Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][N:9]=[C:10]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[C:11]([O-])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([NH+](CC)CC)C.C(Cl)(=O)C([Cl:41])=O.CN(C)C=O>C(Cl)Cl>[C:1]1([C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][N:9]=[C:10]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[C:11]([Cl:41])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])C(=NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1cccs1
Reactant: O=C(Cl)C(=O)Cl
Agent: CC[NH+](CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C(=NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1cccs1
Reaction time: 2 h
Yield: 103 %

Procedure:
A solution of triethylammonium 2-triphenylmethoxyimino-2-(thien-2-yl)-acetate (syn isomer) (2.30 g, 4.46 mmole) in dry methylene chloride (50 ml) was cooled to 0° to +5° and stirred whilst oxalyl chloride (0.38 ml, 4.46 mmole) was added. N,N-Dimethylformamide (ca 0.1 ml) was added and the mixture was stirred at 0° to +5° for 21/2 hours. The solvent was evaporated and the residue was stirred with ether (100 ml) for 1 hour, and the suspension then filtered. The filtrate and ether washings (100 ml) were evaporated to give the title compound as a white crystalline solid (1.985 g, quantitative). This acid chloride was used without further purification.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23](Cl)[CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)=[CH:17][CH:16]=1>CN(C)C=O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]([CH2:24][N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[S:3][C:4]2[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: Clc1ccc(CCC(Cl)Cn2ccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(CCc2ccc(Cl)cc2)Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
11 mg of a 55% w/w suspension of sodium hydride in mineral oil were added, whilst ice-cooling, to a solution of 40 mg of methyl 4-mercaptobenzoate in 0.25 ml of dry dimethylformamide, and the resulting mixture was stirred at room temperature for 30 minutes. A solution of 52 mg of 1-[4-(4-chlorophenyl)-2-chlorobutyl]imidazole in 0.25 ml of dry dimethylformamide was added to this solution, and the resulting mixture was heated at 60°-70° C. for 5 hours. At the end of this time, the reaction mixture was treated and purified according to the same method as described in Example 1, to give 34 mg of the title compound as an oil.
Reaction SMILES: O[C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C@@H:10]([NH:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][O:26]3)=[CH:19][CH:18]=1)[CH2:9][CH2:8]2)([CH3:4])[CH3:3].C[Si](C#[N:36])(C)C.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C>[NH2:36][C:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C@@H:10]([NH:15][C:16](=[O:30])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C@@H:25]3[CH2:29][CH2:28][CH2:27][O:26]3)=[CH:19][CH:18]=1)[CH2:9][CH2:8]2)([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(O)c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(N)c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Reaction time: 12 h

Procedure:
A mixture, cooled to 0° C., of N-[(S)-6-(1-hydroxy-1-methylethyl)-1,2,3,4-tetrahydronaphthalen-2-yl]-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (0.30 g), glacial acetic acid (1 ml) and trimethylsilyl cyanide (145 mg) was admixed dropwise with sulfuric acid (1.2 ml; 96%). The cooling bath was removed and the mixture was stirred for another 12 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with sodium chloride solution, dried over sodium sulfate and concentrated. The residue was taken up in 1,4-dioxane (20 ml) and boiled at reflux with dilute hydrochloric acid for 30 minutes. The reaction mixture was washed with ethyl acetate and basified with concentrated sodium hydroxide solution. Extraction with dichloromethane gave rise to an organic phase which was dried over sodium sulfate and concentrated. (Alternatively, the hydrolysis of the intermediate formamide can also be achieved by boiling with sodium hydroxide solution.) The product was thus obtained with the molecular weight of 408.55 (C25H32N2O3); MS (ESI): 409 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@@H:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])=[C:4]([F:26])[CH:3]=1.[OH-].[Na+].[NH2:29]O.Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@@H:12]([C:14]3[O:21][NH:29][C:16](=[O:17])[CH:15]=3)[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])=[C:4]([F:26])[CH:3]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(Cl)cc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(Cl)cc1F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 47.1 %

