Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])(O)(O)=O.[Na+].[OH-].[Na+].[Cl:9][C:10]1[C:11]([N:16]2[C:20]([S:21]([O-:23])=[O:22])=[CH:19][C:18]([C:24]([F:27])([F:26])[F:25])=[N:17]2)=[N:12][CH:13]=[CH:14][CH:15]=1.[Li+].ClN1C(=[O:35])CCC1=O>O.C(OCC)(=O)C>[Cl:9][C:10]1[C:11]([N:16]2[C:20]([S:21]([OH:35])(=[O:23])=[O:22])=[CH:19][C:18]([C:24]([F:27])([F:25])[F:26])=[N:17]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=S([O-])c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Agent: O=P([O-])(O)O
Agent: [Li+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=S(=O)(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Yield: 78.1 %

Procedure:
To 100 mL of pH 6 buffer (prepared by dissolving 1.2 g (10 mmol) of sodium dihydrogenphosphate in 100 mL of water and adding 11.2 mL of 1N sodium hydroxide) was added 3.52 g (11.1 mmol) of the title material from Step B. This solution was cooled in an ice bath and 75 mL of ethyl acetate and 1.48 g (11.1 mmol) of N-chlorosuccinimide were added. After 30 minutes the layers were separated. The organic layer was dried (sodium sulfate) and the solvent was removed with a rotary evaporator. To the residue was added carbon tetrachloride and the solids were removed by filtration. The solvent was removed from the filtrate with a rotary evaporator to afford 2.84 g of the title compound as an amber oil. 1HNMR(CDCl3) δ 7.45 (s, 1H), 7.58 (dd, 1h), 8.01 (dd, 1h), 8.58 (dd, 1h).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][C:5](=[O:7])[N:6]=1.[Cl:8][C:9]1[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=[CH:22][C:10]=1[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[O:20][CH3:21]>>[NH2:1][C:2]1[S:3][C:4](=[CH:16][C:15]2[CH:18]=[CH:19][C:12]([O:11][C:10]3[CH:22]=[CH:23][C:24]([C:26]#[N:27])=[CH:25][C:9]=3[Cl:8])=[C:13]([O:20][CH3:21])[CH:14]=2)[C:5](=[O:7])[N:6]=1
Reactant: NC1=NC(=O)CS1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C#N)cc1Cl
Product: COc1cc(C=C2SC(N)=NC2=O)ccc1Oc1ccc(C#N)cc1Cl

