Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.CN(CCN(C)C)C.[Li]C(CC)C.[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1>C1COCC1.C(=O)=O>[Br:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]([OH:35])[C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[CH:32][CH:31]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1
Agent: CN(C)CCN(C)C
Agent: O=C=O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1C(O)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a −78° C. solution of tert-butyl (4-chlorophenyl)carbamate (3.0 g, 13.2 mmol) in 100 ml of THF was added TMEDA (1.53 g, 13.2 mmol) followed by sec-BuLi (21 ml, 32.9 mmol) slowly and dropwise via syringe. The reaction mixture turns bright yellow after about half the s-BuLi was added. The reaction mixture was allowed to stir for 15 min at −78° C. then allowed to warm to about −20° C. (tip of flask in dry-ice bath) for 1 hr, then the reaction mixture was cooled to −78° C. again. The reaction mixture was in now a dull yellow/orange, slightly heterogeneous and 4-bromobenzaldehyde was added dropwise, and stirred for 30 min at −78° C. The reaction mixture was quenched with 100 mL sat NH4Cl (pink fades to yellow), extracted with 150 ml of ether, washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography using 5-30% EtOAc/hex as the eluent to provide tert-butyl {2-[(4-bromophenyl)(hydroxy)methyl]-4-chlorophenyl}carbamate as a yellow solid. 1HNMR: (400 MHz, CDCl3) δ 7.72 (d, J=8.4 Hz, 1H), 7.48 (d, J=8.4, 1H), 7.40˜7.50 (m, 1H), 7.27 (s, 1H), 7.26 (d, J=8.8 Hz, 2H), 7.02 (d, J=2.0 Hz, 1H), 5.81 (s, 1H), 4.70˜4.90 (m, 1H), 1.43 (s, 9H).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[C@@:13]3([CH3:19])[N:14]=[C:15]([NH2:18])[S:16][CH2:17][C@H:12]3[CH2:11][O:10][C:8]=2[CH:9]=1.[OH-].[Na+].O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:5]1[C:4]([F:3])=[CH:9][C:8]2[O:10][CH2:11][C@@H:12]3[CH2:17][S:16][C:15]([NH2:18])=[N:14][C@:13]3([CH3:19])[C:7]=2[CH:6]=1
Reactant: C[C@]12N=C(N)SC[C@H]1COc1cc(F)ccc12
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: C[C@]12N=C(N)SC[C@H]1COc1cc(F)c(Br)cc12
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
Bromine (0.20 mL, 3.80 mmol) was added dropwise to a solution of rel-(4aR,10bS)-8-fluoro-10b-methyl-4,4a,5,10b-tetrahydrochromeno[4,3-d][1,3]thiazin-2-amine from step F6 (644 mg, 2.55 mmol), in acetic acid (20 mL) at rt. The mixture was stirred for 30 min. The reaction was poured onto ice. The slurry was made pH 3 upon slow addition of 50% NaOH/water. The aqueous mixture was made basic pH 7-8 by the addition of solid sodium bicarbonate. The aqueous layers were extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (0.25%-10% MeOH/CHCl3) to afford rel-(4aR,10bS)-9-bromo-8-fluoro-10b-methyl-4,4a,5,10b-tetrahydrochromeno[4,3-d][1,3]thiazin-2-amine (667 mg, 1.62 mmol, 64% yield) as a viscous oil. LCMS (M+H)+=333.02. 1H NMR (500 MHz, methanol-d4) δ 7.73 (d, J=7.5 Hz, 1H), 6.79 (d, J=9.8 Hz, 1H), 4.53 (dd, J=11.9, 2.9 Hz, 1H), 4.30 (dd, J=12.0, 6.0 Hz, 1H), 3.50 (dd, J=13.7, 3.9 Hz, 1H), 3.23 (dd, J=13.6, 8.1 Hz, 1H), 2.64 (dtd, J=10.0, 3.9, 3.0 Hz, 1H), 1.80 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[N:10]=[CH:9]1)=O)(C)(C)C.[CH3:23][O:24][CH2:25]Cl.C(=O)([O-])O.[Na+]>C(#N)C>[C:19]([O:18][C:16]([NH:15][CH2:14][CH2:13][C:11]1[N:10]([CH2:23][O:24][CH3:25])[CH:9]=[N:8][CH:12]=1)=[O:17])([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCCc1cn(C(=O)OC(C)(C)C)cn1
Reactant: COCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COCn1cncc1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
1-t-Butoxycarbonyl-4-{2-(t-butoxycarbonyl-amino)ethyl}imidazole (78.1 g) is dissolved in acetonitrile (500 ml), and thereto is added methoxymethyl chloride (22.2 g), and the mixture is stirred at room temperature overnight. The reaction solution is poured into 10% aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract is washed, dried, and the solvent is distilled off to give 4-{2-(t-butoxycarbonyl-amino)ethyl]-3-methoxymethylimidazole (54.4 g) as oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]([O:27][C@H:28]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:29][C:30](O)=[O:31])(=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(Cl)CCl.CI>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:14])[C@H:10]([CH2:12][OH:13])[NH:11][C:30](=[O:31])[CH2:29][C@H:28]([O:27][C:15](=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCC[C@H](CC(=O)O)OC(=O)CCCCCCCCCC
Reactant: N[C@@H](CO)C(=O)OCc1ccccc1
Solvent: CI
Solvent: ClCCCl
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC(=O)N[C@@H](CO)C(=O)OCc1ccccc1)OC(=O)CCCCCCCCCC
Yield: 91.5 %

