Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([CH3:11])[CH:5]=[C:4]([Cl:12])[N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][NH2:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([F:13])[CH:15]=2)=[O:10])=[C:6]([CH3:11])[CH:5]=[C:4]([Cl:12])[N:3]=1
Reactant: NCc1cccc(F)c1
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(Cl)nc(Cl)c1C(=O)NCc1cccc(F)c1
Temperature: 70 °C
Yield: 73.8 %

Procedure:
To a solution of 17.4 g (84.4 mmol) of 2,6-dichloro-4-methyl-pyridine-3-carboxylic acid in THF (340 ml) were added 10.6 ml (92.9 mmol) 3-fluorobenzylamine, 32.0 g (84.4 mmol) HATU and 35.0 ml (253.3 mmol) NEt3. The RM was then heated at 70° C. for 16. After dilution with EtOAc (350 ml) the mixture was washed with a 4M aq. NH4Cl sol., a 1M aq. NaHCO3 sol. and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:2) provided 19.5 g (62.3 mmol, 74%) 2,6-dichloro-N-(3-fluorobenzyl)-4-methyl-pyridine-3-carboxylic acid amide.
Reaction SMILES: FC(F)(F)C(O[C:6](=[O:11])[C:7](F)(F)F)=O.ClCCl.[Br:17][C:18]1[C:23]([CH3:24])=[CH:22][N+:21]([O-])=C(C)[CH:19]=1>CCCCCC>[Br:17][C:18]1[C:23]([CH3:24])=[CH:22][N:21]=[C:7]([CH2:6][OH:11])[CH:19]=1
Reactant: Cc1c[n+]([O-])c(C)cc1Br
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1cnc(CO)cc1Br
Reaction time: 0.33 h
Yield: 83.3 %

Procedure:
Under an argon atmosphere, trifluoroacetic anhydride (20.6 ml, 0.146 mol) was added to a dichloromethane solution (100 ml) solution of 4-bromo-2,5-dimethylpyridine 1-oxide (9.8 g, 48.5 mmol) under ice cooling. The resulting mixture was stirred for 20 minutes and then, stirred at room temperature for 7.5 hours. The reaction mixture was concentrated under reduced pressure. To a dichloromethane solution (50 ml) of the residue was added a saturated aqueous solution (100 ml) of sodium bicarbonate. The resulting mixture was stirred for 14 hours. The reaction mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate (=1:1) eluate was concentrated under reduced pressure to give the title compound (8.17 g, 40.4 mmol, 83%) as a yellow powder.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:8])[C:5]([CH3:7])=[CH2:6])O.C1(C=CC(O)=CC=1)O.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>O>[N:17]1([CH2:1][NH:3][C:4](=[O:8])[C:5]([CH3:7])=[CH2:6])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: C1COCCN1
Reactant: C=C(C)C(=O)NCO
Agent: Oc1ccc(O)cc1
Solvent: O
Product: C=C(C)C(=O)NCN1CCOCC1

Procedure:
In a 300 cc capacity round bottom flask equipped with a stirrer were put 57.5 g (0.5 mole) of N-methylolmethacrylamide and 50 cc of water and, as a polymerization inhibitor, 500 mg of hydroquinone. On the other hand, 43 g (0.5 mole) of morpholine were gradually added thereto while stirring. Afterwards, the contents were stirred for 1 hour at 50°-60°C. Finally, the reaction mixture was concentrated and then was recrystallized from ethyl acetate. m.p.; 78.0°C. Yield: 48.3 g (52.5%).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([NH:8][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1cc(Cl)cnc1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CNc2cc(Cl)cnc2Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
5.16 g (24.8 mmol) of 2-bromo-5-chloro-pyridin-3-ylamine, 7.09 g (52.1 mmol) of p-anisaldehyde and 13.1 g (62.0 mmol) of sodium triacetoxyborohydride were dissolved in 100 mL of DCM and stirred at r.t. overnight. The next day DCM was replaced with chloroform, 5 g excess of sodium triacetoxyborohydride and 3 g excess of p-anisaldehyde were added and the reaction was conducted at 65° C. for 3 h. The mixture was worked up with aqueous sodium bicarbonate and purified on silica followed by recrystallization from ethyl acetate/hexanes mixture to give 3.40 g (42%) of the product as a white solid. MS (M+H)/z=328.9
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=1[O:36][CH3:37].[I-].[K+]>C(O)CCC>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][C:28]=3[O:36][CH3:37])[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: Clc1ccc(C(=C2CCNCC2)c2ccc(Cl)cc2)cc1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CC1