Procedure:
4-[4-(2-Amino-4-oxo-4H-thiazol-5-ylidenemethyl)-2-methoxy-phenoxy]-3-chloro-benzonitrile was prepared using 2-amino-thiazol-4-one and 4-(2-Chloro-4-cyanophenoxy)-3-methoxybenzaldehyde according to General Procedure B. 1H NMR (400 Hz, DMSO-d6) δ 9.47 (bs, NH), 9.21 (bs, NH), 8.17 (d, 1H), 7.70 (dd, 1H), 7.64 (s, 1H), 7.46 (d, 1H), 7.32 (d, 1H), 7.23 (dd, 1H), 6.81 (d, 1H), 3.79 (s, 3H); LC/MS (m/z) [M+1]+386.0 (calculated for C18H13ClN3O3S, 386.82).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl([O-])(=O)(=O)=O.CN([P+](N(C)C)(N(C)C)Cl)C.C(N(CC)C(C)C)(C)C.[NH2:37][CH2:38][CH2:39][CH2:40][N:41]([C:49]1[S:50][CH:51]=[C:52]([C:54]2[O:55][C:56]3[CH:62]=[CH:61][CH:60]=[CH:59][C:57]=3[CH:58]=2)[N:53]=1)[C:42]([C:44]1[S:45][CH:46]=[CH:47][CH:48]=1)=[O:43]>CN1C(=O)CCC1>[O:55]1[C:56]2[CH:62]=[CH:61][CH:60]=[CH:59][C:57]=2[CH:58]=[C:54]1[C:52]1[N:53]=[C:49]([N:41]([CH2:40][CH2:39][CH2:38][NH:37][C:9](=[O:11])[CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:42]([C:44]2[S:45][CH:46]=[CH:47][CH:48]=2)=[O:43])[S:50][CH:51]=1
Reactant: NCCCN(C(=O)c1cccs1)c1nc(-c2cc3ccccc3o2)cs1
Reactant: O=C(O)CCN1CCCCC1
Agent: CN(C)[P+](Cl)(N(C)C)N(C)C
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(CCN1CCCCC1)NCCCN(C(=O)c1cccs1)c1nc(-c2cc3ccccc3o2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
A mixture of 1-piperidinepropionic acid (3 mg, 0.02 mmol) and tris(dimethylamino)chlorophosphonium perchlorate (7 mg, 0.02 mmol) was dissolved in NMP (200 μL) followed by the addition of N,N-diisopropylethylamine (17 μL, 0.1 mmol). The reaction mixture was maintained at room temperature for 20 min, then N-(3-aminopropyl)-N-(4-(benzofuran-2-yl)thiazol-2-yl)thiophene-2-carboxamide (7.7 mg, 0.02 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The resulting mixture was subjected to HPLC purification (Method Z) to provide the title compound (3.2 mg) as a pale yellow solid. LC/MS (ESI) m/z 523.5 [M+H]. HPLC retention time (Method C)=3.15 min.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O=[C:16]([CH3:35])[CH2:17][CH2:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][N:25]=2)=[CH:21][CH:20]=1.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(O)(=O)C>CO.ClCCCl>[CH2:36]([NH:43][CH:16]([CH3:35])[CH2:17][CH2:18][C:19]1[CH:34]=[CH:33][C:22]([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][N:25]=2)=[CH:21][CH:20]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NCc1ccccc1
Reactant: CC(=O)CCc1ccc(Oc2ccc(C(N)=O)cn2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCCl
Product: CC(CCc1ccc(Oc2ccc(C(N)=O)cn2)cc1)NCc1ccccc1
Yield: 68.8 %

Procedure:
Add sodium triacetoxyborohydride (0.2301 g, 1.086 mmol) to a stirred solution of 6-[4-(3-oxo-butyl)-phenoxy]-nicotinamide (0.2051 g, 0.7214 mmol), benzylamine (0.079 mL, 0.723 mmol), glacial acetic acid (0.045 ml 0.786 mmol), and 1,2-dichloroethane (7 mL). Stir the reaction for 18 h at room temperature under nitrogen. Add methanol (1.5 mL) and load the reaction mixture directly onto a 2 g prepacked SCX cartridge. Wash the cartridge with methanol (100 mL) and elute the product off of the cartridge with 2 M ammonia in methanol (50 mL). Concentrate the eluant on a rotary evaporator to yield 0.1863 g (69%) of 6-[4-(3-benzylamino-butyl)-phenoxy]-nicotinamide: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 4.09 minutes, Purity: 99.9%; mass spectrum (ion spray): m/z=376.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:33]C)=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[CH:8]([NH:13][C:14]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]3[C:15]=1[CH:16]=[N:17][C:18]([CH3:25])=[N:19]3)[C:7]([C:27]([F:30])([F:29])[F:28])([OH:26])[CH2:6][C:5]2([CH3:32])[CH3:31].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]2[CH:8]([NH:13][C:14]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]4[C:15]=3[CH:16]=[N:17][C:18]([CH3:25])=[N:19]4)[C:7]([C:27]([F:28])([F:29])[F:30])([OH:26])[CH2:6][C:5]([CH3:31])([CH3:32])[C:4]=2[C:3]=1[OH:33]
Reactant: COc1c(Cl)c(C)cc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1ccc(F)c2nc(C)ncc12
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ncc2c(NC3c4cc(C)c(Cl)c(O)c4C(C)(C)CC3(O)C(F)(F)F)ccc(F)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
40 mg (0.08 mmol) of (rac.) 6-chloro-1-[(8-fluoro-2-methylquinazolin-5-yl)amino]-5-methoxy-4,4,7-trimethyl-2-(trifluoromethyl)-1,2,3,4-tetrahydronaphthalen-2-ol is mixed at room temperature with 0.8 ml of a 1 molar solution of boron tribromide in dichloromethane, and it is stirred for four hours at room temperature. Since no reaction was carried out, another 0.8 ml of the boron tribromide solution was added. After 16 hours of stirring at room temperature, the reaction was complete. At −30° C., saturated sodium bicarbonate solution is now carefully added in drops, and the batch is diluted with ethyl acetate. After the cold bath is removed, it is stirred vigorously at room temperature for 10 minutes. The batch is extracted twice with ethyl acetate. The combined organic phases are washed with water and with brine, dried, and the residue is chromatographed on silica gel (mobile solvent:methanol/dichloromethane) after the solvent is spun off. 38.2 mg (98.4%) of the desired compound is isolated.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:20]([O-:22])=[O:21])=[C:11]([CH3:19])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](OCC)(=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].[O-]CC.[K+]>C(OCC)C>[CH2:1]([O:8][C:9]1[C:10]([N+:20]([O-:22])=[O:21])=[C:11]([CH2:19][C:23](=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(F)(F)F)ccc(OCc2ccccc2)c1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCOC(=O)C(=O)Cc1c(C(F)(F)F)ccc(OCc2ccccc2)c1[N+](=O)[O-]

