Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Cl[CH2:9][C:10]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=2)[C:17]2[C:12](=[CH:13][C:14]([O:37][CH3:38])=[C:15]([O:35][CH3:36])[CH:16]=2)[N:11]=1.O>CN(C)C=O>[CH3:36][O:35][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][C:14]=1[O:37][CH3:38])[N:11]=[C:10]([CH2:9][N:3]1[CH:7]=[N:6][CH:5]=[N:4]1)[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]2[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cn2cncn2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.8 %

Procedure:
Oily sodium hydride (60%, 0.323 g) was added to a solution of 1H-1,2,4-triazole (0.558 g) in N,N-dimethylformamide (30 ml), and the mixture was stirred at room temperature for 15 minutes. Then ethyl 2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate(3.0 g) was added. The mixture was stirred at 80° C. for 1 hour, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel. The fractions firstly eluted with chloroform/methanol (40/1, v/v) gave ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylate (1.7 g, 53%) which was then recrystallized from ethyl acetate-hexane. Colorless prisms. mp. 176°-177° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Cl[S:11]([N:14]=C=O)(=[O:13])=[O:12].C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][S:11](=[O:13])(=[O:12])[NH2:14]
Reactant: Oc1cccc(Cl)c1Cl
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: NS(=O)(=O)Oc1cccc(Cl)c1Cl
Yield: 71.9 %

Procedure:
This compound was prepared according to the procedure of Example 56. Thus, a mixture of 16.3 g (0.10 mole) of 2,3-dichlorophenol and 9.1 ml (0.105 mole) of chlorosulfonyl isocyanate in 75 ml of toluene gave 17.4 g (72%) of the title compound as an off-white solid, mp 116°-117° C. (benzene).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@@H:15]([CH2:22][CH2:23][CH3:24])[C:16](N(OC)C)=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(OCC)(=O)C.CCCCCC>O1CCCC1>[CH2:25]([N:14]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C@@H:15]([CH2:22][CH2:23][CH3:24])[CH:16]=[O:17])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCC[C@@H](C(=O)N(C)OC)N(Cc1ccccc1)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To anhydrous tetrahydrofuran (1.5 L) previously cooled to −20° C. to −30° C. was added solid lithium aluminum hydride (33.5 g; 0.882 mol; 120 mole %) slowly with stirring. A solution of (S)-2-(dibenzylamino)-N-methoxy-N-methylpentanamide (6) (250 g; 0.735 mol) in anhydrous tetrahydrofuran (1 L) at −30° C. was slowly added to the above mixture under a nitrogen atmosphere. The reaction was continued for 2 hours at −30° C., monitoring progress of the reaction by TLC analysis (ethyl acetate/hexane, 1:9). Upon completion of the reaction, the excess reagent was quenched by the dropwise addition of ethyl acetate (1 L) and ice-cold water (300 ml) at −30° C. The insoluble salts were filtered through celite, the filtrate diluted with water (3 L), and the product extracted into ethyl acetate (2 L). The combined ethyl acetate layers were washed with water (2 L), dried over sodium sulfate, filtered, and solvent removed under reduced pressure to provide (S)-2-(dibenzylamino)pentanal (7) (195 g) as a light yellow oil, which was used without purification in the next step.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([OH:12])[CH:3]=1.C([Mg]Cl)(C)C.[C:18]1([CH:24]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27](=[O:34])[C:26]2=[O:35])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>ClCCl.O1CCCC1>[C:36]1([CH:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([C:3]3[C:4]([OH:12])=[CH:5][C:6]4[O:11][CH2:10][CH2:9][O:8][C:7]=4[C:2]=3[F:1])([OH:34])[C:26]2=[O:35])[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Oc1cc(F)c2c(c1)OCCO2
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1c(O)cc2c(c1F)OCCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.8 %

Procedure:
A 100 mL round-bottom flask was charged with 8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-ol (6.4 g, 37 mmol) and tetrahydrofuran (60 mL). A 2 M solution of isopropylmagnesium chloride in tetrahydrofuran (20.0 mL, 40.0 mmol) was added at 5° C. and the reaction mixture was stirred for 15 min. The reaction mixture was concentrated in vacuo and dichloromethane (60 mL) was added, followed by a solution of 1-(diphenylmethyl)-1H-indole-2,3-dione (10.9 g, 35.0 mmol) in dichloromethane (60 mL). The reaction mixture was heated at reflux for 5 h, allowed to cool to ambient temperature and stirred for a further 16 h. Saturated aqueous ammonium chloride (30 mL) was added and the phases were separated. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. Trituration of the residue in methanol (30 mL) afforded 1-(diphenylmethyl)-3-(5-fluoro-7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-3-hydroxy-1,3-dihydro-2H-indol-2-one (10.8 g, 64%) as an off-white solid: MS (ES+) m/z 506.0 (M+23).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]([O:28]C(C)(C)C)=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:11]3[CH:33]=[CH:34][CH:35]=[CH:36][C:10]=3[N:9]=2)[N:3]=1.FC(F)(F)C(O)=O>>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[C:21]([C:26]([OH:28])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][CH:19]=3)[C:11]3[CH:33]=[CH:34][CH:35]=[CH:36][C:10]=3[N:9]=2)[N:3]=1
Reactant: Cc1cc(C)n(-c2nc3ccccc3n2Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)n(-c2nc3ccccc3n2Cc2ccc(-c3ccccc3C(=O)O)cc2)n1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-(3,5-dimethyl-pyrazol-1-yl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: [C:1]1(C)C=CC=C[CH:2]=1.C(OCC)(=O)C.[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH:25]=[O:26])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([CH:25]([OH:26])[CH2:1][CH3:2])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1ccccc1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Solvent: CCOC(C)=O
Product: CCC(O)c1ccc(OC)c(OCc2ccccc2)c1
Reaction time: 0.08 h

Procedure:
To a three-neck flask, 187 ml of a 30M ethyl magnesium bromide ether solution was poured and stirred for 5 minutes under ice cooling. To this solution, 400 ml of a toluene solution in which 123.51 g of 3-benzyloxy-4-methoxybenzaldehyde was dissolved, and the mixture was added dropwise from a dropping funnel over 20 minutes. The reaction solution was stirred for additional 2 hours under ice cooling. After the completion of the reaction, the reaction solution was diluted by adding 300 ml of ethyl acetate. Further, pulverized sodium sulfate decahydrates was added to the reaction solution, which was stirred for 2 hours until a precipitate becomes smoothly. After allowed to stand still for 3 hours, the reaction solution was filtered under reduced pressure, separating into a supernatant and a precipitate. The supernatant was concentrated to dryness, affording 140.57 g of 1-(3'-benzyloxy-4'-methoxyphenyl) propanol.
Reaction SMILES: Br[C:2]1[CH:40]=[CH:39][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]2([C:34]([O:36]CC)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:4][CH:3]=1.[S:41]1[CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[N:43]=[CH:42]1>>[N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][C:18]=1[CH2:17][O:16][C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH2:6][C:5]3[CH:39]=[CH:40][C:2]([C:44]4[N:43]=[CH:42][S:41][CH:45]=4)=[CH:3][CH:4]=3)[C:8]([CH2:28][C:29]3([C:34]([OH:36])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]3)=[N:9][C:10]=2[CH:15]=1
Reactant: CCOC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)CCCC1
Reactant: CC1(C)OB(c2cscn2)OC1(C)C
Product: O=C(O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(-c3cscn3)cc2)CCCC1

Procedure:
The title compound was prepared using similar methods to those in Example 97 using ethyl 1-((1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate and thiazole-4-boronic acid pinacol ester in Step A. MS (ESI): mass calcd. for C34H30N4O3S, 574.20; m/z found, 575.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.90-8.86 (m, 1H), 8.21 (d, J=8.5 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 7.88 (d, J=8.3 Hz, 2H), 7.86-7.82 (m, 1H), 7.78-7.72 (m, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.59-7.54 (m, 1H), 7.54-7.51 (m, 1H), 7.40-7.35 (m, 1H), 7.22-7.17 (m, 1H), 7.13-7.05 (m, 3H), 5.43 (s, 2H), 5.38 (s, 2H), 3.14 (s, 2H), 2.38-2.28 (m, 2H), 1.76-1.67 (m, 2H), 1.58-1.49 (m, 4H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.BrC[CH2:24][O:25][C:26]1[C:31]([O:32][CH2:33][CH2:34][CH:35]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[CH3:36])=[C:30]([O:44][CH3:45])[C:29]([Cl:46])=[C:28]([CH3:47])[C:27]=1[C:48](=[O:50])[CH3:49].C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl.CN(C=O)C.O>[Cl:46][C:29]1[C:28]([CH3:47])=[C:27]([C:48](=[O:50])[CH3:49])[C:26]([O:25][CH2:24][CH2:1][N:8]2[CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][CH2:13]2)=[C:31]([O:32][CH2:33][CH2:34][CH:35]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[CH3:36])[C:30]=1[O:44][CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCN2CCC(O)CC2)c1OCCC(C)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 0.1 h