Procedure:
In the same manner as described in Example 2-(5), L-serine benzyl ester (390 mg, 2.0 mmol) was acylated with (R)-3-undecanoyloxytetradecanoic acid (905 mg, 2.2 mmol) in the presence of EDC·MeI (745 mg, 2.5 mmol) in CH2Cl2 to afford 1.08 g (92%) of N-[(R)-3-undecanoyloxytetradecanoyl]-L-serine benzyl ester: mp 53-54° C.; 1H NMR (CDCl3) δ 0.88 (t, 6H, J=6.9 Hz), 1.1-1.7 (m, 44H), 2.30 (t, 2H, J=7.7 Hz), 2.49 (d, 2H, J=5.8 Hz), 3.99 (m, 2H), 4.65 (m, 1H), 5.19 (m, 3H), 6.58 (d, 1H, J=6.9 Hz), 7.35 (br s, 5H).
Reaction SMILES: [CH:1]([CH:4]([C:10]([CH3:12])=O)[C:5](OCC)=[O:6])([CH3:3])[CH3:2].[C:13]([O:17][CH3:18])(=[O:16])[CH2:14][SH:15].[Na]>>[OH:6][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[C:10]([CH3:12])[S:15][C:14]=1[C:13]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CS
Reactant: CCOC(=O)C(C(C)=O)C(C)C
Agent: [Na]
Product: COC(=O)c1sc(C)c(C(C)C)c1O

Procedure:
Prepared by the method described in Example 1 from ethyl α-isopropylacetoacetate (prepared by the procedure of Manuel and Hagen, Org. Syn., 7, 248 (1951)) (12 g, 70 mmoles), methyl thioglycolate (15.7 g, 140 mmoles) and sodium (3.2 g, 139 mmoles). The product is extracted with CH2Cl2 twice. The combined extracts are washed with aqueous NaCl twice, dried over MgSO4 and stripped of solvent under reduced pressure. Distillation of the residue gave the product (3.3 g); bp 68°-71° C. (0.3 mmHg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](C)(C)[O:14][SiH](C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CCc1ccccc1
Reactant: C[SiH](C)O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.8 %

Procedure:
A 30-mL eggplant flask equipped with a magnetic stirrer was heat dried while pumping to a vacuum of 5 Pa before its interior was purged with nitrogen atmosphere. To the flask, 4-phenyl-2-butanone (148 mg, 1.0 mol) and 1,1,1,3,3-pentamethyldisiloxane (371 mg, 2.5 mmol) were added through a syringe, and iron complex A (5.0 mg, 0.01 mmol) was added as catalyst. The solution was stirred at room temperature for 24 hours. At 0° C., THF (1 mL) and tetrabutylammonium fluoride in THF (1 M, 1 mL) were then added to the solution, which was stirred at 0° C. for 1 hour. The solvent was distilled off in vacuum. The crude product was purified by silica gel-packed column chromatography using hexane/ethyl acetate (3/1) as developing solvent, obtaining 4-phenyl-1-butanol (139 mg, 0.92 mmol, 92%). The results are shown as Entry 2 in Table 7. The resulting alcohol was identified for geometry by 1H and 13C-NMR spectroscopy.
Reaction SMILES: [C:1]([O:5][C:6]([C@:8]1([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][C@H:12]([OH:14])[C@@H:11]2[C@H:9]1[C@H:10]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.S([O-])(O)(=O)=O.[K+].O>CN(C)C1C=CN=CC=1.ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([C@:8]1([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][C@H:12]([O:14][S:36]([C:33]2[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=2)(=[O:38])=[O:37])[C@@H:11]2[C@H:9]1[C@H:10]2[C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@H](O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@](NC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)[C@@H]3[C@@H](C(=O)OC(C)(C)C)[C@@H]32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.7 %