Procedure:
The reaction was carried out in a manner similar to Reference Example 12 b) except for using 14.6 g (46.9 mmol) of 3-benzyloxy-6-trifluoromethyl-2-nitrotoluene, 13.7 g (93.8 mmol) of diethyl oxalate, 7.90 g (93.8 mmol) of potassium ethoxide and 300 ml of diethyl ether. Ethyl (3-benzyloxy-6-trifluoromethyl-2-nitrophenyl)pyruvate was thus obtained in the yield of 10.9 g (56.9%).
Reaction SMILES: C(OCC)(=O)C.[CH2:7](O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[I-:37].[Na+]>CC(C)=O>[CH2:7]([I:37])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCCCC/C=C\C/C=C\CCCCCCCCI

Procedure:
A solution of linoleyl alcohol (5.32 g, 200 mmole) and pyridine (40 ml) was cooled to 0° C. and added to p-toluene-sulfonic chloride (4.2 g, 220 mmole) in 10 ml of pyridine. The resulting solution was stirred overnight at 0° C. and poured into 50 ml of ice water. The organic layer was extracted with 100 ml of ether and the organic layer was washed with 1% aqueous hydrochloric acid until acidic and then washed three times with water. The organic solution was dried over magnesium sulfate, filtered and the solvent evaporated to give 6 g of oily material having an Rf of 0.3 on thin layer chromatography (20Δ ethyl acetate/Skelly B linoleyl alcohol Rf =0.1). To the crude tosylate (6 g, 140 mmole) was added acetone (150 ml) and sodium iodide (300 mmole, 4.5 g), and the mixture was heated gently on a steam bath for 3 hours. The solvent was removed in vacuo and 200 ml of ether added thereto. The organic layer was washed twice with an aqueous solution of sodium bisulfite, twice with water and dried over magnesium sulfate, filtered and solvent removed. The crude iodide was purified by column chromatography over silica gel and eluted with Skelly B to yield 5.2 g of linoleyl iodide Rf ethyl acetate--Skelly B (10:90 v/v)=0.7 of formula II of Chart A.
Reaction SMILES: [C:1](O)(=[O:5])[CH:2]([CH3:4])[OH:3].[OH:7][CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[NH2:10]>>[C:1]([NH:10][C@@H:9]1[C@@H:11]([OH:12])[C@H:13]([OH:14])[C@@H:15]([CH2:17][OH:18])[O:16][CH:8]1[OH:7])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CC(O)C(=O)O
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Product: CC(O)C(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 120 °C

