Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][NH:27][CH2:26]2>CN(C=O)C>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=1[F:16])[CH2:26]2
Reactant: COc1ccc2c(c1)CNC2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 62.2 %

Procedure:
170 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 268 mg of 5-methoxyisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 154 mg of the target compound.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C:3]([NH:5][C:6]1[NH:7][C:8](=O)[C:9]2[NH:14][C:13]([CH3:15])=[CH:12][C:10]=2[N:11]=1)=[O:4].[OH-].[NH4+].P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:8]1[C:9]2[NH:14][C:13]([CH3:15])=[CH:12][C:10]=2[N:11]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:18])([CH3:17])[CH3:1])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc2nc(NC(=O)C(C)(C)C)[nH]c(=O)c2[nH]1
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc2nc(NC(=O)C(C)(C)C)nc(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
To a 100-mL round-bottomed flask was added 9 (1.16 g, 4.67 mmol) suspended in 30 mL phosphorus oxychloride. The reaction mixture was heated at reflux with stirring in an anhydrous atmosphere for 3 h. The dark orange solution was allowed to cool to room temperature and concentrated in vacuo. Water (20 mL) was then added to the residue at 0° C. with vigorous stirring to give an exothermic reaction. Concentrated aqueous ammonium hydroxide was added to pH 5 to give a precipitate, which was collected by filtration, washed with water (3×5 mL), and dried in vacuo. The crude product was purified by silica gel column chromatography with 2% MeOH/CHCl3. Recrystallization from MeOH afforded 1.07 g (86%) of 10 as a white solid: TLC Rf0.35 (MeOH/CHCl3, 1:10); mp 162-163° C.; 1H NMR (DMSO-d6) δ 1.19 (s, 9 H), 2.47 (s, 3 H), 6.33 (s, 1 H), 9.85 (s, 1 H), 12.07 (s, 1 H) Anal. (C12H15ClN4O) C, H, N, Cl.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[CH:13]([CH:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:14].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.P([O-])([O-])([O-])=O>C(OCC)(=O)C.CC(C)=O>[OH:14][CH2:13][CH:15]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C=O)Cc1ccccc1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CO)Cc1ccccc1
Temperature: 30 °C
Reaction time: 0.33 h

Procedure:
A liquid medium (pH 7.0) was prepared so as to contain 4% glucose, 0.3% of yeast extract, 1.3% of KH2PO4, 0.7% of (NH4)2HPO4, 0.01% of NaCl, 0.08% of MgSO4.7H2O, 0.006% of ZnSO4.7H2O, 0.009% of FeSO4.7H2O, 0.0005% of CuSO4.5H2O, and 0.001% of MnSO4.4 to 5 H2O. The liquid medium was dispensed to large test tubes in an amount of 5 ml per each tube and the test tubes were sterilized by steam at 120° C. for 20 minutes. The liquid medium was inoculated each of the microorganisms shown in Table 3 by a platinum loop and incubated with shaking at 30° C. for 2 to 3 days. Microbial cells were centrifugally collected from each culture solution, and washed with water. After ice cold acetone was added, the cells were dried under reduced pressure to obtain acetone dried microbial cells. 5 mg of the acetone dried microbial cells, 2 mg of ethyl 2-formyl-3-phenylpropionate, 10 mg of glucose, 1 mg of NAD (or NADP), 0.5 ml of 0.1M phosphate buffer (pH=6.5) and 0.5 ml of ethyl acetate were added to each test tube with a cap and shaken at 30° C. for 24 ours. Subsequently, the same operation as in Example 9 was performed to determine a conversion rate and optical purity. The results are shown in Table 3.
Reaction SMILES: C(Br)CCC.[Cl:6][C:7]1[C:12]2[C:13](=[O:18])[O:14][C:15](=[O:17])[NH:16][C:11]=2[CH:10]=[CH:9][CH:8]=1.N1[C:24]2N=C[CH:27]=[CH:28][C:23]=2[C:22](=O)OC1=O>>[Cl:6][C:7]1[C:12]2[C:13](=[O:18])[O:14][C:15](=[O:17])[N:16]([CH2:27][CH2:28][CH:23]([CH3:24])[CH3:22])[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=c1[nH]c2cccc(Cl)c2c(=O)o1
Reactant: O=c1[nH]c2ncccc2c(=O)o1
Solvent: CCCCBr
Product: CC(C)CCn1c(=O)oc(=O)c2c(Cl)cccc21