Procedure:
Charge a 2-necked round bottom flask under nitrogen atmosphere with ditert-butyl(1S,2S,4S,5R,6R)-2-(tert-butoxycarbonylamino)-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate (20.7 g, 0.5 mol, see WO03/104217/A2 for synthesis details), 4-dimethylaminopyridine (10.4 g, 0.85 mol), triethylamine (6.98 mL, 0.5 mmol) and p-toluenesulfonyl chloride (10.6 g, 0.55 mol) in dichloromethane (200 mL), and stir the mixture at room temperature overnight. Add 1N solution of potassium hydrogen sulfate (200 mL), water (100 mL) and extract the organic layer. Wash with water (200 mL), brine (200 mL), dry over magnesium sulfate, filter and evaporate to dryness. Add tetrahydrofuran (30 mL) then heptanes (90 mL). Heat the mixture at 60° C. and slowly add more heptanes (200 mL). Cool the mixture to room temperature. Filter the solid and dry under reduced pressure to yield the title compound as a white solid (24.6 g, 87%). MS (m/z): 590 (M+23).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=[O:12])[NH:6]2.[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O)[CH3:15]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=[O:12])[NH:6]2)[CH3:15]
Reactant: CCc1ccccc1B(O)O
Reactant: O=C(O)c1cc2c(Br)cccc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCc1ccccc1-c1cccc2[nH]c(C(=O)O)cc12

Procedure:
To a mixture of 0.28 g of 4-bromo-indole-2-carboxylic acid and 0.069 g of tetrakistriphenylphosphinepalladium in 11 ml of toluene and 2 ml of 2M soda is added a solution of 0.300 g of 2-ethylphenylboronic acid in 3 ml of ethanol. This mixture is refluxed for 16 h, filtered and the aqueous phase acidified with 2N HCl and extracted with ethyl acetate. Concentration of the organic phase gives the product as a brownish powder, m.p. 230-233°, sufficiently pure for the next step.
Reaction SMILES: [CH:1]([N:4]([CH3:25])[C:5]1[C:6]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[CH:1]([N:4]([CH3:25])[C:5]1[C:6]([C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3ccncc3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccncc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Into a 10-mL sealed tube, was placed a solution of methyl 3-(isopropyl(methyl)amino)-2-(pyridin-4-yl)quinoxaline-6-carboxylate (50 mg, 0.15 mmol, 1.00 equiv) in methanol (15 mL), sodium hydroxide (30 mg, 0.75 mmol, 5.04 equiv), water (2 mL). The resulting solution was stirred for 2 hr at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum and diluted with 20 mL of H2O. The pH value of the aqueous solution was adjusted to 4-5 with hydrogen chloride (2 mol/L). The resulting solids were collected by filtration. This resulted in 22 mg (44%) of 3-(isopropyl(methyl)amino)-2-(pyridin-4-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH3:26])[N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[NH:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32]>>[O:32]=[C:28]1[CH2:29][CH2:30][CH2:31][N:27]1[C:2]1[CH:3]=[CH:4][C:5]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[C:20]([CH3:26])[N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3C#N)CC2)nc1C
Reactant: O=C1CCCN1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C#N)CC2)nc1C

Procedure:
Using 5-bromo-2-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]benzonitrile (413 mg) described in Preparation Example 172 and pyrrolidin-2-one (115 μL) and by the reaction and treatment in the same manner as in Example 262, the title compound (378 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.[C:10]([S@@:14]([NH2:16])=[O:15])([CH3:13])([CH3:12])[CH3:11]>C1COCC1.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[N:16]/[S:14]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:15])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)S(=O)/N=C/c1ccc(Br)cn1
Temperature: 73 °C
Reaction time: 2.5 h
Yield: 77 %