Procedure:
A mixture of 3.96 g (0.01305 mole) of 4-[bis(4-chlorophenyl)methylene]piperidine, 3.16 g (0.013 mole) of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone in 300 ml of 1-butanol containing 0.3 g of potassium iodide was heated overnight at gentle reflux. The reaction mixture was stripped to dryness and partitioned between chloroform-water and chloroform-5% sodium hydroxide. Removal of chloroform gave an oil which crystallized from isopropyl alcohol. The solid was again crystallized from isopropyl alcohol to give 4.16 g (61%) of light yellow solid, m.p. 143°-144° C.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][CH2:24][NH:25][C:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:27].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][CH2:24][NH:25][C:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:27])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(=O)NCCON
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.210 g, 0.760 mmol, US 2005/20572 A1) in DCM (6.0 mL) were added tert-butyl {[2-(aminooxy)ethyl]carbamoyl}carbamate 84 (0.250 g, 1.140 mmol), 1-hydroxybenzotriazole (0.154 g, 1.140 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.218 g, 1.140 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 85 (0.31 g, 85%) as a white solid.
Reaction SMILES: [N+]([N:4]1[C:10]([O:17][CH3:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:8]=2[N:7]([CH3:26])[C:6](=[O:27])[CH2:5]1)([O-])=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:18][O:17][C:10]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:8]=2[N:7]([CH3:26])[C:6](=[O:27])[CH:5]=[N:4]1
Reactant: COC1(c2ccccc2)c2cc([N+](=O)[O-])ccc2N(C)C(=O)CN1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1(c2ccccc2)N=CC(=O)N(C)c2ccc([N+](=O)[O-])cc21
Reaction time: 72 h
Yield: 56.1 %

Procedure:
A solution of 4.7-dinitro-5-methoxy-1-methyl-5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one (400 mg) and triethylamine (1.1 g) in methylene chloride (10 ml) is allowed to stand at room temperature for 72 hours. The reaction mixture is washed with water, dried over sodium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is washed with diethyl ether to give 5-methoxy-1-methyl-7-nitro-5-phenyl-1,5-dihydro-2H-1,4-benzodiazepin-2-one (196 mg) as crude product.
Reaction SMILES: C(OC([N:8]1[C:12]2[C:13](Cl)=[N:14][CH:15]=[C:16]([C:17]([OH:19])=[O:18])[C:11]=2[C:10]([CH3:21])=[CH:9]1)=O)(C)(C)C.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>O1CCOCC1.CCOC(C)=O.[OH-].[Na+]>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:13]2[C:12]3[NH:8][CH:9]=[C:10]([CH3:21])[C:11]=3[C:16]([C:17]([OH:19])=[O:18])=[CH:15][N:14]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)O)c12
Reactant: Nc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1c[nH]c2c(Nc3cccc(Cl)c3)ncc(C(=O)O)c12
Temperature: 110 °C

Procedure:
A mixture of 7-chloro-3-methyl-pyrrolo[2,3-c]pyridine-1,4-dicarboxylic acid 1-tert-butyl ester (200 mg) and 3-chloroaniline (0.68 ml) in 1,4-dioxane (3 ml) was heated at 110° C. for 16 hours. The reaction mixture was diluted with EtOAc and basified with 1M NaOH, the aqueous layer was extracted and acidified to pH1 using 1M HCl to afford a precipitate. The precipitate was filtered off and washed with water until neutral. The solid was then sucked dry and dried over sodium hydroxide at 50° C. under vacuum to afford the title compound (197 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=3)=[O:10])=[CH:4][CH:3]=1.Br[CH2:30][C:31](=O)[C:32]([CH3:35])([CH3:34])[CH3:33]>C(#N)C>[C:32]([C:31]1[N:1]=[C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]3[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=4)=[O:10])=[CH:6][N:7]2[CH:30]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)C(=O)CBr
Reactant: Nc1ccc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)cn1
Solvent: CC#N
Product: CC(C)(C)c1cn2cc(NC(=O)c3cc4cc(F)ccc4n3Cc3cccc(F)c3)ccc2n1
Yield: 99.8 %

