1S,2S)-6-fluoro-1-isopropyl-2-(2-methylamino-ethyl)-1,2,3,4-tetrahydro-naphthalen-2-ol were dissolved in DCM (138 mL)/AcOH (15 mL). 5.36 g of 3-methoxy-2-methoxymethyl-2-methyl-N-(3-oxo-propyl)-propionamide and 6.39 g of sodium cyanoborohydride were added. The reaction mixture was stirred for 2 h at room temperature, quenched with sat.-NaHCO3 and extracted with DCM. The organic phase was washed with brine, dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude material was purified by CC using DCM/MeOH/NEt3 from 100/0/1 to 40/1/0.4 as eluant to yield 10.57 g of N-(3-{[2-((1S,2S)-6-Fluoro-2-hydroxy-1-isopropyl-1,2,3,4-tetrahydro-naphthalen-2-yl)-ethyl]-methyl-amino}-propyl)-3-methoxy-2-methoxymethyl-2-methyl-propionamide as amber resin.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:7](O)=[N:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:7]1[C:6]([C:11]([F:14])([F:13])[F:12])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc(O)c(C(F)(F)F)c1
Product: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1

Procedure:
Heat a mixture of 5-nitro-3-trifluoromethyl-pyridin-2-ol (416 mg, 2.0 mmol) and phosphorus oxychloride (1 mL) at 85° C. for 18 hours. Cool the mixture and remove the volatiles by rotary evaporation. Dissolve the residue in EtOAc (15 mL) and wash with water (10 mL), saturated NaHCO3(aq) (10 mL) and brine (10 mL). Dry the organic extract over MgSO4 and remove the solvent under reduced pressure to yield the title compound.
Reaction SMILES: [CH:1]1([C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=O)[CH2:4][CH2:3][CH2:2]1.O.NN.C([O-])([O-])=O.[K+].[K+]>C(O)COCCO>[CH:1]1([CH2:5][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COc1ccc(C(=O)C2CCC2)cc1
Agent: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCOCCO
Solvent: O
Product: COc1ccc(CC2CCC2)cc1
Yield: 95 %

Procedure:
A mixture of compound (G) (5.00 g), hydrazine hydrate (4.12 g), K2CO3 (7.00 g) and diethylene glycol (16 ml) were heated to reflux temperature for 1 hour. The condenser was exchanged by a distillation device and the mixture was distilled at 220-230° C. The distillate was extracted with MTBE and the organic phase washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography to yield a colorless oil (4.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7]([CH3:19])([CH3:18])[N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>ClCCl.C(N(CC)CC)C>[CH3:18][C:7]1([CH3:19])[CH2:6][C:5]2[C:10](=[CH:11][C:2]([NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([O:21][CH3:20])=[C:23]([C:31]([F:34])([F:32])[F:33])[CH:24]=3)=[CH:3][CH:4]=2)[CH2:9][N:8]1[C:12](=[O:17])[C:13]([F:16])([F:14])[F:15]
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Reactant: CC1(C)Cc2ccc(N)cc2CN1C(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccc3c(c2)CN(C(=O)C(F)(F)F)C(C)(C)C3)cc1C(F)(F)F
Yield: 62.1 %

Procedure:
A solution of 7-amino-3,3-dimethyl-1,2,3,4-tetrahydro-2-trifluoroacetylisoquinoline (408 mg; 1.5 mmol) in dichloromethane (20 ml) and triethylamine (0.6 ml) was treated with 4-methoxy-3-trifluoromethylbenzoyl chloride (358 mg; 1.5 mmol). The resultant solution was stirred at 25° C. for 1 h. The reaction mixture was then washed with water, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica, eluting with 1% methanol in dichloromethane, to give the title compound (442 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([N:10]([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:17][O-:18].[Na+]>>[CH:11]([N:10]([CH:14]([CH3:16])[CH3:15])[C:8]([C:7]1[C:2]([O:18][CH3:17])=[N:3][CH:4]=[CH:5][CH:6]=1)=[O:9])([CH3:13])[CH3:12]
Reactant: CC(C)N(C(=O)c1cccnc1Cl)C(C)C
Reactant: C[O-]
Agent: [Na+]
Product: COc1ncccc1C(=O)N(C(C)C)C(C)C
Yield: 98 %

