Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[C:5]([CH3:13])=[C:4]([Cl:14])[CH:3]=1.CO[CH2:17][Cl:18].OS(O)(=O)=O>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:11])([F:10])[F:12])[C:5]([CH3:13])=[C:4]([Cl:14])[C:3]=1[CH2:17][Cl:18]
Reactant: COCCl
Reactant: Cc1c(Cl)cc(Cl)cc1OC(F)(F)F
Agent: O=S(=O)(O)O
Product: Cc1c(OC(F)(F)F)cc(Cl)c(CCl)c1Cl
Temperature: 20 °C
Yield: 92.9 %

Procedure:
1,3-Dichloro-5-(trifluoromethoxy)-4-methylbenzene (8.0 g, 33 mmol) and 5.0 g (78 mmol) of chloromethyl methyl ether were added to 50 ml of H2SO4 (98%) with stirring at 20° C. The temperature rose slowly to 30° C. The mixture was stirred for 15 hours, then poured into 200 ml of ice water and extracted with 2×100 ml portions of hexane. The hexane extracts were combined, washed with 100 ml of water, dried (MgSO4), filtered, and concentrated. The residue was dissolved in 50 ml of hexane, filtered and concentrated. The resulting white solid was dried (25° C./0.001 mm) to give 9.0 g of 1,3-dichloro-2-chloromethyl-4-methyl-5-(trifluoromethoxy)benzene.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]1(=[O:16])[NH:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N>CCOC(C)=O.[Cu]I.O1CCOCC1>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([N:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:16])=[CH:8][C:2]=1[F:1]
Reactant: Nc1ccc(I)cc1F
Reactant: O=C1CCCCN1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1ccc(N2CCCCC2=O)cc1F

Procedure:
2-Fluoro-4-iodoaniline (10.0 g, 42.2 mmol) was combined with δ-valerolactam (6.27 g, 63.3 mmol), CuI (0.804 g, 4.22 mmol), and K3PO4 (22.4 g, 105 mmol). 1,4-Dioxane (60 mL) was added followed by trans-1,2-diaminocyclohexane (1.01 mL, 8.44 mmol). The mixture was heated to reflux for 22 h before cooling and diluting with EtOAc. The mixture was filtered through a plug of silica, eluting with EtOAc, and the filtrate concentrated under reduced pressure. Purification of the crude product by flash chromatography revealed 7 (3.40 g, 39%) as a brown solid. MS: APCI (AP+): 209.1 (M)+.
Reaction SMILES: S(Br)([Br:3])=O.[C:5]([OH:14])(=O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>O>[C:5]([Br:3])(=[O:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=S(Br)Br
Reactant: CCCCCCCC(=O)O
Solvent: O
Product: CCCCCCCC(=O)Br
Temperature: 50 °C

Procedure:
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 10.07 ml (130 mmol) of thionyl bromide, and a water condenser, is placed 10.30 ml (65 mmol) of octanoic acid. Addition of the thionyl bromide is completed with heating to about 50° C. over the course of about 50 minutes. When addition of the thionyl bromide is complete the mixture is heated and stirred for an additional hour. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl bromide, octanoyl bromide. This acyl bromide, 4.88 g (30 mmol), is put into a dry separatory funnel and combined with 25 ml of dry dichloromethane for use in the next step of the reaction.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:25])[C@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:16]=[CH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([Si:29]([CH3:32])([CH3:31])[CH3:30])C=C.C(Cl)(Cl)Cl>C(Cl)Cl.Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:25])[C@H:15]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)/[CH:16]=[CH:17]/[CH2:26][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[Si](C)(C)C
Reactant: C=C[C@@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C[Si](C)(C)C/C=C/[C@@H](Cc1ccccc1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1

