Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:65])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18]CC4C=CC(OC)=CC=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([N:42]5[CH2:47][CH2:46][CH:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:44][CH2:43]5)=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:53]([F:64])[C:54]2[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=2)[CH2:4][CH2:3]1.Cl.O1CCOCC1.C(=O)([O-])O.[Na+]>C(O)C>[F:65][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:37]=[CH:38][C:39]([N:42]5[CH2:47][CH2:46][CH:45]([C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:44][CH2:43]5)=[CH:40][N:41]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:53]([F:64])[C:54]2[CH:55]=[CH:56][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:58][CH:59]=2)[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1CCN(c2cnc(N3CCC(c4nc5c(c(C6CCC(F)(F)CC6)c4C(F)c4ccc(C(F)(F)F)cc4)C(OCc4ccc(OC)cc4)CC(C)(C)C5)CC3)nc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)C1CCN(c2cnc(N3CCC(c4nc5c(c(C6CCC(F)(F)CC6)c4C(F)c4ccc(C(F)(F)F)cc4)C(O)CC(C)(C)C5)CC3)nc2)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
To a solution of 98 mg (0.11 mmol) of 4-(4,4-Difluorocyclohexyl)-2-(1-{5-[4-(ethoxycarbonyl)piperidin-1-yl]pyrimidin-2-yl}piperidin-4-yl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 13, in 2 ml of ethanol, 1 ml of 4 N hydrogen chloride/1,4-dioxane solution was added, and the reaction solution was stirred at 50° C. for 3 hours. After completion of the reaction, saturated sodium hydrogencarbonate aqueous solution was poured into the reaction solution under ice cooling and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=90/10-60/40 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 69 mg of the title compound as a light brown solid (yield: 81%).
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:3].Br[CH2:11][CH2:12][CH2:13][CH2:14][N:15]([S:27]([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28])[C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1.C(O)(=O)C>C(O)C.C(OCC)(=O)C>[C:2]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:11][CH2:12][CH2:13][CH2:14][N:15]([S:27]([C:30]1[CH:31]=[CH:32][C:33]([CH3:34])=[CH:35][CH:36]=1)(=[O:28])=[O:29])[C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1)#[N:3]
Reactant: CCOC(=O)c1ccc(N(CCCCBr)S(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CCOC(=O)CC#N
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N(CCCCC(C#N)C(=O)OCC)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.506 g (0.0220 mol) of sodium in 10 mL of absolute ethanol under nitrogen was refluxed briefly, and a solution formed. After it had cooled to room temperature, to the solution was added dropwise over a 2-min period 2.74 g (0.0242 mol) of ethyl cyanoacetate. The mixture was refluxed for 10 min and was allowed to cool to room temperature. Then to it was added over a 6-min period 5.00 g (0.0110 mol) of ethyl 4-[(4-bromobutyl)tosylamino]benzoate and 15 mL of rinse absolute ethanol. The mixture was refluxed under nitrogen for 6 h, allowed to cool to room temperature, and stand overnight. It was neutralized with glacial acetic acid and concentrated under vacuum to a wet solid to which was added 50 mL of water and 50 mL of ether. The mixture was shaken in a separatory funnel, and the layers were separated. The aqueous layer was washed with 2×50 mL more ether, and the ether washes were combined, dried over magnesium sulfate for three days, filtered, and concentrated