Yield: 47.8 %

Procedure:
To a solution of N—BOC-4-hydroxypiperidine (42 mg, 0.21 mmol) in DCM (1 mL) was added TFA (1 mL) at room temperature and the solution was stirred for 0.1 h. The reaction mixture was concentrated under vacuum and dried on the high vacuum pump for 1 h. Example 8a (100 mg, 0.21 mmol) was added and the mixture was suspended in DMF. Cs2CO3 (123 mg, 0.38 mmol) was added in one portion and the solution was heated at 60° C. overnight. The reaction mixture was cooled to room temperature and diluted with water (20 mL) and extracted with EtOAc (3×15 mL), dried over MgSO4 and concentrated under vacuum. The crude material was purified by flash chromatography (silica-gel, MeOH/DCM 1:49) yielding the title compound (51 mg, 47%) as a clear brown oil. 1H NMR (300 MHz, CDCl3) δ 7.20-7.15 (m, 2H), 7.01-6.95 (m, 2H), 4.12 (m, 2H), 3.95 (t, J=6.6 Hz, 2H), 3.83 (s, 3H), 3.01-2.90 (m, 1H), 2.96-2.68 (m, 4H), 2.50 (s, 3H), 2.18 (s, 3H), 2.05-1.93 (m, 4H), 1.60-1.53 (m, 4H), 1.29 (d, J=6.9 Hz, 3H). MS (ES+) m/z 508 (M+H+).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C@@H:3]([OH:21])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH2:6]1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1.Cl>C(#N)C>[ClH:24].[F:23][C:2]([F:1])([F:22])[C@@H:3]([O:21][C:32](=[O:33])[NH:31][C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1)[CH2:4][N:5]1[CH2:10][CH2:9][O:8][C@H:7]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=2)[CH2:6]1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O[C@@H](CN1CCOC(c2ccc(C(F)(F)F)cc2)C1)C(F)(F)F
Agent: Cl
Solvent: CC#N
Product: O=C(Nc1ccc(Cl)cc1)O[C@@H](CN1CCO[C@H](c2ccc(C(F)(F)F)cc2)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
(S)-1,1,1-Trifluoro-3-[2-(4-trifluoromethyl-phenyl)-morpholin-4-yl]-propan-2-ol (52 mg, 151 μmol) and 1-chloro-4-isocyanatobenzene (25.6 mg, 167 μmol) were combined in acetonitrile (2 mL). The mixture was stirred at room temperature overnight and evaporated. The residue was purified by flash chromatography (20% EtOAc/hexanes) to provide the front-running isomer, which was converted to the HCl salt to afford (4-chloro-phenyl)-carbamic acid (S)-2,2,2-trifluoro-1-[(R)-2-(4-trifluoromethyl-phenyl)-morpholin-4-ylmethyl]-ethyl ester hydrochloride as a white solid (30 mg). (M+H)+=497 m/e.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[C:7](=[O:15])[NH:6]2.[N+:16]([O-])([O-:18])=[O:17].[K+]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:16]([O-:18])=[O:17])[N:9]([CH3:13])[C:8](=[O:14])[C:7](=[O:15])[NH:6]2
Reactant: COc1ccc2c(c1)[nH]c(=O)c(=O)n2C
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1cc2[nH]c(=O)c(=O)n(C)c2cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
To a solution of 0.2 g (0.97 mmol) 6-methoxy-1-methylquinoxaline-2,3(1H,4H)-dione in 10 ml concentrated sulfuric acid was added at 0° C. 0.1 g (0.99 mmol) potassium nitrate. Stirring was continued at 0° C. for 30 min., and then at 25° C. for 1 h. The reaction mixture was poured into 50 ml ice-water to give a precipitate Recrystallization (dimethylformamide-water) of the crude product gave 0.15 g (62%) 6-methoxy-1-methyl-7-nitroquinoxaline-2,3(1H,4H)-dione. M.p. 356° C. NMR (DMSO-d6): 12.0 (1H, broad s), 7.77 (1H, s), 3.90 (3H, s), 3.47 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:22][CH:21]=2)=[CH:13][CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].C1COCC1.O.[OH-].