Procedure:
Lactic acid (30 g) and glucosamine (10 g) were mixed and heated for 4 hours at 120° C. The reaction mixture was cooled and washed with ethyl acetate. The residue (25 g) was dissolved in 100 g of water.
Reaction SMILES: [CH:1]1([C:4]([CH:26]2[CH2:28][CH2:27]2)([C:6]2[S:7][C:8]([C:11]3[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[C:13]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH:12]=3)=[CH:9][N:10]=2)[OH:5])[CH2:3][CH2:2]1.C(O)(=O)C>C(OCC)(=O)C.[Pd]>[NH2:17][C:15]1[CH:16]=[C:11]([C:8]2[S:7][C:6]([C:4]([CH:1]3[CH2:2][CH2:3]3)([CH:26]3[CH2:28][CH2:27]3)[OH:5])=[N:10][CH:9]=2)[CH:12]=[C:13]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:14]=1
Reactant: O=[N+]([O-])c1cc(-c2cnc(C(O)(C3CC3)C3CC3)s2)cc(N2CCOCC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1cc(-c2cnc(C(O)(C3CC3)C3CC3)s2)cc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of the product of Step 4 (239 mg, 0.595 mmol) in ethyl acetate (5.4 mL)/acetic acid (0.54 mL) was added Pd/C (10 wt %, 60 mg, 0.056 mmol) and the reaction flask was purged with N2 and then H2. The reaction was stirred for 4 hr at room temperature under H2 (balloon; 25 mg of Pd/C were added after 2 h to complete the reaction) and then filtered through a microfilter (Glass Acrodisc 25 mm) and was washed with dichloromethane. The filtrate was concentrated, stripped with toluene (3×) and then dried under vacuum overnight to provide 221 mg (0.595 mmol, quant. yield) of {5-[3-amino-5-(morpholin-4-yl)phenyl]-1,3-thiazol-2-yl}(dicyclopropyl)methanol as a fluffy solid of sufficient purity to be used directly. MS APCI: [M+H]+ m/z 372.1.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:26][CH3:27])[C:15]2[C:20]([NH:21][CH:22]([CH3:24])[CH3:23])=[CH:19][CH:18]=[C:17]([F:25])[N:16]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[CH2:26]([N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:15]1[C:20]([NH:21][CH:22]([CH3:24])[CH3:23])=[CH:19][CH:18]=[C:17]([F:25])[N:16]=1)[CH3:27]
Reactant: CCN(c1nc(F)ccc1NC(C)C)C1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCN(c1nc(F)ccc1NC(C)C)C1CCNCC1
Reaction time: 12 h

Procedure:
1-Benzyl-4-[N-ethyl-N-(6-fluoro-3-(isopropylamino)-2-pyridinyl)amino]piperidine (EXAMPLE 196, 2.1 g, 5.76 mmol) is dissolved in ethanol (100 ml) and 0.96 g of palladium hydroxide is added. The reaction is placed on a Parr hydrogenator at 40 psi for 12 hr. Then the reaction is filtered through diatomaceous earth, concentrated under reduced pressure, and used without further purification, NMR (300 MHz, CDCl3) 6.93, 6.55, 4.32, 3.51, 3.11, 3.10-2.95, 2.59, 1.77, 1.55, 1.18 and 0.86δ.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[F:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:29])[C:26](O)=[O:27])[CH2:21][CH2:20]2)=[CH:16][CH:15]=1>C(OCC)C>[F:13][C:14]1[CH:31]=[CH:30][C:17]([CH2:18][CH:19]2[CH2:20][CH2:21][N:22]([C:25](=[O:29])[C:26]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=4[CH:12]=3)=[O:27])[CH2:23][CH2:24]2)=[CH:16][CH:15]=1
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Solvent: CCOCC
Product: O=C1COc2ccc(NC(=O)C(=O)N3CCC(Cc4ccc(F)cc4)CC3)cc2N1

Procedure:
The title compound is prepared from 6-amino-4H-benzo[1,4]oxazin-3-one [Indian J. Chem. Sect. B, 24, 1263. (1985)] and [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) according to the method described in Example 2. Melting Point: 197-200° C. (diethylether)
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>CN(C=O)C>[F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccncc1F
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccncc1F
Temperature: 25 °C