under high vacuum at 60° C. to a viscous, pink oil; yield, 5.97 g. The oil was purified by a flash chromatography column consisting of 400 g of Silica Gel 60 with 3:1 hexanes/ethyl acetate as the eluting solvent. Fractions containing clean product were combined and concentrated under vacuum to a colorless, viscous oil; yield, 2.76 g (50%): NMR (Me2SOd6) δ 1.19 (t, 3H), 1.29 (t, 3H), 1.3-1.5 (m, 4H), 1.65-1.85 (m, 2H), 2.37 (s, 3H), 3.5-3.7 (m, 2H), 4.14 (t, 1H), 4.15 (q, 2H), 4.29 (q, 2H), 7.22 (d, 2H), 7.3-7.5 (AA'BB', 4H), 7.90 (d, 2H), 0.15 mol of ethyl acetate.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:15])[CH2:4][P:5]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=[O:7])[OH:6].C(=O)([O-])[O-].[K+].[K+].Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>O.C1COCC1.C(OCC)(=O)C.Cl>[CH2:26]([O:25][C:23]([NH:1][CH2:2][C@@H:3]([OH:15])[CH2:4][P:5]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=[O:6])[OH:7])=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NC[C@@H](O)CP(=O)(O)CC1CCCCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NC[C@@H](O)CP(=O)(O)CC1CCCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
To a mixture of ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid (7.05 g, 30 mmol) and potassium carbonate (12.42 g, 90 mmol) in water (90 mL) and THF (30 mL) was added benzyl chloroformate (7.65 g, 45 mmol). After stirring for 3 h at room temperature, the reaction mixture was diluted with ethyl acetate (150 mL) and 2N HCl (90 mL). After stirring vigorously for 10 min the aqueous layer was removed and the organic layer was diluted with heptane (200 mL). The resulting white precipitate was collected to yield ((R)-3-benzyloxycarbonylamino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid (10.5 g, 28 mmol). 1H NMR (CDCl3, 300 MHz): δ 7.32 (m, 5H), 5.45 (br s, 1H), 5.10 (s, 2H), 4.2 (m, 1H), 3.4 (dd, 1H), 3.20 (dd, 1H), 2.01-1.55 (m, 10H), 1.40-0.95 (m, 5H). 31P NMR (CDCl3, 300 MHz): δ 57.3. LC/MS m/z: [M+H]+=370.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1([C:38]([O:40][CH2:41][CH:42]=[CH2:43])=[O:39])[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][C@H:17]([N:19]([CH2:28][C@@H:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=3)[OH:30])C(OCC(Cl)(Cl)Cl)=O)[CH3:18])=[CH:15][C:9]=2[O:8]1)=[O:6])[CH:2]=[CH2:3]>[Zn].C(O)(=O)C>[CH2:1]([O:4][C:5]([C:7]1([C:38]([O:40][CH2:41][CH:42]=[CH2:43])=[O:39])[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][C@H:17]([NH:19][CH2:28][C@@H:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=3)[OH:30])[CH3:18])=[CH:15][C:9]=2[O:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C1(C(=O)OCC=C)Oc2ccc(C[C@@H](C)N(C[C@H](O)c3cccc(Cl)c3)C(=O)OCC(Cl)(Cl)Cl)cc2O1
Agent: [Zn]
Solvent: CC(=O)O
Product: C=CCOC(=O)C1(C(=O)OCC=C)Oc2ccc(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)cc2O1
Temperature: 25 °C
Reaction time: 40 h
Yield: 66 %

Procedure:
A mixture of 370 mg (0.55 mmol) 5-{(2R)-2-[[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid diallyl ester, 10 mL glacial acetic acid and 357 mg (5.46 mmol) of Zn dust were stirred at room temperature for 40 h. The reaction mixture was filtered through celite, poured into 50 mL brine, and extracted with 3×50 mL EtOAc. The combined organics were washed with 3×75 mL sat. NaHCO3, 1×75 mL brine, dried over Na2SO4, filtered and evaporated to a colorless oil. Flash chromatography on silica gel, eluting with CHCl3 /MeOH (20/1 to 10/1), gave 180 mg (0.36 mmol, a 66% yield) of the title compound (Rf =0.35; 10/1 CHCl3 /MeOH) as a colorless gum; 1H NMR (300 MHz, CDCl3): δ 1.20-1.33 (m, 3H), 2.70-2.81 (m, 1H), 3.00-3.19 (m, 2H), 3.36-3.45 (m, 2H), 4.50-5.50 (br s, 2H), 4.70-4.80 (m, 4H), 5.10-5.20 (m, 1H), 5.25-5.40 (m, 4H), 5.82-6.00 (complex m, 2H), 6.70-6.91 (m, 3H), 7.17-7.30 (m, 3H), 7.41 (s, 1H); MS (ES) m/z (relative intensity): 502 (M+, 100).