[Li+]>CCOC(C)=O>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:24][CH:25]=2)=[CH:15][CH:16]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCO[C@@H](Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To the oil of ethyl (S)-2-ethoxy-3-[4(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoate (723 g (71.2% assay), 1.18 mol. 1.0 eq) was added THF (3900 ml). When a homogenous solution was formed, water (900 ml) was added. The mixture was cooled to +10° C. Lithium hydroxide solution (390 ml, 4 M, 1.32 eq) was added over 1 hour. The temperature was then raised to +30° C. and the reaction allowed to proceed at this temperature for 2-3 hours. The reaction was stopped when the conversion was >99%. EtOAc (500 ml) was added and the mixture cooled to room temperature. The solution was stirred for about 30 minutes and the THF was evaporated off. When about 80-90% of the THF was evaporated, water (1900 ml) was added. The evaporation was continued until no THF remained in the mixture. The alkaline water solution was then washed with EtOAc (1000 ml, 2×1250 ml, and 950 ml). The pH of the water solution of (S)-2-ethoxy-3-[4(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid was then adjusted to 2.0-2.5 with HCl (aq) (550 ml, 3.0 M). EtOAc (2500 ml) was added and the phases separated. The ethyl acetate solution of (S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid was then washed with water (700 ml) and after separation evaporated to dryness. The remaining oil was then used in the following crystallisation.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:11])[NH:9][OH:10])([CH3:6])([CH3:5])[CH3:4].[CH3:12][N:13]([CH3:17])[C:14](Cl)=[O:15].O>CN(C)C=O.O1CCCC1>[C:3]([O:7][C:8](=[O:11])[NH:9][O:10][C:14]([N:13]([CH3:17])[CH3:12])=[O:15])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)NO
Reactant: CN(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)ONC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
To a suspension of sodium hydride (865 mg) in dimethylformamide (12 mL) and tetrahydrofuran (15 mL) was added t-butyl-N-hydroxycarbamate (2.5 g) on an ice bath. After stirring for 30 minutes, dimethylcarbamoyl chloride (2.32 g) was added and was stirred for 1 hour. Water was added to the reaction solution, and the solution was extracted with ethyl acetate. The solid that was obtained by drying the organic layer and removing the solvent by evaporation was washed with hexane, and a colorless solid (3.18 g) were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[CH2:15]([CH:17]([NH2:31])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])[CH3:16].C1(C)C=CC=CC=1.C(C(N1C(=O)C2=C(N=[N+]=[N-])C=CC=C2C1=O)CCCCCCCCC(C)(C)CO)C>CN(C)C=O>[CH2:15]([CH:17]([N:31]1[C:10](=[O:11])[C:5]2=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]1=[O:9])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28])[CH3:16]
Reactant: CCC(N)CCCCCCCCC(C)(C)CO
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Agent: CCC(CCCCCCCCC(C)(C)CO)N1C(=O)c2cccc(N=[N+]=[N-])c2C1=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCC(CCCCCCCCC(C)(C)CO)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Yield: 99.9 %

Procedure:
The starting material used in the above example can be prepared as follows: A mixture of 9.6 g (0.05 mol) of 3-nitrophthalic anhydride, 12.9 g (0.055 mol) of 1-ethyl-10,10-dimethyl-11-hydroxy-1-aminoundecane, 150 ml of toluene and 250 ml of dimethylformamide is heated to the boil, the water formed being removed azeotropically. The reaction mixture is then evaporated to dryness. The residue is dissolved in 150 ml of methylene chloride and the solution is extracted with three times 50 ml of 10% sodium carbonate solution. The methylene chloride solution is then dried over anhydrous sodium sulphate and evaporated. 20.9 g (about 100% of theory) of N-(1-ethyl-10,10-dimethyl-11-hydroxyundecyl)-3-nitrophthalimide are obtained in the form of a viscous oil which gradually crystallises after standing for several weeks; melting point 66°-68° C.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCC/C=C\C/C=C\CCCCCCCC=O
Reaction time: 4 h
Yield: 70.9 %

Procedure:
A solution of linoleyl alcohol (15 g, 56 mmol) in anhydrous CH2Cl2 (400 mL) was treated with pyridinium chlorochromate (36.4 g, 169 mmol) and Na2CO3 (2.98 g, 28.2 mmol) and then stirred (4 h). The reaction mixture was diluted with EtOAc and filtered through a pad of silica and then concentrated. The crude material was subjected to chromatography (1%→3%→6% EtOAc-heptane) to yield (9Z,12Z)-octadeca-9,12-dienal (10.5 g, 71%) as a colorless oil. Rf 0.58 (10% EtOAc-hexanes), FW 264.45, C18H32O.