Procedure:
Compound 7 was prepared according to a process similar to that described in step 4.3, by reacting 0.1 g (0.26 mmol) of N-[6-aminopyrid-3-yl]-5-fluoro-1-[(3-fluorophenyl)-methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in step 4.2, with 0.096 g (0.53 mmol) of 1-bromo-3,3-dimethylbutan-2-one in 4 mL of acetonitrile. 0.119 g of the expected product is thus obtained in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24]1.CCN(C(C)C)C(C)C>CC(O)C>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: OC1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCC(O)C2)c(Br)c1
Temperature: 140 °C

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 1 g, 2.53 mmol) and (Rac.)-pyrrolidin-3-ol (264 mg, 3.03 mmol) and DIPEA (883 μL, 5.06 mmol), in iPrOH (4213 μL) were added a MW vial and heated at 140° C. for 30 min. The RM was evaporated to dryness under reduced pressure, treated with 0.5 M HCl (10 mL) and EtOAc (20 mL) and extracted with EtOAc. The combined extracts were washed with water, dried over MgSO4 and evaporated to dryness under reduced pressure. Trituration of the residue in cyclohexane and filtration of the solid afforded the title compound as an off-white solid. UPLC-MS (condition 1) tR=2.63 min, m/z=445.9-447.9 [M+H]+, m/z=444.0-446.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.80-2.02 (m, 2H) 3.58 (d, J=11.49 Hz, 1H) 3.67-3.79 (m, 1H) 3.82-3.93 (m, 2H) 4.32-4.40 (m, 1H) 4.98 (br. s, 1H) 7.36 (d, J=8.56 Hz, 2H) 7.86 (d, J=9.05 Hz, 2H) 8.35 (d, J=1.96 Hz, 1H) 8.69 (d, J=1.96 Hz, 1H) 10.23 (s, 1H).
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:19](=[O:21])[CH3:20])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCc1ccc(NC(C)=O)cc1
Yield: 58.5 %

Procedure:
To 4-butyl aniline (20 g; 134 mmol) dissolved in toluene (160 mL) with stirring was added 4-dimethylaminopyridine (0.82 g; 6.70 mmol) and triethylamine (26.0 mL; 188 mmol). The mixture was then treated with acetic anhydride (15.2 mL; 161 mmol) dropwise via an addition funnel over 30 minutes. After addition, the ice bath was removed and the reaction mixture was stirred for 12 hours at room temperature. The mixture was poured into aqueous hydrochloric acid (240 mL; 2M) and stirred 20 minutes. The layers were separated and the organic layer was washed with water. The organic layer was separated and crystals formed while standing. The resulting precipitate was isolated by filtration and dried under vacuum to give the title product as white crystals (15.0 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:13]2[C:12]([CH3:15])([CH3:14])[O:11][C:10]([CH3:17])([CH3:16])[C:9]=2[S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:29]([F:32])([F:31])[F:30])=[C:24]([CH:28]=1)[C:25](Cl)=[O:26]>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:29]([F:30])([F:31])[F:32])=[C:24]([CH:28]=1)[C:25]([NH:18][C:7]1[S:8][C:9]2[C:10]([CH3:17])([CH3:16])[O:11][C:12]([CH3:15])([CH3:14])[C:13]=2[C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:26]
Reactant: O=C(Cl)c1cc(F)ccc1C(F)(F)F
Reactant: CCOC(=O)c1c(N)sc2c1C(C)(C)OC2(C)C
Product: CCOC(=O)c1c(NC(=O)c2cc(F)ccc2C(F)(F)F)sc2c1C(C)(C)OC2(C)C