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[CH2:7][N:6]1[C:20]1[N:21]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([Cl:32])[CH:27]=2)[N:22]=[C:23]([CH3:25])[CH:24]=1)=[O:4].[OH-].[Li+]>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([C@H:8]1[CH2:7][N:6]([C:20]2[N:21]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([Cl:32])[CH:27]=3)[N:22]=[C:23]([CH3:25])[CH:24]=2)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]1)(=[O:11])=[O:12]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2Cl)CN1c1cc(C)nn1-c1ccnc(Cl)c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)O)n(-c2ccnc(Cl)c2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-(2-chloro-benzenesulfonyl)-1-[2-(2-chloro-pyridin-4-yl)-5-methyl-2H-pyrazol-3-yl]-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as yellow oil. MS (ESI): m/z=481.0 [M+H]+.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[Li]CCCC.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)=[C:25]([C:30]2[N:31]=[N:32][N:33]([C:35]([CH3:38])([CH3:37])[CH3:36])[N:34]=2)[CH:26]=[CH:27][CH:28]=[O:29])=[CH:20][CH:19]=1>O1CCCC1>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=2)=[C:25]([C:30]2[N:31]=[N:32][N:33]([C:35]([CH3:38])([CH3:36])[CH3:37])[N:34]=2)[CH:26]=[CH:27][CH:28]([OH:29])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:20][CH:19]=1
Reactant: CC(C)(C)n1nnc(C(C=CC=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(C(C)(C)C)n1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A solution of the dianion of ethyl acetoacetate (400 μL, 3.1 mmoles) in 8 mL of dry tetrahydrofuran was generated as described in Example 10 using 130 mg (3.2 mmoles) of NaH (60% in mineral oil) and 2.5M n-BuLi in hexanes (1.27 mL, 3.2 mmoles) at 0° C. under argon. The orange dianion solution, after being chilled to -78° C., was transferred via a cannula into a tetrahydrofuran (12 mL) solution at -78° C. containing 5,5-bis(4-fluorophenyl)-4-[2-(1,1-dimethylethyl)-2H-tetrazol-5-yl]-2,4-pentadienal (0.96 g, 2.4 mmoles). The reaction mixture was stirred at -78° C. for five minutes. Analytical TLC eluted once with 50% (v/v) EtOAc in hexanes showed the major product spot at Rf =0.35. The reaction mixture was diluted with 20 mL of 1N HCl and the organic material was extracted with EtOAc (20 mL×2). The organic layers were combined, dried over MgSO4, evaporated under reduced pressure, and dried under high vacuum (0.001 mmHg) at ambient temperature overnight (16 hours) to give the title compound which was used in the next step without further purification.
Reaction SMILES: C[N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.N([CH2:33][CH:34]([OH:36])[CH3:35])N>>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[CH:6]=[N:2][N:3]([CH2:33][CH:34]([OH:36])[CH3:35])[C:4]=2[C:13]2[CH:14]=[CH:15][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:29][CH:30]=2)=[CH:12][CH:11]=1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Reactant: CC(O)CNN