Reaction SMILES: [SH:1][C:2]1[S:6][C:5]([S:7][CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][O:11][C:10]3[CH:19]=[CH:20][C:21]([C:23]([O:25][CH3:26])=[O:24])=[CH:22][C:9]2=3)=[N:4][N:3]=1.[CH2:27](Br)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:44]([S:1][C:2]1[S:6][C:5]([S:7][CH:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][O:11][C:10]3[CH:19]=[CH:20][C:21]([C:23]([O:25][CH3:26])=[O:24])=[CH:22][C:9]2=3)=[N:4][N:3]=1)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH3:27]
Reactant: COC(=O)c1ccc2c(c1)C(Sc1nnc(S)s1)c1ccccc1CO2
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCSc1nnc(SC2c3ccccc3COc3ccc(C(=O)OC)cc32)s1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
After 50 ml of an N,N-dimethylformamide solution containing a mixture of 2.0 g of Compound 153a obtained in Example 119, 2 ml of octadecyl bromide and 2.0 g of potassium carbonate was stirred at 80° C. at 1.5 hours, the solvent was distilled off under reduced pressure. The aqueous phase was extracted with 200 ml of methylene chloride. The extract was washed with saturated sodium chloride aqueous solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluting solvent; hexane:ethyl acetate=15:1) to give 0.8 g of the product.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][CH:13]([CH3:27])[C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=1)=[O:15].[C:28]([N:35]1[CH2:40][CH2:39][CH:38]([C:41](O)=[O:42])[CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].CN1CCOCC1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CCOC(C)=O.CN(C)C=O>[C:31]([O:30][C:28]([N:35]1[CH2:40][CH2:39][CH:38]([C:41](=[O:42])[NH:12][CH:13]([CH3:27])[C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([C:23]([F:26])([F:24])[F:25])[CH:17]=2)=[O:15])[CH2:37][CH2:36]1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(N)C(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(NC(=O)C1CCN(C(=O)OC(C)(C)C)CC1)C(=O)c1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
Add dimethylformamide (20 mL) is to a mixture of 2-amino-1-(4-fluoro-3-trifluoromethyl-phenyl)-propan-1-one toluene-4-sulfonic acid salt (900 mg; 1.00 equiv; 2.21 mmoles) and 1-Boc-piperidine-4-carboxylic acid (Boc-Inp-OH) (613.96 mg, 1.20 equiv; 2.65 mmoles) at room temperature. Add N-methylmorpholine (6.00 equiv; 13.26 mmoles; 1.46 mL) to the above solution, then 1-propanephosphonic acid cyclic anhydride (1.50 equiv; 3.31 mmoles; 862.14 μL) at 0° C. Warm the mixture to room temperature while stirring for one hour. Dilute the mixture with EtOAc, wash with water, 1M citric acid, water, saturated NaHCO3, and saturated aqueous sodium chloride and dry over Na2SO4. Purify the residue by dissolving in CH2Cl2, loading onto a silica gel column and eluting with EtOAc to give 500 mg (51%) of the title compound.