Procedure:
In a similar manner but by refluxing 2-chloro 3-diisopropylaminocarbonyl pyridine and sodium methylate for 45 hours, 3-diisopropylaminocarbonyl 2-methoxy pyridine is obtained.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:25]1([C:31]2[S:35][C:34](CO)=[N:33][CH:32]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[Br:5][CH2:1][C:34]1[S:35][C:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:32][N:33]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ncc(-c2ccccc2)s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1ncc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
CBr4 (8.65 g, 26.1 mmol) and Ph3P (5.1 g, 19.6 mmol) were added to a solution of (5-phenylthiazol-2-yl)methanol (2.5 g, 13.07 mmol) in dry CH2Cl2 (30 mL) at 0° C. The resulting reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was diluted with diethyl ether and filtered. The clear filtrate was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 5-10% EtOAc in petroleum ether) to afford 2-(bromomethyl)-5-phenylthiazole (2 g, yield 60%). 1H NMR (300 MHz, CDCl3) δ 7.89 (s, 1H), 7.57-7.55 (m, 2H), 7.45-7.36 (m, 3H), 4.76 (s, 2H). MS (ESI) m/z: Calculated for C10H8BrNS: 254.95. found: 256.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:8]=[O:9])[CH2:2][CH3:3]>CCO>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:8][OH:9])[CH2:2][CH3:3]
Reactant: CCCOc1cc(C=O)ccc1OC
Solvent: CCO
Product: CCCOc1cc(CO)ccc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
Crude 3-(propyloxy)-4-methoxybenzaldehyde (2.60 g) was dissolved in EtOH (30 mL) and cooled to 0° C. NABH4 (0.499 g, 13.2 mmol) was added portionwise. after the addition was completed, the ice-water bath was removed and the reaction mixture was stirred at room temperature for 2 hours. Water (50 mL) was added and the resulting mixture was extracted with diethyl ether (3×100 mL). The combined organic layers were dried over anhydrous MgSO4. Removal of the solvent gave a pale yellow oil which was purified by silica gel column chromatography (hexanes/EtOAc, 4:1) to give 3-(propyloxy)-4-methoxybenzyl alcohol (2.29 g, 89% over two steps) as a colorless oil.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](=[O:17])([O-])[O-].[Na+].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:17][CH2:14][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCO
Reactant: O=C([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Product: CCCCCCCCCCCCOCCCCCCCCCCCC
Temperature: 125 °C

Procedure:
After placing 390 parts by weight of n-dodecanol into a reaction vessel and heating to 125° C., one part by weight of p-toluene sulfonic acid as a catalyst was added to the solution, and then the pressure in the vessel was reduced to 5-10 mmHg. Separately, 100 parts by weight of anhydrous crystalline cyclotetrasaccharide, obtained by the method in Example B-3, was suspended in 130 parts by weight of n-dodecanol. The suspension was added into the above vessel drop by drop in a flow rate of 2.3 parts by weight/min with taking a time of 100 min for the reaction. Successively, the reactant was neutralized with aqueous sodium carbonate solution, and cyclotetrasaccharide dodecyl ether was obtained by evaporating residual alcohol.
Reaction SMILES: [O-]CC.[Na+].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1.[CH2:15]([O:17][CH2:18][C:19](OCC)=[O:20])[CH3:16]>C(O)C>[CH2:15]([O:17][CH2:18][C:19](=[O:20])[CH:12]([C:9]1[CH:10]=[CH:11][C:6]([CH3:5])=[CH:7][CH:8]=1)[C:13]#[N:14])[CH3:16]
Reactant: CCOCC(=O)OCC
Reactant: Cc1ccc(CC#N)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOCC(=O)C(C#N)c1ccc(C)cc1
Reaction time: 1 h
Yield: 70 %