Procedure:
To a solution of (4R)-4-benzyl-3-[(2R)-2-benzylbut-3-enoyl]-1,3-oxazolidin-2-one (3.42 mmol, 1.10 g) and allyltrimethylsilane (10.26 mmol, 1.63 mL) in DCM (50 mL) at reflux was added 5 mol % of Grubbs' second generation catalyst (145 mg). After 68 hrs the solvent was removed in vacuo. The crude product was purified by column chromatography to yield a white solid. (1.37 g, 95%); 1H NMR (400 MHz, CDCl3): δ=7.0-7.32 (m, 10H), 5.62 (dt, J=8.1, 15.2, 1H), 5.29-5.36 (m, 1H), 4.82 (m, 1H), 4.61 (m, 1H), 4.01-4.15 (m, 2H), 3.22 (dd, J=8.3, 13.4, 1H), 3.02 (dd, J=3.3, 13.3, 1H), 2.85 (dd, J=6.1, 13.4, 1H), 2.57 (dd, J=9.1, 13.4, 1H) 1.42 (d, J=8.1, 1H) −0.08 (s, 9H); 13C NMR (100 MHz, CDCl3): δ=174.2, 138.9, 135.1, 131.6, 129.4, 128.9, 128.3, 127.2, 126.3, 124.9, 65.7, 55.2, 48.2, 38.9, 37.6, 23.1, −2.1; IR (CHCl3): v 3444, 2955, 1767, 1694, 1454, 1393, 1248, 1182 cm−1; MS (CI(NH3)): m/z 422 (M+H+); HMRS required for C25H32NO3Si ([M]+) 422.2158 found 422.2151; [α]D23=117.8° (c, 0.5 CHCl3); Mp 132-135° C.
Reaction SMILES: [F-:1].[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.C(#N)C.[N+]([C:35]1[CH:36]=[C:37]2[C:42](=[O:43])[O:41][C:39](=[O:40])[C:38]2=[CH:44][CH:45]=1)([O-])=O>C(Cl)Cl>[F:1][C:35]1[CH:36]=[C:37]2[C:42](=[O:43])[O:41][C:39](=[O:40])[C:38]2=[CH:44][CH:45]=1
Reactant: [F-]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Agent: [K+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CC#N
Solvent: ClCCl
Product: O=C1OC(=O)c2cc(F)ccc21
Temperature: 82 °C
Yield: 75.3 %

Procedure:
To a reaction vessel equipped with a reflux condenser, nitrogen inlet and oil bath were introduced 2.008 grams (0.035 mol) anhydrous potassium fluoride, 0.458 gram (0.0013 mol) dibenzo-18-crown-6, and 20 ml. dry acetonitrile. This mixture was refluxed at about 82°C. for 30 minutes, and thereafter 3.011 grams (0.016 mol) 4-nitrophthalic anhydride was added and the mixture refluxed for an additional 43 hours. After cooling to room temperature, methylene chloride was added to the reaction mixture, and the latter filtered to remove solid material. Concentration of the filtrate under vacuum yielded 2 grams of 4-fluorophthalic anhydride containing a small amount of the dibenzo-18-crown-6. To remove this latter crown ether, the material was dissolved in aqueous potassium hydroxide, extracted with ethyl acetate, and acidified with hydrochloric acid to a pH 1. Extraction with ethyl acetate yield 1.195 grams (42% yield) of pure 4-fluorophthalic acid which can be dehydrated to yield 4-fluorophthalic anhydride.
Reaction SMILES: [OH:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH2:5][N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[S:7]([CH3:10])(=[O:9])=[O:8].[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(OCC)C>[C:25]([O:1][CH:2]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:3][CH2:4][CH2:5][N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[S:7]([CH3:10])(=[O:8])=[O:9])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(O)CCCN(CCCCCCC(=O)O)S(C)(=O)=O
Solvent: CCOCC
Product: CCCCCC(CCCN(CCCCCCC(=O)O)S(C)(=O)=O)OC(C)=O
Temperature: 60 °C