Procedure:
The title compound was prepared according to the procedure of Example 1B substituting 1-bromo-3-methylbutane for n-butyl bromide and substituting the product of Example 101A for the product of Example 1A (0.610 g, 45%). MS (DCI) m/z 285 (M+NH4)+.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:23][N:24]=[C:25]=[O:26]>C1C=CC=CC=1>[CH3:23][NH:24][C:25]([N:12]1[CH2:11][CH2:10][C:9]([O:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:22][CH:21]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:14][CH2:13]1)=[O:26]
Reactant: O=[N+]([O-])c1ccc(OC2(c3ccccc3)CCNCC2)cc1
Reactant: CN=C=O
Solvent: c1ccccc1
Product: CNC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.7 %

Procedure:
To a stirred solution of 4.9 g of 4-(4-nitrophenoxy)-4-phenylpiperidine in 50 ml of benzene was added, dropwise, a solution of 0.91 g of methyl isocyanate in 15 ml of benzene. The reaction mixture was stirred at room temperature for two hours. Evaporation of the volatiles afforded a solid which was purified by means of high pressure liquid chromatography (silica gel; elution with 50% ethyl acetate/dichloromethane) to yield 6.05 g of 1-(N-methylamino)carbonyl-4-(4-nitrophenoxy)-4-phenylpiperidine, m.p. 110°-115° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].CN(C)C1C=CC=CC=1.C([O:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]2[CH:35]=[C:34]([O:36]CC3C=CC=CC=3)[CH:33]=[C:32]([O:44]CC3C=CC=CC=3)[CH:31]=2)=[CH:24][CH:23]=1)C1C=CC=CC=1>ClCCl>[OH:36][C:34]1[CH:35]=[C:30](/[CH:29]=[CH:28]/[C:25]2[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][CH:24]=2)[CH:31]=[C:32]([OH:44])[CH:33]=1
Reactant: C(=C/c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1)\c1ccc(OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: Oc1ccc(/C=C/c2cc(O)cc(O)c2)cc1
Temperature: 45 °C
Reaction time: 0.75 h

Procedure:
In a 3 lit. round-bottomed flask equipped with a thermometer are added aluminum chloride (390.35 gm) and N, N-dimethylaniline (413.10 gm) maintaining the temperature at 40-50° C.(exothermic). To this solution, (E)-1-[4-(benzyloxy)phenyl]-2-[3,5-bis(benzyloxy)phenyl]ethene (243 gm) in dichloromethane (800 ml) is added and stirred for further 0.75 hour. After the reaction is over, the reaction mixture is quenched into dil. hydrochloric acid at 0-5° C. and extracted with ethyl acetate. The organic layer is charcoalized and concentrated to get pure (E)-1-(3,5-dihydroxyphenyl)-2-(4-hydroxyphenyl)ethene (trans-Resveratrol) in the exclusive trans form. Mp 257-259° C. 1H NMR (DMSO-d6, 400 MHz) δ 6.11 (t, J=1.8 Hz, 1H), 6.38(d, J=1.8 Hz, 2H), 6.75 (d, J=8.5 Hz, 2H), 6.82(d, J=16.3 Hz, 1H), 6.92(d, J=16.3, 1H), 7.39(d, J=8.4 Hz, 2H); Mass M/e:228.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].[Br:15]C1C=C(CBr)C=CC=1OC(F)(F)F>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:15])=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12]
Reactant: FC(F)(F)Oc1ccc(CBr)cc1Br
Reactant: OCc1ccc(Cl)c(OC(F)(F)F)c1
Product: FC(F)(F)Oc1cc(CBr)ccc1Cl

Procedure:
Compound 35.2 was synthesized from (4-chloro-3-(trifluoromethoxy)phenyl)-methanol using the procedure described for the preparation of 19.2. 1H NMR (500 MHz, DMSO-d6) δ 7.74 (1H, d, J=2.0 Hz), 7.38-7.53 (2H, m), 4.53 (2H, d, J=5.6 Hz)
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][O:8][CH3:9])=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][N:17]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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>[CH3:9][O:8][CH2:7][C:5]1[O:6][C:2]([C:19]2[CH:18]=[N:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=2)=[CH:3][C:4]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COc1ccc(B(O)O)cn1
Reactant: COCc1oc(Br)cc1C(=O)OC
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: COCCOC
Solvent: O
Product: COCc1oc(-c2ccc(OC)nc2)cc1C(=O)OC
Yield: 83.8 %