Procedure:
Sodium ethoxide (2 eq) is dissolved in ethanol (200 mL) and 4-methylphenylacetonitrile (10.0) and ethyl ethoxyacetate (1.5 eq) are slowly added. The reaction mixture is stirred for 1 hour under reflux. Upon completion of the reaction, ethanol is removed under reduced pressure and water (100 mL) and ethyl acetate are added. The organic layer is removed and the aqueous layer is acidified by adding acetic acid (10 mL) and extracted 3 times with ethyl acetate. The extracted organic layer is collected, washed with water and dehydrated with MgSO4. After concentration under reduced pressure, the produced solid is recrystallized with Hx:EA=20:1 to obtain the target compound (70-95%).
Reaction SMILES: [NH2:1][CH:2]([CH:20]([CH3:22])[CH3:21])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=[O:4].[CH2:23](Br)[C:24]#[CH:25]>>[CH2:25]([NH:1][CH:2]([CH:20]([CH3:22])[CH3:21])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=[O:4])[C:24]#[CH:23]
Reactant: C#CCBr
Reactant: CC(C)C(N)C(=O)OCc1cccc(Oc2ccccc2)n1
Product: C#CCNC(C(=O)OCc1cccc(Oc2ccccc2)n1)C(C)C

Procedure:
Following the procedure of Example 2, (6-phenoxy-2-pyridyl)methyl 2-amino-3-methylbutanoate and 2-propyn-1-yl bromide are reacted, resulting in a mixture of two end products, which are separated to give (6-phenoxy-2-pyridyl)methyl 2-[N-(2-propynyl)amino]-3-methylbutanoate and (6-phenoxy-2-pyridyl)methyl 2-[N,N-(di-2-propynyl)amino]-3-methylbutanoate.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:16][CH:15]1[CH2:17][C:10]2[C:8]3[C:9]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[S:6][C:7]=3[CH:13]=[CH:12][C:11]=2[C:14]1=[O:18]
Reactant: C=C(C)C(=O)Cl
Reactant: c1ccc2c(c1)sc1ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1Cc2c(ccc3sc4ccccc4c23)C1=O
Reaction time: 8 h

Procedure:
20 g (108.7 mmol) of dibenzothiophene (1) were added at −78° C. to an agitated solution of 10.6 ml methacryloyl chloride (108.7 mmol) and 15.3 g AlCl3 (114.8 mmol) in 250 ml methylene chloride and brought to room temperature overnight. The solution was hydrolysed carefully at 0° C., the organic phase was separated, washed with an aqueous solution of K2CO3 and dried over Na2SO4. After removal of the solvent and crystallisation in toluene/pentane≈10:1, 2-methyl-1,2-dihydrobenzo[b]indeno[4,5-d]thiophen-3-one (2) was obtained as crystalline solid material (21.6 g, 85.9 mmol, 79%).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:10](=[CH2:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)C>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: C=C(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C

Procedure:
20 mg (R)-5-Biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylenepentanoic acid (2-a, R1=Boc, R2=H, R3=CO2H) is added to ethanol (400 μl). 10% Palladium on carbon (2 mg, 50% water wet, Degussa type E101 NE/W) is then added. Hydrogen gas at ambient pressure is applied to the mixture. The mixture is stirred at ambient temperature and pressure overnight. The mixture is then filtered over Celite and washed with ethanol (2×0.5 ml). The mixture is then concentrated in vacuo to give (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-a, R1=Boc, R2=H, R3=CO2H) and (2S,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (1-b, R1=Boc, R2=H, R3=CO2H). 1H NMR (CDCl3): 1.11-1.16, 1.21 and 1.33, 1.39-1.53, 1.70-1.92, 2.32-2.81, 3.72-3.97, 4.44-4.50, 6.41 and 6.56, 7.16-7.49, 10.84.
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].[NH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:8][CH2:7]1.C(N(C(C)C)CC)(C)C>C1COCC1>[CH:1]([NH:5][CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:8][CH2:7]1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCC1CCC(N)CC1
Reactant: CC(C)I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC1CCC(CNC(=O)OC(C)(C)C)CC1
Temperature: 40 °C
Reaction time: 24 h
Yield: 22 %