Procedure:
A mixture of 7-[N-4-hydroxynonyl)methanesulfonamido]heptanoic acid (10.9 g., 0.03 mole) (Example 1, Step B) and acetic anhydride (6.1 g., 0.06 mole) is heated at 60° C. for 18 hours. The mixture is cooled and taken up in 80 ml. of ethyl ether. The solution is extracted with an ice-cold solution of 8 g. of sodium hydroxide in 150 ml. of water. The basic solution is separated and acidified with concentrated hydrochloric acid. The crude product that separates is extracted into ether, washed with water and dried over sodium sulfate. The ether is evaporated and the residual oil is purified by chromatography on silica gel using 2% methanol in chloroform as the eluting solvent. There is obtained 7-[N-(4-acetoxynonyl)methanesulfonamido]heptanoic acid as a viscous oil.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].I[C:38]1[CH:43]=[CH:42][NH:41][C:40](=[O:44])[CH:39]=1>>[CH3:36][C:2]([CH3:1])([CH2:5][C@@:6]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([C:38]3[CH:43]=[CH:42][NH:41][C:40](=[O:44])[CH:39]=3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Reactant: O=c1cc(I)cc[nH]1
Product: C[C@@H](c1ccc(-c2cc[nH]c(=O)c2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile and 4-iodopyridin-2(1H)-one following a procedure analogous to that described in Example 4. LC-MS Method 1 tR=1.36 min, m/z=456(M+1); 1H NMR (CDCl3) 7.77 (d, 1H), 7.43-7.32 (m, 7H), 7.01 (t, 4H), 5.67 (q, 1H), 2.99 (dd, 1H), 2.57-2.43 (m, 2H), 2.32 (m, 1H), 2.17 (s, 2H), 1.57 (d, 3H), 1.40 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[CH3:32][O:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O)=[O:35]>COCCOC>[CH3:32][O:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])=[O:35]
Reactant: COC(=O)c1ccccc1B(O)O
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccccc1-c1cc(F)ccc1OCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 14.1 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-methoxycarbonylphenyl boronic acid (33 mg, 0.183 mmol) and Pd[PPh3]4 (27 mg, 0.0244 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was purified first on a silica gel column with a 20-30% ethyl acetate/hexanes gradient and then by RP HPLC to afford the product as a white solid (8 mg, 14%). MS m/e 465.23 (M+H+)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][CH2:19][O:20][CH3:21]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][CH2:19][O:20][CH3:21])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
To a mixture of 4-bromophenol (15 g), sodium iodide (13.0 g) and potassium carbonate (14.4 g) in DMF (200 ml) was added at room temperature 2-chloroethylmethyl ether (9 ml), and the mixture was stirred at 80° C. for 3 days. To the mixture was added water, and the mixture was extracted with diethylether. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give orange oil of 1-bromo-4-(2-methoxyethoxy)benzene (17.44 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[SH:11].C(O)C>C(O)(=O)C>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([SH:11])=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1S
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cc(N)ccc1S
Reaction time: 40 h
Yield: 31.3 %

Procedure:
To a solution of 2-methyl-4-nitrothiophenol (7.0 g) in acetic acid (100 ml) was added reduced iron (21.0 g) and the mixture was stirred for 40 hours. Ethanol was added to the mixture, and the insolubles were filtered off, and the solvent was distilled off under reduced pressure. To the obtained residue was added water, and the solution was neutralized with an aqueous solution of saturated sodium bicarbonate, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (hexane-ethyl acetate=3:1→hexane:ethyl acetate=0.2:1), to give 4-amino-2-methylthiophenol (1.8 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]([C:18](=[O:20])[CH3:19])[CH:15]=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:32](O)[CH2:33][OH:34]>>[CH3:19][C:18]1([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:10]3[CH:9]=[N:8][N:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:11]=3)[N:17]=2)[O:34][CH2:33][CH2:32][O:20]1
Reactant: CC(=O)c1cccc(-c2cnn(-c3cccnc3)c2)n1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1(c2cccc(-c3cnn(-c4cccnc4)c3)n2)OCCO1