Procedure:
The title compound was prepared from the product of Example 18A and commercially available 5-fluoro-2-(trifluoromethyl)benzoyl chloride using the procedure described for Example 1B. 1H NMR (DMSO-d6, 300 MHz) δ 1.30 (t, J=7.1 Hz, 3H), 1.54 (s, 6H), 1.49 (s, 6H), 4.30 (q, J=7.1 Hz, 2H), 7.63-7.70 (m, 1H), 7.82 (dd, J=8.6, 2.5 Hz, 1H), 8.01 (dd, J=8.8, 5.1 Hz, 1H), 11.48 (br s, 1H). MS (ESI+) m/z 460 (M+H)+. Anal. calcd. for C21H21F4NO4S: C, 54.90; H, 4.61; N, 3.05. Found: C, 54.72; H, 4.68; N, 2.98.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([CH3:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:26](Cl)(=[O:28])[CH3:27]>>[C:26]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:24])([F:25])[F:23])=[C:17]([CH3:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: Cc1cc(C(C)NC(=O)c2ccnc(N)n2)cnc1OCC(F)(F)F
Product: CC(=O)Nc1nccc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(C)c2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carb oxamide (20 mg, 0.06 mmol, Step-1 of Example 223, single enantiomer) and acetyl chloride (22 mg, 0.28 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:16][S:17][CH2:18][C@@H:19]([C:38](O)=[O:39])[NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][P:68](=[O:75])([O:72][CH2:73][CH3:74])[O:69][CH2:70][CH3:71].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:35]1[C:36]2[CH:24]([CH2:23][O:22][C:21]([NH:20][C@@H:19]([CH2:18][S:17][CH2:16][C@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C:38](=[O:39])[NH:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][P:68](=[O:75])([O:69][CH2:70][CH3:71])[O:72][CH2:73][CH3:74])=[O:37])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: CCOP(=O)(CCOCCOCCOCCN)OCC
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5R,9R)-9-(dodecanoyloxy)-1-(9H-fluoren-9-yl)-3,12-dioxo-2,11-dioxa-7-thia-4-azatricosane-5-carboxylic acid (6, 1 eq) in DCM (0.1 M) was added diethyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethylphosphonate (1.2 eq), DIEA (2.5 eq) and HBTU (1.1 eq). The resulting mixture was stirred at room temperature for 2 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% MeOH/DCM to give the product.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:16][O:17][C:18](=[O:40])[C@H:19]([CH2:36][CH2:37][S:38][CH3:39])[NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][C:23]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])(O)=O.[Na+]>ClCCl.CN(C=O)C>[CH3:16][O:17][C:18](=[O:40])[C@H:19]([CH2:36][CH2:37][S:38][CH3:39])[NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:9])=[CH:24][C:23]=1[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Reactant: O=C(O)c1cccnc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(=O)c2cccnc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
Nicotinic acid (345 mg, 2.8 mmol) was suspended in 10 mL of dichloromethane and oxalyl chloride (2.8 mL of a 2.0 M soln in methylene chloride) was added by syringe followed by one drop of DMF. The reaction mixture was stirred at 25° C. for 2 hours and then was evaporated and azeotroped with toluene. The resulting acid chloride was then dissolved in dichloromethane and a solution of (4-amino-2-phenylbenzoyl)methionine methyl ester (669 mg, 1.87 mmol), prepared as in Example 192B, in 5 mL of dichloromethane was added followed by 4 mL of saturated aqeuous NaHCO3 and the reaction was stirred at 25° C. for 3 hours. The layers were separated and the organic layer was dried over Na2SO4, filtered and evaporated to give 830 mg (96%) of [4-(3-pyridylcarbonylamino)-2-phenylbenzoyl]methionine methyl ester as an oil. 1H NMR (300 mHz, CDCl3) δ 9.2 (d, 1H), 8.76 (d, 1H), 8.42 (bs, 1H), 8.2 (dt, 1H), 7.72-7.65 (m, 2H), 7.6 (dd, 1H), 7.45-7.35 (m, 5H), 6.02 (bd, 1H), 4.65 (dq, 1H), 3.68 (s, 3H), 2.20 (t, 2H), 2.01 (s, 3H), 1.98-1.88 (m, 1H), 1.80-1.78 (m, 1H). CIMS 464 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:9][CH:10]=[O:11].[CH2:13]=O>C(NCC)C>[CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[C:9](=[CH2:13])[CH:10]=[O:11]
Reactant: CC1(C)C2CCC(CC=O)C1C2
Reactant: C=O
Solvent: CCNCC
Product: C=C(C=O)C1CCC2CC1C2(C)C
Yield: 86.4 %