Procedure:
A mixture of 1.5 g of 3-fluoroisonicotinic acid, 5 ml of thionyl chloride and 50 mg of DMF was heated to reflux for two hours. The reaction mixture was cooled to room temperature, and then the reaction mixture was concentrated under reduced pressure to give 3-fluoroisonicotinic acid chloride. A mixture of the resultant 3-fluoroisonicotinic acid chloride and 5 ml of DMF was added dropwise to a mixture of 1.76 g of 2-amino-4-tert-butylphenol, 2.18 g of triethylamine and 10 ml of DMF while ice-cooling. The reaction mixture was stirred at room temperature for 1.5 hours and at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature, and then water was added. Precipitated crystals were collected by filtration. The resultant crystals were dissolved in ethyl acetate, washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give 2.41 g of N-(5-tert-butyl-2-hydroxyphenyl)-3-fluoroisonicotinamide.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:44])[CH2:7][CH2:8][NH:9][C:10](=[O:43])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=3)=[C:27]([CH3:41])[CH:26]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:13]([F:42])[CH:12]=1)C>C(O)C>[F:42][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[O:17][CH:18]([C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:33][CH:32]=2)=[C:27]([CH3:41])[CH:26]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:10]([NH:9][CH2:8][CH2:7][C:6]([OH:44])=[O:5])=[O:43]
Reactant: CCCCCCC(Oc1ccc(C(=O)NCCC(=O)OCC)cc1F)c1ccc(-c2ccc(C(F)(F)F)cc2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(Oc1ccc(C(=O)NCCC(=O)O)cc1F)c1ccc(-c2ccc(C(F)(F)F)cc2)c(C)c1
Reaction time: 3 h
Yield: 82.8 %

Procedure:
Add sodium hydroxide (5.0N, 0.03 mL, 0.15 mmol) to 3-{3-Fluoro-4-[1-(2-methyl-4′-trifluoromethyl-biphenyl-4-yl)-heptyloxy]-benzoylamino}-propionic acid ethyl ester (0.024 g, 0.041 mmol) in ethanol (5 mL) and stir for three hours. Acidify with 1.0 N HCl and extract desired compound with ethyl acetate three times. Wash organic phase with saturated sodium chloride solution, dry over Na2SO4, filter, and concentrate under reduced pressure to provide 0.019 g (83%) of title compound. MS (ESI) m/z 560.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:9]1[CH:15]=[CH:14][C:12](N)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl.N([O-])=O.[Na+].[I-:21].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O.CCOCC>[I:21][C:12]1[CH:14]=[CH:15][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:10][CH:11]=1
Reactant: [I-]
Reactant: CCCCCCCCc1ccc(N)cc1
Agent: Cl
Agent: O=N[O-]
Agent: O=S([O-])([O-])=S
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCc1ccc(I)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-octylaniline (80.0 g, 389.6 mmol) in water (780 mL) was added aqueous HCl (40 mL) at room temperature. After the mixture was cooled to 0° C., more aqueous HCl (43 mL) was added, followed by dropwise addition of a solution of NaNO2 (26.9 g, 389.6 mmol) in water (195 mL). To the resulting arenediazonium salt solution was added dropwise a solution of potassium iodide (64.67 g, 389.6 mmol) in water (195 mL). The resulting mixture was heated with stirring at 40° C. After two hours, sodium thiosulfate was added to decolorize and the product was extracted with ether. The ethereal extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to give a crude oil. The crude material was dissolved in ether and filtered through a plug of silica gel three times and dried in vacuo to give 1-iodo-4-octylbenzene as a colorless oil. The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(O)(=O)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)/C=C/c1ccc(-c2ccc(OC)cc2)cc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(-c2ccc(OC)cc2)cc1
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a solution of ethyl (2E)-3-(4′-methoxybiphenyl-4-yl)prop-2-enoate (1 g, 3.5 mmol) in ethyl acetate was added acetic acid and degassed well with argon and added palladium carbon (100 mg) and stirred under hydrogen for overnight, TLC shows a new spot, RM filtered through celite and washed with ethyl acetate and concentrated to afford white solid (0.7 g, Yield: 71.4%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[Mg].II.[B:13](OC)([O:16]C)[O:14]C>O1CCCC1>[CH3:9][S:8][C:4]1[CH:3]=[C:2]([B:13]([OH:16])[OH:14])[CH:7]=[CH:6][CH:5]=1
Reactant: COB(OC)OC
Reactant: CSc1cccc(Br)c1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CSc1cccc(B(O)O)c1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A solution of 3-bromothioanisole (10.3 g, 50.9 mmol) in anhydrous tetrahydrofuran (15 ml) was added dropwise to a stirred mixture of magnesium turnings (1.86 g, 75 mmol) and a crystal of iodine under nitrogen. Once the reaction was initiated, the remainder of the solution was added at such a rate as to keep the reaction mixture under reflux. When the addition was complete, the mixture was stirred under reflux for a further 1 hour, allowed to cool to room temperature and then added to a solution of trimethyl borate (5.8 ml, 51 mmol) in anhydrous tetrahydrofuran (25 ml), whilst keeping the internal temperature at about −10° C. The reaction mixture was allowed to warm to about 0° C., stirred for 30 minutes and then quenched with 2M hydrochloric acid. The resulting mixture was extracted with ether, then the combined extracts extracted, in turn, with 2M aqueous sodium hydroxide solution. The combined aqueous extracts were acidified with concentrated hydrochloric acid and extracted with ether. The combined ether extracts were dried (MgSO4) and evaporated under reduced pressure to provide the title compound (7.8 g, 100%) as a white solid. δ(DMSOd6): 2.45 (s,3H), 7.27 (m,2H), 7.54 (m,1H), 7.67 (s,1H), 8.05 (brs,2H),
Reaction SMILES: [OH:1][C@H:2]([C@@H:7]([OH:15])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([O:5][CH3:6])=[O:4].[CH3:16][CH2:17][C:18](=O)[CH2:19][CH3:20].OS(O)(=O)=O>CCOC(C)=O>[CH3:6][O:5][C:3]([C@H:2]1[C@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:15][C:18]([CH2:19][CH3:20])([CH2:17][CH3:16])[O:1]1)=[O:4]
Reactant: COC(=O)[C@H](O)[C@@H](O)Cc1ccccc1
Reactant: CCC(=O)CC
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCC1(CC)O[C@@H](Cc2ccccc2)[C@H](C(=O)OC)O1
Reaction time: 20 h
Yield: 45.3 %