Procedure:
In 100 ml of 1,1-benzotrifluoride, 0.13 g (0.49 mmol) of 1-[6-(1-pyridin-3-yl-1H-pyrazol-4-yl)pyridin-2-yl]ethanone, 0.1 g (0.58 mmol) of 4-toluenesulphonic acid and 1.8 ml (32 mmol) of 1,2-ethanediol were heated under reflux in a reflux apparatus with Soxleth extractor which had been charged with 4 Å molecular sieve for 2 h. The reaction mixture concentrated by evaporation, ethyl acetate, dil. aqueous sodium hydroxide solution, citrate buffer to pH=9 and also aq. NaCl were added to the residue, the aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried with MgSO4 and concentrated by evaporation. The residue was purified by chromatography on silica gel (petroleum ether/acetone).
Reaction SMILES: [Cl-].[Cl-].C(O)(O)C.CS(C)=O.[OH:11][CH:12]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:23]([O:38][CH3:39])=[CH:22][N:21]=1)[CH2:13][N:14]1[CH:18]=[CH:17][NH:16][C:15]1=[O:19].C(N(CC)CC)C>C(Cl)Cl.O>[CH3:39][O:38][C:23]1[C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:25][C:20]([C:12](=[O:11])[CH2:13][N:14]2[CH:18]=[CH:17][NH:16][C:15]2=[O:19])=[N:21][CH:22]=1
Reactant: COc1cnc(C(O)Cn2cc[nH]c2=O)cc1OCCCCCc1ccccc1
Agent: CC(O)O
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1cnc(C(=O)Cn2cc[nH]c2=O)cc1OCCCCCc1ccccc1
Reaction time: 0.08 h
Yield: 65 %