Procedure:
A mixture of methyl 5-bromo-2-(methoxymethyl)furan-3-carboxylate (3.0 g), 2-methoxy-5-pyridineboronic acid (2.1 g), tetrakis(triphenylphosphine)palladium(0) (0.7 g), 2N aqueous sodium carbonate solution (14 mL) and 1,2-dimethoxyethane (30 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 25% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.8 g, 84%) as a white crystal.
Reaction SMILES: Cl.NCCS.Cl.Cl.N(C(C)(C)C(N)=N)=NC(C)(C)C(N)=N.[C:22]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)(=[O:25])[CH:23]=[CH2:24].OCC[NH:35][C:36](=[O:39])[CH:37]=[CH2:38]>O>[C:22]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)(=[O:25])[CH:23]=[CH2:24].[OH:25][CH2:22][CH2:23][C:37](=[CH2:38])[C:36]([NH2:35])=[O:39]
Reactant: C=CC(=O)NCCO
Agent: C=CC(=O)N1CCOCC1
Agent: CC(C)(N=NC(C)(C)C(=N)N)C(=N)N
Agent: Cl
Solvent: O
Product: C=C(CCO)C(N)=O
Temperature: 60 °C

Procedure:
A 1000 mL three-necked round bottom flask is charged with a solution of 28.4 g (250 mmol) cysteamine hydrochloride in 400 mL deionized water. 407 mg (1.5 mmol) α,α′-azodiisobutyramidine dihydrochloride and 70.6 g (500 mmol) acryloyl morpholine and 28.8 g (250 mmol) N-hydroxyethyl acrylamide are added. An intensive cooler and an internal thermometer are connected to the flask. The apparatus is evacuated to 100 mbar and filled with argon. This is repeated five times. The mixture is heated to 60° C. for four hours and then cooled to room temperature. An analytical sample is freeze-dried and the monomer conversion is determined by 1H-NMR spectroscopy. No resonances corresponding to C═C double bonds can be detected, indicating >98% conversion of the monomer. The remaining mixture is adjusted to pH=10 by addition of 30% KOH solution. Salts and low molecular weight residues such as unreacted chain transfer agent are removed by reverse osmosis using a Millipore Proscale system equipped with a Millipore Helicon RO-4 Nanomax 50 membrane operating at a pressure of 15 bar. The product is isolated from the obtained retentate by freeze-drying. Yield: 85 g of a white powder. The concentration of amino-groups is determined by functional group titration, result 0.95 mmol/g NH2 corresponding to an average molecular weight of the co-telomer of 1050 g/mol. GPC-analysis indicates a monomodal molecular weight distribution and the absence of high molecular weight polymer.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([S:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH:8]=[C:7]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:6]=1[OH:21])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[C:17]([C:7]1[CH:8]=[C:9]([S:11]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:30])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:21])([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)c1cc(Sc2nccs2)cc(C(C)(C)C)c1O
Solvent: ClCCl
Product: CC(C)(C)c1cc(S(=O)c2nccs2)cc(C(C)(C)C)c1O
Yield: 72 %

Procedure:
2,6-Di-tert-butyl-4-(2-thiazolylthio)phenol (produced in Example 42) (1.60 g) was dissolved in 100 ml of dichloromethane and, with stirring and ice cooling, 1.21 g of 70% m-chloroperbenzoic acid was added, and the mixture was stirred for further 30 minutes. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution and then with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. Purification of the crude product obtained by silica gel column chromatography (chloroform-ethyl acetate=35:1) gave 1.21 g of the desired product as a colorless solid.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:18][C:17]4[CH2:19][CH2:20][CH2:21][CH2:22][C:16]=4[N:15]=3)[CH2:9]2)C=CC=CC=1.Cl>C(O)C.[Pd]>[NH:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[NH:15][C:16]3[CH2:22][CH2:21][CH2:20][CH2:19][C:17]=3[N:18]=2)[CH2:9]1
Reactant: c1ccc(CN2CCOC(c3nc4c([nH]3)CCCC4)C2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: C1CCc2[nH]c(C3CNCCO3)nc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 147.3 %

Procedure:
2-[4-(Phenylmethyl)-2-morpholinyl]-4,5,6,7-tetrahydro-1H-benzimidazole (0.78 g, 2.62 mmol) was hydrogenated in ethanol (30 mL) in the presence of Pd/C (10 wt %, 0.279 g, 0.262 mmol). To the reaction mixture was added 0.2 mL of concentrated hydrochloric acid. After stirring at room temperature overnight, the catalyst was filtered off. The filtrate was concentrated to afford the title compound (0.8 g) as a yellow oil. LC-MS (ES) m/z=208 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:16])=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:6]([Cl:10])=[CH:7][C:8]=1[Cl:9])#[N:2].[OH-:17].[Na+]>O>[C:1]([C:3]1[C:4]([Cl:16])=[C:5]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:6]([Cl:10])=[CH:7][C:8]=1[Cl:9])(=[O:17])[NH2:2]
Reactant: N#Cc1c(Cl)cc(Cl)c(CCC(=O)O)c1Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: NC(=O)c1c(Cl)cc(Cl)c(CCC(=O)O)c1Cl
Temperature: 60 °C
Yield: 90 %