Procedure:
In a similar manner to Example 49, 342 g of 6,6-dimethylbicyclo[3.1.1]hept-2-yl acetaldehyde at a purity of 97% (1.99 moles), 178 g of 37% formaldehyde (2.2 moles), 7.3 g of diethylamine (0.1 mole), and 0.8 g of BHT were refluxed for 1.5 hours. After the usual work-up, 370 g of crude propenal was distilled to afford 317 g of purified product (89% yield). BP 75° C./0.5 mmHg; 1H-NMR (300 MHz), δ 0.92 (3H, s), 1.23 (3H, s), 1.47-2.40 (8H, m), 3.1 (1H, t, J=8.91 Hz), 5.91 (1H, s), 6.20 (1H, s), 9.50 (1H, s); 13C-NMR (75 MHz), δ 20.06, 20.92, 23.88, 26.76, 28.03, 32.82, 40.08, 41.32, 44.34, 131.53, 155.46, 194.97; IR (Neat), 2960, 2700, 1690, 940 cm-1 ; MS (m/e), 177 (M+ -1), 163, 145, 135, 121, 107, 91, 79, 41 (Base);
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15]S(C1C=CC(C)=CC=1)(=O)=O.[CH2:26]([O:28][C:29](=[O:41])[C:30]([O:33][C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][CH:35]=1)([CH3:32])[CH3:31])[CH3:27].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:26]([O:28][C:29](=[O:41])[C:30]([CH3:32])([O:33][C:34]1[CH:39]=[CH:38][C:37]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:36][CH:35]=1)[CH3:31])[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Yield: 78 %

Procedure:
A mixture of the toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester (See Japan Tobacco Inc International Application WO 9518125) (24 g, 66.9 mmol), 2-(4-hydroxyphenoxy)-2-methylpropanoic acid ethyl ester (See American Home Products U.S. Pat. No. 3,795,691) (12.5 g, 55.71 mmol) and Cs2CO3 (22.7 g, 69.6 mmol) was heated at 55° C. in DMF (45 mL) for 18 h. The reaction was partitioned between EtOAc (160 mL) and H2O (180 mL), and the aqueous phase extracted with EtOAc (150 mL). The combined organic phases were dried (MgSO4) and concentrated under reduced pressure to an oil which was purified by column chromatography (1500 mL SiO2, 10% EtOAc/hexanes to 20% EtOAc/hexanes) to provide 2-methyl-2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}propionic acid ethyl ester (17.8 g, 78%) as a colorless, viscous oil: Rf=0.48 in 35% EtOAc/hexanes; 1H NMR (400 MHz, CDCl3) δ 7.99-7.96 (m, 2H), 7.43-7.40 (m, 3H), 6.83-6.75 (m, 4H), 4.22 (q, J=9.2 Hz, 2H), 4.18 (t, J=8.8 Hz, 2H), 2.95 (t, J=8.8 Hz, 2H), 2.36 (s, 3H), 1.52 (s, 6H), 1.27 (t, J=9.2 Hz, 3H).
Reaction SMILES: CS(O[C:6]#[C:7][CH3:8])(=O)=O.[Br:9][C:10]1[C:11]([C:21]2[CH:26]=[C:25]([OH:27])[C:24]([Cl:28])=[CH:23][C:22]=2[F:29])=[C:12]([Cl:20])[N:13]([CH3:19])[C:14]=1[C:15]([F:18])([F:17])[F:16].C(=O)([O-])[O-].[K+].[K+].O>CC(CC(C)C)=O>[Br:9][C:10]1[C:11]([C:21]2[CH:26]=[C:25]([O:27][CH2:8][C:7]#[CH:6])[C:24]([Cl:28])=[CH:23][C:22]=2[F:29])=[C:12]([Cl:20])[N:13]([CH3:19])[C:14]=1[C:15]([F:16])([F:17])[F:18]
Reactant: CC#COS(C)(=O)=O
Reactant: Cn1c(Cl)c(-c2cc(O)c(Cl)cc2F)c(Br)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: C#CCOc1cc(-c2c(Br)c(C(F)(F)F)n(C)c2Cl)c(F)cc1Cl
Temperature: 80 °C
Yield: 42.8 %

Procedure:
2 propinyl methanesulfonate (0.22 g; 1.61 mmoles) is added to a mixture of 4-bromo-3-(4-chloro-2-fluoro-5-hydroxyphenyl)-2-chloro-1-methyl-5-trifluoromethyl pyrrole (0.6 g; 1.47 mmoles) and potassium carbonate (0.21 g; 1.54 mmoles) in methylisobutylketone (6 ml). The mixture is heated to 80° C. for 3 hours. The reaction mixture is poured into water (10 ml), extracted with ethyl ether (3×20 ml), the ether phase is washed with a saturated solution of sodium chloride, anhydrified with sodium sulfate and concentrated in a rotavapor. The raw product obtained (0.65 g) is chromatographed on silica gel, eluating with n-hexane/ethyl acetate 85:15. 0.28 g of solid white product with a melting point of 87° C., are obtained.