Procedure:
Reaction under N2. A solution of ethanediol dichloride (0.0210 mol) in CH2Cl2 (40 ml) was stirred at −60° C. A solution of dimethyl sulfoxide (0.0420 mol) in CH2Cl2 (10 ml) was added dropwise and stirring was continued for 5 min at −60° C. A solution of 1,3-dihydro-1-[2-hydroxy-2-[5-methoxy-4-[(5-phenylpentyl)oxy]-2-pyridinyl]ethyl]-2H-imidazol-2-one (compound 18) (0.0070 mol) in CH2Cl2 (10 ml) was added dropwise at −60° C. and stirring was continued for 15 min at −60° C. Triethylamine (0.0770 mol) was added dropwise at −60° C. and stirring was continued for 5 min. The mixture was treated with water, then extracted with CH2Cl2. The separated organic layer was dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 94/6). The pure fractions were collected and the solvent was evaporated, yielding 1.8 g (69.6%) of 1,3-dihydro-1-[2-[5-methoxy-4-[(5-phenylpentyl)oxy]-2-pyridinyl]-2-oxoethyl]-2H-imidazol-2-one (interm. 11).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:36])[N:20]([C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=3)[CH3:21])[C@H:14]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([Cl:44])[CH:38]=3)[CH2:13]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH2:45](I)[CH3:46]>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:12]2[CH2:17][CH2:16][C@@H:15]([N:18]([CH2:45][CH3:46])[C:19]([N:20]([C:22]3[CH:23]=[C:24]([C:32]([F:35])([F:33])[F:34])[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=3)[CH3:21])=[O:36])[C@H:14]([C:37]3[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([Cl:44])[CH:38]=3)[CH2:13]2)=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CCI
Reactant: CC(=O)N1CCC(C(=O)N2CC[C@@H](NC(=O)N(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1
Product: CCN(C(=O)N(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CCN(C(=O)C2CCN(C(C)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
By reaction and purification in the same manner as in the method described in Example 2 and using the compound obtained in Example 40 and ethyl iodide, the title compound was obtained.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH3:8][NH:9][C:10](=[O:47])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:32]1[NH:33][C:34]([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=2)=[CH:35][NH+:36]=1)[NH:17][C:18](C1CCCN(C2C=CC=CN=2)C1)=[O:19].CCN(C(C)C)C(C)C.[CH2:57]([N:64]=C=O)[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH2:57]([NH:64][C:18]([NH:17][C@H:16]([C:32]1[NH:33][C:34]([C:37]2[CH:46]=[CH:45][C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=2)=[CH:35][NH+:36]=1)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]([NH:9][CH3:8])=[O:47])=[O:19])[C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1
Reactant: O=C=NCc1ccccc1
Reactant: CNC(=O)CCCCC[C@H](NC(=O)C1CCCN(c2ccccn2)C1)c1[nH]c(-c2ccc3ccccc3c2)c[nH+]1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)CCCCC[C@H](NC(=O)NCc1ccccc1)c1[nH]c(-c2ccc3ccccc3c2)c[nH+]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The amine from Example 327, BB2 (1 eq.) was dissolved in DCM, then DIPEA (1 eq.) and benzyl isocyanate were added. After stirring for 1 hr at RT the solvent were removed under reduced pressure and the crude was purified by preparative RP-HPLC, using H2O (0.1% TFA) and MeCN (+0.1% TFA) as eluents (column: C18). The desired fractions were lyophilized to afford the titled compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 8.36 (1H, s), 8.16 (1H, s), 8.07 (1H, d, J=8.6 Hz), 8.02-7.93 (2H, m), 7.91 (1H, dd, J=8.6 Hz, J2=1.5 Hz), 7.71-7.55 (3H, m), 7.35-7.19 (5H, m), 6.75-6.67 (2H, m), 4.97-4.87 (1H, m), 4.30-4.15 (2H, m), 2.53 (3H, d, J=4.6 Hz), 2.04 (2H, t, J=7.4 Hz), 1.97-1.83 (2H, m), 1.55-1.44 (2H, m), 1.42-1.22 (4H, m). MS (ES) C29H33N5O2 requires: 483, found: 484 (M+H)+.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[O:4]1[CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:5]1.S(=O)(=O)(O)O.[CH2:28]([OH:32])[CH:29]([OH:31])[CH3:30].O1C(CCCCCCCCCC)C1.C(=O)([O-])O.[Na+]>>[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:31][CH2:29][CH2:28][OH:32].[CH2:28]([OH:32])[CH:29]([OH:31])[CH3:30]
Reactant: CCCCCCCCCCCCCCCCC1CO1
Agent: CCCCCCCCCCC1CO1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(O)CO
Product: OCCCCCCCCCCCCCCCCCCOCCO
Temperature: 72.5 °C
Reaction time: 0.25 h
Yield: 96.7 %

Procedure:
Separately, a 1.0 liter mixing vessel equipped with a calcium chloride-containing tube was charged with 402.7 g (1.50 moles) of 1,2-epoxyoctadecane. While the charged 1,2-epoxyoctadecane was stirred at room temperature, a concentrated sulfuric acid was gradually dropped in an amount of 2.7 g (0.027 mole) into 1,2-epoxyoctadecane. After stirring for 15 minutes, the resultant mixture was placed into the dropping apparatus attached to the reaction vessel and was dropped into the 1,2-propanediol contained in the reaction vessel and maintained at a temperature of 70 to 75° C. over a time of 2 hours. Then the reaction of the mixture was carried out at a temperature of 70 to 75° C. for one hour. After the exhaustion of the starting material, namely 1,2-epoxydodecane was confirmed by a thin-layer chromatography, the reaction was stopped. A powdered sodium hydrogen carbonate was mixed in an amount of 2.5 g (0.03 mole) into the resultant reaction liquid in the reaction vessel, the resultant mixture was stirred for 30 minutes to neutralize the reaction liquid. From the reaction liquid, the precipitated crystals were separated by filtration. A 1,2-propanediol monohydroxyoctadecyl ether mixture was obtained in an amount of 510.9 g (yield: 96.7%).
Reaction SMILES: [CH:1]([C:4]([CH:18]([CH3:20])[CH3:19])([P:14]([OH:17])([OH:16])=[O:15])[O:5][C@@H:6]([CH:12]=[CH2:13])[CH2:7][O:8]COC)([CH3:3])[CH3:2].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CO>[CH:18]([C:4]([CH:1]([CH3:3])[CH3:2])([P:14]([OH:17])([OH:16])=[O:15])[O:5][C@@H:6]([CH:12]=[CH2:13])[CH2:7][OH:8])([CH3:19])[CH3:20]
Reactant: C=C[C@@H](COCOC)OC(C(C)C)(C(C)C)P(=O)(O)O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CO
Product: C=C[C@@H](CO)OC(C(C)C)(C(C)C)P(=O)(O)O
Yield: 92.2 %