Procedure:
Cis-methyl 2-(4-chloro-2-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.31 g, 5.99 mmol) was dissolved in MeOH (24 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (1.761 mL, 5.99 mmol) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.367 mL, 5.99 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30.8 mL, 185.01 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a slightly yellow solid. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 10-55% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(4-chloro-2-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1 g, 47%) was isolated after. MS m/z 355 (M+H)+
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[OH:21][CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][CH2:27]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[OH:21][CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][N:26]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:27]2
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: OCc1cccc2c1CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC1COc2c(N3Cc4cccc(CO)c4C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 29.3 %

Procedure:
281 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido [1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 179 mg of 4-hydroxymethylisoindoline, 304 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 120 mg of the target compound.
Reaction SMILES: Cl.C(OCC)(=O)C.C(OC([NH:15][CH2:16][CH2:17][CH2:18][C:19]([NH:21][C:22]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25])=[O:20])=O)(C)(C)C>C(OCC)(=O)C>[ClH:32].[NH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH:21][C:22]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25])=[O:20]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)CCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cl)ccc1NC(=O)CCCN
Temperature: 25 °C
Reaction time: 3 h
Yield: 196.9 %

Procedure:
4N hydrogen chloride/ethyl acetate was added to an ethyl acetate solution comprising 2.16 g (5.82 mmol) of methyl 2-({4-[(tert-butoxycarbonyl)amino]butanoyl}amino)-5-chlorobenzoate at 0° C., and the mixture was stirred at room temperature for 3 hours. Thereafter, IPE was added to the reaction mixture. Crystals were collected by filtration, followed by drying, thereby giving 1.76 g of methyl 2-[(4-aminobutanoyl)amino]-5-chlorobenzoate hydrochloride (yield: 99%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:22][N:23]([CH3:25])[CH3:24])=[C:11]([CH:14]=1)[CH2:12][OH:13]>C(#N)C.C(N(CC)CC)C>[C:1]([O:13][CH2:12][C:11]1[CH:14]=[C:7]([Cl:6])[CH:8]=[CH:9][C:10]=1[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][N:23]([CH3:25])[CH3:24])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CN(C)Cc1ccccc1Sc1ccc(Cl)cc1CO
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)OCc1cc(Cl)ccc1Sc1ccccc1CN(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.2 %

Procedure:
A solution of acetyl chloride (2.5 g) in 50 mL of acetonitrile was added dropwise to a solution of 9.8 g of 5-chloro-2-((2-((dimethylamino)methyl)phenyl)thio)benzyl alcohol (Example 2) in 25 mL of triethylamine and 200 mL of acetonitrile. The reaction mixture was stirred for 3 hr at room temperature, filtered and concentrated in vacuo to give a yellow oil. This oil was chromatographed on silica gel with EtOAc as the eluent. Concentration of solvents afforded 3.8 g (34% yield) of 5-chloro-2-((2-((dimethylamino)methyl)phenyl)thio)benzyl acetate as a light yellow oil. Upon standing, oil crystallized to a beige solid, m.p. 41°-44° C.
Reaction SMILES: [Br:1][CH2:2][CH:3]1[O:12][CH2:11][CH:10]2[CH:6]([O:7][C:8]([CH3:14])([CH3:13])[O:9]2)[CH2:5][O:4]1.Br[CH2:16]C1OCC(O)C(O)CO1.C(C(C)=O)C>>[Br:1][CH2:2][CH:3]1[O:12][CH2:11][CH:10]2[CH:6]([O:7][C:8]([CH2:14][CH3:16])([CH3:13])[O:9]2)[CH2:5][O:4]1
Reactant: CC1(C)OC2COC(CBr)OCC2O1
Reactant: OC1COC(CBr)OCC1O
Solvent: CCC(C)=O
Product: CCC1(C)OC2COC(CBr)OCC2O1
Yield: 82 %