Procedure:
To a solution of 5-bromo-2-formyl-pyridine (3.0 g, 16.1 mmol) in dry THF (95 mL), (S)-tert-butylsulfinamide (2.05 g, 16.9 mmol) was added at RT under argon. Then titanium tetra-isopropoxyide (7 mL, 33.9 mmol) was added drop wise. The reaction mixture was stirred at 73° C. (external temperature) for 2.5 h, and was allowed to cool down. The reaction mixture was slowly poured into a vigorously stirring mixture of ca. 200 mL of brine and ice. The slurry was filtered and washed with DCM. The organic layer was separated and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over MgSO4, filtered, evaporated to give a brown solid. The product was triturated in cold ether and successive filtered solids were combined to give the title intermediate (3.66 g, 12.4 mmol, 77%). HPLC: EtRet=4.987 min; LC-MS: m/z 291.0 [M+H]+.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([CH2:30][OH:31])[CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH2:27][CH:26]([CH2:30][O:31][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(OCc1ccccc1)N1CCCC(CO)C1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.9 %

Procedure:
Imidazole (3.00 g, 44.0 mmol) and tert-butyldimethylsilyl chloride (6.63 g, 44.0 mmol) were added to 1-(benzyloxycarbonyl)piperidin-3-yl methanol (9.15 g, 36.7 mmol) in N,N-dimethylformamide (40 mL). The solution was stirred at room temperature for 6 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate. The extract washed with brine and was dried over magnesium sulfate, followed by evaporation of the solvent. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate=20:1->5:1) gave 13.2 g (99%) of the desired compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([N:11]1[CH2:16][CH2:15][N:14]([C:17]3([C:30]#N)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[CH2:13][C@@H:12]1[CH3:32])[CH2:6][CH2:5]2.C[Mg]Br>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([N:11]1[CH2:16][CH2:15][N:14]([C:17]3([CH3:30])[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]3)[CH2:13][C@@H:12]1[CH3:32])[CH2:6][CH2:5]2
Reactant: C[C@H]1CN(C2(C#N)CCN(C(=O)OC(C)(C)C)CC2)CCN1C1CCc2cc(Br)ccc21
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: C[C@H]1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1C1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a solution of tert-butyl 4-[(3S)-4-(5-bromo-2,3-dihydro-1H-inden-1-yl)-3-methylpiperazin-1-yl]-4-cyanopiperidine-1-carboxylate (0.32 g, 0.64 mmol) in THF (2 mL) was added a 3 M solution of methylmagnesium bromide (1.1 mL, 3.3 mmol). After stirring at room temperature overnight, the solution was concentrated. Purification on silica (2:1 hexane/EtOAc) afforded the title compound (0.25 g). MS calculated for C25H37BrN3O2: (M+H)+491; found 491.2, 494.2.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([NH:20][C:21]([CH3:29])([CH3:28])[CH2:22]/[CH:23]=[CH:24]/[C:25]([OH:27])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH2:30]([C@@H:37]([N:50]([CH3:67])[C:51](=[O:66])[C@H:52]([NH:64][CH3:65])[CH2:53][C:54]1[CH:63]=[CH:62][C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:55]=1)[C:38]([N:40]1[CH2:45][CH2:44][CH:43]([CH2:46][N:47]([CH3:49])[CH3:48])[CH2:42][CH2:41]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(C(C)C)C(C)C)C>ClCCl.CN(C)C=O.C(OCC)(=O)C>[C:13]([O:17][C:18](=[O:19])[NH:20][C:21]([CH3:29])([CH3:28])[CH2:22]/[CH:23]=[CH:24]/[C:25](=[O:27])[N:64]([C@@H:52]([C:51](=[O:66])[N:50]([C@H:37]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:38]([N:40]1[CH2:45][CH2:44][CH:43]([CH2:46][N:47]([CH3:48])[CH3:49])[CH2:42][CH2:41]1)=[O:39])[CH3:67])[CH2:53][C:54]1[CH:63]=[CH:62][C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH:55]=1)[CH3:65])([CH3:14])([CH3:15])[CH3:16]
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N1CCC(CN(C)C)CC1
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC1CCN(C(=O)[C@@H](Cc2ccccc2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 72927.8 %