Procedure:
(S)-2-O-(Diisopropyl phosphonomethyl)-1-O-methoxymethyl-3-butene-1,2-diol (3.45 g, 11.12 mmol) and camphorsulfonic acid (0.2 g, 0.8 mmol) were mixed in 45 mL of methanol. The resulting solution was heated at reflux for 5 hours. The solvent was evaporated, and the residue was purified by flash chromatography (ethyl acetate:petroleum ether=1:1 to 1:0 then ehtyl acetate:methanol 20:1) to give 2.73 g (92%) of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2](=[O:11])[CH2:3][C:4]([CH3:10])([CH3:9])[CH2:5][C:6]([OH:8])=[O:7].[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[NH2:1][C:2](=[O:11])[CH2:3][C:4]([CH3:9])([CH3:10])[CH2:5][C:6]([O:8][CH3:12])=[O:7]
Reactant: CC(C)(CC(N)=O)CC(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CC(C)(C)CC(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Amino-3,3-dimethyl-5-oxopentanoic acid (10.9 g; 68.6 mmoles) was dissolved in DMF (50 mL). Potassium carbonate (14.2 g; 103 mmoles) and methyl iodide (8.5 mL; 137.2 mmoles) were added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered, washing the filter cake with DMF. The DMF was removed under vacuum and the residue was suspended in ethyl acetate. The solids were removed by filtration and the ethyl acetate was removed under vacuum to give the product, methyl 5-amino-3,3-dimethyl-5-oxopentanoate, as a yellow oil (11.5 g; 97%). 1H NMR (400 MHz) DMSO-d6 δ 7.22 (1H, s, br), 6.73 (1H, s, br), 3.58 (3H, s), 2.39 (2H, s), 2.09 (2H, s), 1.02 (6H, s).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])=[O:4].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C(OCC)(=O)C.O>ClCCl.O1CCCC1>[O:24]1[CH2:25][CH2:26][N:21]([CH2:2][C:3]([NH:5][C:6]2[CH:7]=[C:8]([CH:13]=[C:14]([N:16]3[CH:20]=[CH:19][CH:18]=[CH:17]3)[CH:15]=2)[C:9]([O:11][CH3:12])=[O:10])=[O:4])[CH2:22][CH2:23]1
Reactant: C1COCCN1
Reactant: COC(=O)c1cc(NC(=O)CBr)cc(-n2cccc2)c1
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1cc(NC(=O)CN2CCOCC2)cc(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of methyl 3-bromoacetylamino-5-(pyrrol-1-yl)benzoate (0.5 g) and morpholine (0.28 ml) in dichloromethane (5 ml) and tetrahydrofuran (7 ml) was stirred for 17 hours at room temperature. The reaction mixture was poured into the mixture of ethyl acetate and water. The organic layer was successively washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with chloroform. The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-morpholinoacetylamino-5-(pyrrol-1-yl)benzoate (0.48 g).