Procedure:
4-Bromomethyl-9-ethyl-9-methyl-3,5,8, 10-tetraoxabicyclo[5.3.0]decane was prepared in a similar way to 4-bromomethyl-9,9-dimethyl-3,5,8, 10-tetraoxabicyclo [5.3.0]decane starting from 198.2 mmole (45 g ) of 2-bromomethyl-5,6-dihydroxy-1,3-dioxepane and 1.225 mol (88.3 g) of ethylmethylketone, fractional distillation giving 46 g (82% yield) from 95° to 100° C. (0.25 mbar).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[O:33]([CH2:40][C:41](Cl)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:41](=[O:42])[CH2:40][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)COc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)COc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 μmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, phenoxyacetyl chloride (21 mg, 197 μmol, 3 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Kromasil C18 column, 5 μm, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (20.9 mg, 56% of theory).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:19]([CH3:22])([O-:21])=[O:20].Cl.O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C@H:10]([OH:11])[CH2:22][N+:19]([O-:21])=[O:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](C=O)Cc1ccccc1
Reactant: C[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@H](O)C[N+](=O)[O-]
Yield: 60.6 %

Procedure:
To a stirred solution of 62.3 mg (0.25 mmol) of (R)-2-t-butoxycarbonylamino-3-phenylpropanal [synthesized by the method described in Journal of Medicinal Chemistry, 130, 1162 (1987)] in 1.0 ml of THF was added at 0° C., 0.27 ml (5 mmol) of nitromethane, followed by dropwise addition of 0.5 ml (0.025 mmol) of the lanthanum/(R)-1,1'-bi-2-naphthol complex solution (Reference Example 1, 0.05 mol/l). The resultant mixture was stirred at 0° C. for 2 hours. To this solution were added 0.5 ml of 1N hydrochloric acid and 3 ml of water. The mixture was extracted with diethylether, the extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent; n-hexane-ethyl acetate 8:2) to give 47 mg of ⟦(2S,3R)⟧ (2R,3R)-3-t-butoxycarbonylamino-1-nitro-4-phenyl-2-butanol. Yield 60%. ⟦(2S,3R)⟧ (2R,3R)-3-t-Butoxycarbonylamino-1-nitro-4-phenyl-2-butanol:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[CH2:22]([O:32][C:33](Cl)=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C1C=CC=CC=1>[C:33](=[O:34])([O:32][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCCCOC(=O)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CCCCCCCCCCOC(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1