Procedure:
16 g of 3-(3-cyano-2,4,6-trichlorophenyl)propionic acid is dissolved in a solution of 5 g of solution of caustic soda in 80 ml of water. The mixture is maintained at 60° C. for 3 hours, filtered over active carbon, and the filtrate is brought to pH 1 under cooling by the addition of concentrated hydrochloric acid under agitation. After several hours of stirring, the precipitate is vacuum-filtered, washed with water, and dried at 50° C. Recrystallization from five times the amount of toluene yields 15.5 g (90% of theory) of 3-(3-carbamoyl-2,4,6-trichlorphenyl)propionic acid as a white powder, mp 196°-198° C.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.Cl.[N:54]1([CH:60]2[C:72]3[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=3[C:66]3[C:61]2=[CH:62][CH:63]=[CH:64][CH:65]=3)[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]1>CN(C=O)C.C(OCC)C>[CH:62]1[C:61]2[CH:60]([N:54]3[CH2:59][CH2:58][N:57]([C:12]([C@@H:11]([NH:10][C:8]([N:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]4)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:56][CH2:55]3)[C:72]3[C:67](=[CH:68][CH:69]=[CH:70][CH:71]=3)[C:66]=2[CH:65]=[CH:64][CH:63]=1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: c1ccc2c(c1)-c1ccccc1C2N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)N1CCN(C2c3ccccc3-c3ccccc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
(S)-2-[(Azepane-1-carbonyl)-amino]4-methyl-pentanoic acid (0.300 g, 1.17 mmol, Example 1, Step B) was dissolved in dry DMF (4 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.816 mL, 4.68 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.444 g, 1.17 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; solid 9-piperazinofluorene dihydrochloride (0.293 g, 1.17 mmol, Maybridge Chemical Co. Ltd., Tintagel Cornwall, U.K.) was then added. After stirring for, sequentially, 20 minutes at 0° C. and 20 minutes at ambient temperature, reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with saturated aqueous NaHCO3 solution (2×60 mL), brine (2×60 mL), and was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was further purified by flash chromatography (50% EtOAc in hexane containing 1% MeOH to provide 0.21 g (37%) of the pure titled compound as a white foam: mp 63-73° C. APCI-MS m/z 489.3 (MH+).
Reaction SMILES: [CH2:1]([Cl:5])[C:2](=[CH2:4])[CH3:3].S(=O)(=O)(O)O.[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:4][C:2]([C:14]1[CH:15]=[CH:16][C:11]([CH3:17])=[CH:12][CH:13]=1)([CH3:3])[CH2:1][Cl:5]
Reactant: C=C(C)CCl
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Product: Cc1ccc(C(C)(C)CCl)cc1
Yield: 85 %

Procedure:
24 g Methallyl chloride is added to a mixture of 92 g toluene and 49 g concentrated sulphuric acid, keeping the temperature at 40° C. No exothermal reaction occurs. Subsequently the reaction mixture is stirred during half an hour, after which the layers are separated. The organic layer is washed neutral with soda solution, dried on MgSO4 and evaporated. The residue is distilled under diminished pressure to obtain 2-methyl-2-(p-tolyl)-propyl chloride (p-methyl-neophyl chloride) in a yield of 85%.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[C:9]([C:17]([O:19]CC)=[O:18])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Na].O>O1CCOCC1>[CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[C:9]([C:17]([OH:19])=[O:18])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=Cc2ccccc2N(C(=O)OCC)CC1
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)N1CCC(C(=O)O)=Cc2ccccc21
Yield: 93.5 %