Procedure:
To a stirred solution of (2R,3S)-methyl 2,3-dihydroxy-4-phenylbutanoate (Preparation example 260, 2.0 g, 9.51 mmol) in 3-pentanone (5 mL, 47.55 mmol) was added a catalytic amount of H2SO4 (0.051 mL, 0.951 mmol) at room temperature. The mixture was stirred for 20 h. The resulting mixture was diluted with EtOAc, washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude compound was purified by a silica gel column to produce the title compound (1.2 g, 50˜75%)
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH:6]([OH:11])[CH2:7][N:8]([CH3:10])[CH3:9]>[Pd]>[C:3]([NH:1][C:2]1[CH:15]=[C:14]([NH:16][C:6](=[O:11])[CH3:5])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH:6]([OH:11])[CH2:7][N:8]([CH3:10])[CH3:9])(=[O:4])[CH3:2]
Reactant: CN(C)CC(O)COc1ccc([N+](=O)[O-])cc1N
Agent: [Pd]
Product: CC(=O)Nc1ccc(OCC(O)CN(C)C)c(NC(C)=O)c1

Procedure:
Under the conditions described in the second step of Example 10, an alcoholic solution of 0.1 mol (25.5 g) of 1-(2'-amino-4'-nitrophenoxy)-3-dimethylaminopropan-2-ol is subjected to catalytic hydrogenation in the presence of palladium-on-charcoal. The catalyst is removed by filtration, the solvent is driven off in vacuo, the oily residue is taken up in 200 ml of ethyl acetate, and 17 ml of acetic anhydride are added gradually thereto. The expected diacetylated derivative precipitates in the form of crystals. It is filtered off, washed with acetone and dried in vacuo. It melts at 118°-120° C.