Procedure:
Isopropyl iodide (2 equivalents) was added dropwise to a suspension of tert-butyl N-[4-aminocyclohexyl]methyl-carbamate (1 equivalent) and diisopropylethyl amine (3 equivalents) in THF. The resulting mixture was stirred for 1 day. TLC analysis showed some starting amine. Additional isopropyl iodide (1 equivalent) and diisopropylethyl amine (3 equivalents) were added to the reaction mixture and heated at 40° C. for 1 day. The reaction mixture was concentrated and chromatrographed to give tert-butyl N-[4-(isopropylamino)cyclohexyl]methylcarbamate: 22% yield, 271 (ESMS, MH+); 1H NMR (CDCl3) δ 4.65 (broad, 1H), 2.91 (m, 3H), 2.42 (m, 1H), 1.80 (ABm, 4H), 1.38 (s, 9H), 0.98 (d, 6H, J=6.3 Hz), 1.32–0.85 (m, 5H).
Reaction SMILES: [CH2:1]([N:3]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=O)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[C:4](=[O:6])[CH3:5])[CH3:2].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.[NH2:37][C:38]1[CH:46]=[C:45]([O:47][CH3:48])[CH:44]=[C:43]([O:49][CH3:50])[C:39]=1[C:40]([NH2:42])=[O:41]>CC(N(C)C)=O.O>[CH3:50][O:49][C:43]1[CH:44]=[C:45]([O:47][CH3:48])[CH:46]=[C:38]2[C:39]=1[C:40](=[O:41])[NH:42][C:19]([C:16]1[CH:15]=[CH:14][C:13]([N:10]3[CH2:9][CH2:8][CH:7]([N:3]([CH2:1][CH3:2])[C:4](=[O:6])[CH3:5])[CH2:12][CH2:11]3)=[CH:18][CH:17]=1)=[N:37]2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CCN(C(C)=O)C1CCN(c2ccc(C=O)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCN(C(C)=O)C1CCN(c2ccc(-c3nc4cc(OC)cc(OC)c4c(=O)[nH]3)cc2)CC1
Temperature: 150 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
A mixture of N-ethyl-N-(1-(4-formylphenyl)piperidin-4-yl)acetamide (0.385 g, 1.40 mmol), NaHSO3 (0.162 g, 1.50 mmol), and p-TsOH (0.024 g, 0.12 mmol) were added to a solution of 2-amino-4,6-dimethoxybenzamide (0.250 g, 1.20 mmol) in DMA (10 mL). The reaction was stirred at 150° C. for 4 hours and then cooled to room temperature overnight. The mixture was diluted with H2O and extracted with EtOAc. The organics were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 2% to 10% MeOH/CH2Cl2, afforded the title compound (0.300 g, 55%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): mixture of rotamers δ 11.76 (s, 1H), 8.08 (d, J=8.7 Hz, 2H), 7.02 (d, J=8.7 Hz, 2H), 6.67 (d, J=2.0 Hz, 1H), 6.46 (d, J=2.0 Hz, 1H), 4.29-4.33 (m, 0.5H), 3.99-4.03 (m, 2H), 3.88 (s, 3H), 3.83 (5, 3H), 3.12-3.25 (m, 2H), 2.81-2.93 (m, 2H), 2.07 (s, 1.5H), 2.01 (s, 1.5H), 1.59-1.74 (m, 4.5H), 1.10 (t, J=6.7 Hz, 1.5H), 0.99 (t, J=6.7 Hz, 1.5H). ESI MS m/z 451 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[O:11])=[CH:5][CH:4]=1.[NH2:22][C@@H:23]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[OH:37][C:34]1[CH:33]=[CH:32][C:31]([C@H:23]([NH:22][C:17](=[O:19])[C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[CH2:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)[C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])=[CH:36][CH:35]=1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)O)cc2)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)c1ccc(O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N[C@H](C(=O)OC(C)(C)C)c3ccc(O)cc3)cc2)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
Prepared using General Procedure 6: To a stirred solution of 4-(2-(4-methoxyphenyl)acetamido)benzoic acid INT-12 (500 mg, 1.75 mmol) and (S)-tert-butyl 2-amino-2-(4-hydroxyphenyl)acetate (391 mg, 1.75 mmol) in DMF (10 mL) was added TEA (611 μL, 4.38 mmol) and HATU (700 mg, 1.84 mmol). After stirring for 2 h the reaction was diluted with EA (10 mL) and washed with brine (2×100 mL). The crude material was purified by chromatography (EA/hexanes) to give 860 mg (100%) of (S)-tert-butyl 2-(4-hydroxyphenyl)-2-(4-(2-(4-methoxyphenyl)acetamido)benzamido)acetate INT-13. LCMS-ESI (m/z) calculated for C28H30N2O6: 490; found 489, [M−H]−, tR=2.14 min (Method 4).