Product: CC(O)Cn1ncc(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting 1-hydrazino-propan-2-ol provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J=6.2 Hz, 2 H), 8.23 (d, J=8.7 Hz, 1 H), 8.08 (d, J=8.3 Hz, 1H), 7.84 (m, 2 H), 7.75 (m 2H), 7.57 (t, J=6.6 Hz, 1H), 7.20 (d, J=9.1 Hz, 2H), 7.13 (d, J=8.7 Hz, 2H) 7.00 (dd, J=6.2, 1.7 Hz, 2H), 5.42 (s, 2H), 4.17 (m, 1H), 3.94 (m, 2H), 3.86 (m, 1H), 1.12 (d, J=6.6 Hz, 3H); MS: (M+H m/z=437.3).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[C:30]3[CH:29]=[C:28]4[C:31]5([CH2:37][O:38][C:27]4=[CH:26][C:25]=3[CH2:24][CH2:23]2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[O:21])=[CH:16][CH:15]=1.[CH3:39][O:40][CH2:41][CH2:42]Br>>[CH3:39][O:40][CH2:41][CH2:42][N:34]1[CH2:33][CH2:32][C:31]2([C:28]3[C:27](=[CH:26][C:25]4[CH2:24][CH2:23][N:22]([C:20]([C:17]5[CH:16]=[CH:15][C:14]([C:3]6[CH:4]=[CH:5][C:6]([C:8]7[O:9][C:10]([CH3:13])=[N:11][N:12]=7)=[CH:7][C:2]=6[CH3:1])=[CH:19][CH:18]=5)=[O:21])[C:30]=4[CH:29]=3)[O:38][CH2:37]2)[CH2:36][CH2:35]1
Reactant: Cc1nnc(-c2ccc(-c3ccc(C(=O)N4CCc5cc6c(cc54)C4(CCNCC4)CO6)cc3)c(C)c2)o1
Reactant: COCCBr
Product: COCCN1CCC2(CC1)COc1cc3c(cc12)N(C(=O)c1ccc(-c2ccc(-c4nnc(C)o4)cc2C)cc1)CC3

Procedure:
The title compound was prepared from 5-(2'-methyl-4'-(5-methyl-1,3,4-oxadiazol-2-yl)biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E17 in WO 96/19477) and 2-bromoethyl methyl ether using a similar procedure to Example 2, with a reaction time of 31 hours heating under reflux (33%). Hydrochloride salt m.p. 238-240° C.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:4][C:3]1=2.ClC[C:19](OCC)=[O:20].CC(C)([O-])C.[K+].[Na]>C(O)C.C(OCC)C.O.C(O)(C)(C)C>[CH:19]([CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:4][C:3]1=2)=[O:20]
Reactant: CCOC(=O)CCl
Reactant: CCOC(=O)c1ccc2c(c1)CCCC2=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)c1ccc2c(c1)CCCC2C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
7.6 g of ethyl 5-oxo-5,6,7,8-tetrahydro-2-naphthalenecarboxylate was mixed with 6.4 g of ethyl chloroacetate. The mixture was cooled to 5°-10° C. and then a mixture of 5.9 g of potassium tertiary butoxide and 65 ml of tertiary butanol was added thereto over a period of 1 hour. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo at a temperature not more than 30° C. The residue extracted was with diethyl ether and the extract was washed with water, dried and then concentrated in vacuo to give an oily product. The product was dissolved in 25 ml of ethanol. A solution of 0.58 g of sodium in 25 ml of ethanol, and 0.43 ml of water were added successively to the solution. The mixture was stirred at room temperature for 4 hours. Diethyl ether was added to the reaction mixture and the precipitate formed was collected by filtration. The precipitate was mixed with 10 ml of acetic acid and the mixture was heated at 100° C. for 15 minutes. After cooling, water was added to the raction mixture and the mixture was extracted with diethyl ether. The extract was washed with water, dried and then concentrated in vacuo to give 3.6 g of ethyl 5-formyl-5,6,7,8-tetrahydro-2-naphthalenecarboxylate as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)=[C:11]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:10]=1)[CH3:2].[OH:30][C:31]1[CH:41]=[CH:40][C:34]2[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=2[C:32]=1[CH2:42][CH2:43][CH3:44]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:30][C:31]2[CH:41]=[CH:40][C:34]3[C:35](=[O:39])[CH2:36][CH2:37][O:38][C:33]=3[C:32]=2[CH2:42][CH2:43][CH3:44])=[C:11]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:10]=1)[CH3:2]
Reactant: CCOC(=O)CCCCc1ccc(CCCCCCBr)c(CCC(=O)OCC)c1