Procedure:
At 0° C., N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (112 mg, 0.58 mmol) was added to a solution of (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid (142 mg, 0.58 mmol) and 1-hydroxy-7-azabenzotriazble (79 mg, 0.58 mmol) in dichloromethane (10 ml) and N,N-dimethylformamide (5 ml). The reaction mixture was stirred for 20 min at 0° C. A solution of (2R)-N-[(1R)-1-benzyl-2-(4-((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl]-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide (300 mg, 0.58 mmol) in dichloromethane (5 ml) and N,N-dimethylformamide (5 ml) and ethyldiisopropylamine 0.10 ml, 0.58 mmol) were added successively. The reaction mixture was stirred for 3 days, while it was warming up to room temperature. It was diluted with ethyl acetate (70 ml) and washed with a saturated aqueous solution of sodium hydrogen carbonate (70 ml). The aqueous phase was extracted with ethyl acetate (3×50 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (70 g), using dichloromethane/methanol/25% aqueous ammonia (200:10:1) as eluent, to give 313 g of {(3E)-4-[N-((1R)-1-{N-[(1R)-1-benzyl-2-(4-((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethyl)-N-methylcarbamoyl]-1,1-dimethylbut-3-enyl}carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[CH2:12]([O:14][C:15](=[O:26])[CH2:16][NH:17][C:18](=[O:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH3:13]>>[CH2:12]([O:14][C:15](=[O:26])[CH2:16][NH:17][C:18](=[O:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=1)[CH3:13]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CNC(=O)CCCCCN
Product: CCOC(=O)CNC(=O)CCCCCNC(=O)c1ccc(OC)cc1

Procedure:
By working analogously to what described in example 2 and by using 4-methoxybenzoic acid (33 mmoles) and N-(6-aminohexanoyl)glycine ethyl ester (39.5 mmoles), prepared as described in example 3, N-[6-[(4-methoxybenzoyl)amino]hexanoyl]glycine ethyl ester was obtained as a crude product, used as such in the subsequent reactions.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([O:26]C)=[O:25])=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>O.CO>[CH2:3]([C:15]1[C:23]2[C:18](=[CH:19][C:20]([C:24]([OH:26])=[O:25])=[CH:21][CH:22]=2)[NH:17][CH:16]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCc1c[nH]c2cc(C(=O)OC)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCc1c[nH]c2cc(C(=O)O)ccc12
Temperature: 0 °C
Yield: 73.3 %

Procedure:
A solution of sodium hydroxide (15 g) in water (100 ml) was added dropwise during 30 minutes to a refluxing solution of methyl 3-(n-dodecyl)indole-6-carboxylate (12.8 g prepared as hereinbefore described in Example 85) in methanol (800 ml). The mixture was stirred and refluxed for 12 hours. The mixture was then concentrated to 500 ml volume and water (400 ml) was added. After cooling to 0° C., a solid was collected and was dissolved in hot glacial acetic acid (300 ml). The solution was then poured into water (800 ml) and a solid was collected, washed with water (4×100 ml) and dried at 60° C. Recrystallisation of the solid from methanol gave 3-(n-dodecyl)indole-6-carboxylic acid (9.0 g), in the form of a white solid, m.p. 181°-184° C.
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].CCN(C(C)C)C(C)C.[C:16](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCCCCC>C(Cl)Cl.CO.CCOCC>[C:16]([NH:1][C@H:2]([CH2:5][CH3:6])[CH2:3][OH:4])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC[C@@H](N)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Solvent: CCOCC
Product: CC[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of (R)-(−)-2-aminobutan-1-ol (10 g, 1 eq, 112.18 mmol) in DCM (500 mL) under an argon atmosphere at room temperature, was added DIEA (30 mL, 1.54 eq, 172.22 mmol) followed by trityl chloride (35.4 mL, 1.13 eq, 126.98 mmol). The reaction mixture was stirred at room temperature for 48 h, when TLC (hexane:ether:MeOH; 55:40:5) indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue precipitated from acetone (50 mL) with hexane (900 mL) with stirring, the precipitate was removed by filtration and the filtrate was evaporated in vacuo. The residue was dissolved in hexane (1 L), filtered, and the filtrate was evaporated in vacuo to afford the title compound as a light yellow oil. Yield: 32 g (86%). 1H-NMR (d6-DMSO, 250 MHz): δ 0.56 (t, 3H, J=7.41 Hz, —NHCH(CH2CH3)CH2OH), 1.10 (m, 2H, —NHCH(CH2CH3)CH2OH), 2.22 (m, 1H, —NHCH(CH2CH3)CH2OH), 2.38 (m, 1H, —NHCH(CH2CH3)CH2OH), 2.72+3.00 (2×m, 2H, —NHCH(CH2CH3)CH2OH), 4.28 (t, 1H, J=5.26 Hz, —NHCH(CH2CH3)CH2OH), 7.14-7.49 (m, 15H, 3×Ph).