Procedure:
Compound 9 (5 g, 17.2 mmoles) was dissolved in dioxane (11.5 ml) and a solution of sodium hydroxyde (11.5 ml, 1.5M) was added. The mixture was heated for 2 hours and poured in ice cooled water. The aqueous layer was extracted at pH 12 with Et2O (50 ml), acidified to pH 2 and reextrated with EtOAc (100 ml). This layer was dried (MgSO4), filtered and evaporated to give yellow crystals (4.2 g, 90%), after recrystallization (cyclohexane/CCl4) mp 176° C. 1H NMR (CDCl3) δ=1.25 (3H, t, J=7 Hz) 2.9 (2H, t) 3.5-3.9 (2H, m) 4.2 (2H, q, J=7 Hz) 7-7.6 (4H, m) 7.8 (1H, s). IR (CCl4) 3500-3000 (large signal) 3000 (w) 1695 (s) 1630 (w) 1600 (w) 1575 (w) 1490 (w) 1450 (w) 1410 (m) 1385 (w) 1370 (2) 1340 (w) 1320 (m). Mass spectrum m/z 261.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH2:7][N:8]([CH3:31])[CH2:9][CH2:10][CH2:11][C:12]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)(C(OC)=O)[C:13]([O:15][CH3:16])=[O:14].CO.[H-].[Na+]>C1COCC1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH2:7][N:8]([CH3:31])[CH2:9][CH2:10][CH2:11][CH:12]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C(CCCN(C)CCc1ccc(OC)c(OC)c1)(C(=O)OC)c1ccc(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(CCCN(C)CCc1ccc(OC)c(OC)c1)c1ccc(OC)c(OC)c1
Temperature: 22 °C

Procedure:
To a solution of 0.349 g (0.694 mmol) of 3a in 20 mL of THF at 22° C. was added 0.281 mL (6.94 mmol) of methanol followed by 56 mg (1.39 mmol) of NaH (60% dispersion in mineral oil). The reaction was refluxed for 1 h, cooled to 22° C. and diluted with 100 mL of DCM. The mixture was washed with 50 mL of saturated NaHCO3, 50 mL of water, dried, and evaporated to give an oil. The oil was purified by flash chromatography on silica gel, eluting first with 2% methanol/DCM and then gradually increasing to 4% methanol/DCM to give 3b as a colorless oil; MS found M+H=446. The oxalate salt of 3r was recrystallized from ethyl acetate; mp 112-113.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:4]=1[CH:5]=[O:6].[Na]>C(O)C>[CH3:1][O:2][C:3]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([O:13][CH3:14])=[C:7]([CH3:15])[C:4]=1[CH2:5][OH:6]
Reactant: COc1c(C)c(C)c(OC)c(C=O)c1C
Agent: [Na]
Solvent: CCO
Product: COc1c(C)c(C)c(OC)c(CO)c1C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a solution of 20 g (96 mmol) of 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde in 200 ml of ethanol, 1.8 g (47.6 mmol) of sodium boronhydride was added and stirred for 30 minutes. To the reaction mixture saline was added, and the product was extracted with ethyl acetate. The extract was washed with water and dried, from which the solvent was evaporated off under reduced pressure. The residue was crystallized from isopropyl ether, to give 18.6 g (92.1%) of 2,5-dimethoxy-3,4,6-trimethylbenzylalcohol. m.p. 121°-122° C.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[Cl:59][C:60]1[CH:61]=[C:62]([CH2:66][NH2:67])[CH:63]=[CH:64][CH:65]=1>C(Cl)Cl.O.C(OCC)(=O)C>[Cl:59][C:60]1[CH:61]=[C:62]([CH:63]=[CH:64][CH:65]=1)[CH2:66][NH:67][C:24]([CH:21]1[CH2:20][CH2:19][N:18]([C:16]([C:8]2[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:28][CH:27]=3)[C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[O:17])[CH2:23][CH2:22]1)=[O:26]
Reactant: NCc1cccc(Cl)c1
Reactant: O=C(O)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1cccc(Cl)c1)C1CCN(C(=O)c2cc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reaction time: 8 h

Procedure:
1-(1-(4-chlorobenzyl)-1H-indole-2-carbonyl)piperidine-4-carboxylic acid (336 mg, 0.847 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (203 mg, 1.509 mmol), and 1-Hydroxybenzotriazole (143 mg, 1.059 mmol) were dissolved in 2.0 mL of DCM. The reaction was allowed to stir for 10 minutes before N,N-Diisopropylethylamine (185 μL, 1.059 mmol) and (3-chlorophenyl)methanamine (100 mg, 0.706 mmol) were added as a 1.0 mL DCM solution. The reaction was allowed to stir overnight. The reaction was diluted with water and ethyl acetate. The layers were separated and the organic layer was washed with another aliquot of water. The ethyl acetate layer was washed with 1N HCl followed by saturated sodium bicarbonate then saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude material was triturated with methanol and filtered under vacuum to obtain pure product as a white solid. Yield: 179 mg (White solid)