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Product: CCCc1c(OCCCCCCc2ccc(CCCCC(=O)OCC)cc2CCC(=O)OCC)ccc2c1OCCC2=O
Yield: 99 %

Procedure:
Starting with 0.505 g (1.08 mmol) of 4-(6-bromohexyl)-3-(3-ethoxy-3-oxopropyl)benzenepentanoic acid ethyl ester from the preceding example, and 0.226 g (1.09 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, the title compound (0.636 g; 99.3%) was obtained as a colorless oil, using the procedure of example 214.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[CH:12][CH:11]=2)O)=[N:4][CH:5]=[CH:6][N:7]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[CH:12][CH:11]=2)[N:24]2[C:20](=[O:30])[C:21]3[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:23]2=[O:25])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OC(c1ccc2cccnc2c1)c1nccnc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C(c1ccc2cccnc2c1)c1nccnc1Cl
Temperature: 0 °C
Reaction time: 21.5 h

Procedure:
To a suspension of (3-chloropyrazin-2-yl)-quinolin-7-ylmethanol (600 mg, 2.21 mmol), phthalimide (356 mg, 2.42 mmol), and PS—PPh3 (loading 2.12 mmol/g; 1.56 g, 3.31 mmol) in dry THF (20 mL), cooled by ice/water, was added DIAD (480 L, 493 mg, 2.44 mmol), then the cooling bath was removed and the flask was vortexed at ambient temperature for 21.5 h. More PS—PPh3 (520 mg, 1.10 mmol) and DIAD (160 μL, 164 mg, 0.81 mmol) were added, and vortexing was continued for 6.5 h. The resin was filtered and washed with THF and CH2Cl2. The crude material was chromatographed on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with hexanes:EtOAc 3:1 (1-14)→2:1 (15-29)→1:1 (30-65)→1:2 (66-80)], yielding the title compound as pale yellow solid; 1H NMR (CDCl3, 400 MHz) δ 7.12 (s, 1H), 7.41 (dd, J=4.4, 8.0 Hz, 1H), 7.54 (dd, J=2.0, 8.4 Hz, 1H), 7.72-7.78 (m, 2H), 7.81-7.89 (m, 3H), 8.01 (d, J=0.8 Hz, 1H), 8.16 (dd, J=0.8, 8.4 Hz, 1H), 8.39 (d, J=2.4 Hz, 1H), 8.50 (d, J=2.4 Hz, 1H), 8.90 (dd, J=1.6, 4.2 Hz, 1H); MS (ES+): m/z 401.0/402.9 (100/38) [MH+].
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([NH:15][CH2:16][CH2:17][N:18]([CH2:34][CH2:35][NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:19]([CH2:21][C@H:22]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23]([OH:25])=O)=[O:20])=[O:14])([CH3:11])([CH3:10])[CH3:9].[NH2:44][C@@H:45]([CH2:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:46]([N:48]([CH3:64])[CH2:49][CH2:50][NH:51][C:52]([C:54]1[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=1)=[O:53])=[O:47]>C(Cl)Cl>[C:40]([O:39][C:37]([NH:36][CH2:35][CH2:34][N:18]([CH2:17][CH2:16][NH:15][C:13]([O:12][C:8]([CH3:9])([CH3:11])[CH3:10])=[O:14])[C:19]([CH2:21][C@H:22]([NH:26][C:27](=[O:28])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[C:23](=[O:25])[NH:44][C@H:45]([C:46](=[O:47])[N:48]([CH3:64])[CH2:49][CH2:50][NH:51][C:52]([C:54]1[CH:55]=[CH:56][C:57]([C:60]([F:62])([F:63])[F:61])=[CH:58][CH:59]=1)=[O:53])[CH2:65][CH2:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)=[O:20])=[O:38])([CH3:41])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)NCCN(CCNC(=O)OC(C)(C)C)C(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN(CCNC(=O)c1ccc(C(F)(F)F)cc1)C(=O)[C@@H](N)CCc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN(CCNC(=O)c1ccc(C(F)(F)F)cc1)C(=O)[C@H](CCc1ccccc1)NC(=O)[C@H](CC(=O)N(CCNC(=O)OC(C)(C)C)CCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 68 %

Procedure:
A solution of CDMT (0.22 g, 1.26 mmol) in DCM (30 mL) was cooled to 0° C. before adding N-methylmorpholine (0.3 mL, 2.62 mmol). After 15 min, (2S)-3-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamoyl]-2-{[(tert-butoxy)carbonyl]amino}propanoic acid CXXIV (0.62 g, 1.20 mmol) was added and the solution was stirred for additional 40 min. After that time, (2S)-2-amino-N-methyl-4-phenyl-N-(2-{[4-(trifluoromethyl)phenyl]formamido}ethyl)butanamide CXXIII (0.56 g, 1.26 mmol) was added and the mixture stirred at r.t. overnight. The mixture was washed with 1 M HCl (5×), 1 M K2CO3 (5×), brine and dried over MgSO4. The solvent was evaporated under vacuum and the residue was purified on a silica gel column (50:1 DCM/methanol) to give tert-butyl N-[(1S)-2-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamoyl]-1-{[(1S)-1-[methyl(2-{[4-(trifluoromethyl)phenyl]formamido}ethyl)carbamoyl]-3-phenylpropyl]carbamoyl}ethyl]carbamate as yellow solid (0.78 g, 0.86 mmol, 68% yield). ESIMS found for C44H64F3N7O10 m/z 908 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([Cl:15])=[C:10]2[O:14][CH:13]=[CH:12][C:11]=12)=[O:5])C.[OH-].[Na+]>CO.O>[Cl:15][C:9]1[CH:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[C:11]2[C:10]=1[O:14][CH:13]=[CH:12]2
Reactant: CCOC(=O)c1ccc(Cl)c2occc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(Cl)c2occc12
Temperature: 55 °C

Procedure:
A mixture of 7-chloro-benzofuran-4-carboxylic acid ethyl ester (3.90 mmol) and sodium hydroxide (5.85 mmol) in MeOH (4.4 mL) and water (4.4 mL) is heated to 55° C. for 90 min. The mixture is concentrated in vacuo and made acidic by addition of hydrochloric acid (1.0 M). The obtained precipitate is filtered off and dried in vacuo to give the desired product. 1H-NMR (DMSO-d6): δ=13.3 (bs, 1H); 8.27 (s, 1H); 7.89 (d, J=8.3 Hz, 1H); 7.56 (d, J=8.3 Hz, 1H); 7.42 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]([CH:17]([CH3:23])[CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH2:13][O:14]2)=[CH:9][CH:8]=1)[CH3:2].C(OO)(=[O:26])C>>[O:26]1[C:20]([CH3:21])([CH3:22])[CH:19]1[CH2:18][CH:17]([CH3:23])[C:3]([CH2:1][CH3:2])=[CH:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][CH2:13][O:14]2)=[CH:9][CH:8]=1
Reactant: CCC(=CCOc1ccc2c(c1)OCCC2)C(C)CC=C(C)C
Reactant: CC(=O)OO
Product: CCC(=CCOc1ccc2c(c1)OCCC2)C(C)CC1OC1(C)C

Procedure:
Following the procedure of Example 17, 7-(3-ethyl-4,7-dimethyl-2,6-octadienyloxy)-chromane and peracetic acid are reacted to form 7-(6,7-epoxy-3-ethyl-4,7-dimethyl-2-octenyloxy)-chromane, nD20 = 1.5287.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:28][NH:29][O:30][CH3:31].C(N(CC)CC)C>ClCCl.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([C:10](=[O:12])[N:29]([O:30][CH3:31])[CH3:28])([CH3:14])[CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)C(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 38.8 %

Procedure:
A mixture of afford 2-tert-butoxycarbonylamino-2-methyl-propionic acid (compound K; 60.0 g) and 1-ethyl-3(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl; 86.4 g) in dichloromethane (900 mL) was stirred at ambient temperature, then N,O-dimethyl hydroxylamine hydrochloride (35.3 g) and triethylamine (150 mL) were added. The resulting mixture was stirred at ambient temperature for 3 days. Water was added and most of volatiles were removed in vacuo. The residue was partitioned between DCM and aqueous NaHCO3. The organic layer was washed with 3M aqueous HCl, subsequently with brine before it was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to give [1-(methoxy-methyl-carbamoyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (compound L; 28.2 g) as a white solid sufficiently pure for the next step.