Procedure:
0.384 G. of 4'-cyano-4-hydroxy-biphenyl are dissolved in 3.2 ml. of absolute pyridine and reacted with 0.527 g. of chloroformic acid n-decyl ester as in Example 1. The 0.822 g. of brownish crystals obtained according to the procedure described in Example 1 are dissolved in benzene and chromatographed on 40 g. of silica gel. Benzene elutes 0.714 g. of colorless crystals which are recrytallized from ether-hexane up to constant melting point and clearing point. The pure 4'-cyano-4-biphenylyl n-decyl carbonate obtained melts at 59.3°-60.0° and has a clearing point of 74.0°. The compound is smectic in the entire liquid crystalline range. UV (EtOH): ε 270 = 26400.
Reaction SMILES: O.[NH2:2][NH2:3].[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=O)=[CH:9][CH:8]=1)([O-:6])=[O:5]>C(O)C>[N+:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:2][NH2:3])[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:16])=[CH:9][CH:8]=1)([O-:6])=[O:5]
Reactant: O=C(C(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NN=C(C(=O)c1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
Benzoin, 60 g, is suspended in 600 ml acetic anhydride and 60 ml concentrated sulfuric acid is added under ice cooling. Under continued ice cooling, 33 g potassium nitrate is added in small portions. The reaction is stirred at room temperature for two days and poured over ice. The aqeuous portion is decanted off and the remaining oil is taken up in ether, washed with water, sodium bicarbonate solution, dried over potassium carbonate and stripped. The oil residue is added dropwise to concentrated nitric acid at 0°, followed by heating gently on a steam bath for 2 hours. After cooling, the solution is poured over ice. The solid which forms is removed by filtration (~40 g) and recrystallized three times from glacial acetic acid, to yield 5.5 g of a yellow solid, 4-nitrobenzil. To a solution of 0.7 g hydrazine hydrate in 50 ml ethanol is added a suspension of 4-nitrobenzil, 5.1 g, in 150 ml of ethanol. The reaction is heated on a steam bath for 1 hour and cooled. Plate-like crystals separate out and are removed by filtration. Yield 3.5 g. The product is recrystallized from 200 ml ethanol. M.P. 166°-173°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH:15][C:16](=[O:18])[CH3:17].[CH2:20]([Sn](CCCC)(CCCC)C=C)[CH2:21]CC.O.O.[F-].[K+]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([CH:20]=[CH2:21])[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH:15][C:16](=[O:18])[CH3:17]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1NC(C)=O
Agent: [Pd]
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1cc(C(=O)OC)c(NC(C)=O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
A solution of 2-acetylamino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (18.0 g, 46.5 mmol) in dry toluene (72 mL) was degassed for 5 min at the ultrasound bath. The solution was then treated with tributyl(vinyl)tin (28 mL, 93 mmol) and tetrakis-(triphenylphosphine)-palladium (2.77 g, 2.33 mmol), and heated to reflux for 2 h. The mixture was allowed to cool to r.t. and potassium fluoride dihydrate (22 g) was then added. This suspension was stirred for 30 min at r.t. and was then filtered on a short pad of silica gel. The filter was washed with diethyl ether and the filtrate was concentrated in vacuo. The crude product was taken up in hexanes and the suspension was filtered. The filtrate was concentrated in vacuo again and allowed to stand at r.t. for 7 d. The solid formed was filtered, washed with hexanes and combined with the product previously isolated to give 2-acetylamino-4-trifluoromethyl-5-vinyl-benzoic acid methyl ester (10.0 g, 34.8 mmol, 75%) as a beige solid, m.p. 79-81° C., ESI-MS: m/z 288 [M+H]+.
Reaction SMILES: [C:1]1(Cl)[C:7](=[O:8])[C:6]([Cl:9])=[C:5]([Cl:10])[C:3](=[O:4])[C:2]=1[Cl:11].C(=O)([O-])O.[Na+].[CH3:18][CH:19]([OH:22])[CH2:20][CH3:21]>CCC(C)=O>[Cl:9][C:6]1[C:7]([C:1]([O:22][CH:19]([CH2:20][CH3:21])[CH3:18])=[C:2]([Cl:11])[C:3](=[O:4])[C:5]=1[Cl:10])=[O:8]
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Reactant: CCC(C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCC(C)OC1=C(Cl)C(=O)C(Cl)=C(Cl)C1=O
Temperature: 25 °C
Yield: 86 %

Procedure:
Chloranil (12.3 parts) was dissolved in MEK (300 parts) before adding sodium hydrogen carbonate (8 parts). Aqueous butan-2-ol (50 parts, 1:1) was then added and the mixture was stirred at room temperature until no starting material remained. At the end of the reaction the filtered solution was shown by HPLC to contain 86% title product. The product was used in subsequent reactions without isolation.
Reaction SMILES: NC(C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2C(F)(F)F)C=1)CCC(O)=O.[C:33]([C@H:37]1[CH2:42][CH2:41][C@H:40]([O:43][C:44]2[CH:45]=[C:46]3[C:51](=[CH:52][CH:53]=2)[CH:50]=[C:49]([C:54]([N+:61]([O-])=O)([CH3:60])[CH2:55][CH2:56][C:57]([OH:59])=[O:58])[CH:48]=[CH:47]3)[CH2:39][CH2:38]1)([CH3:36])([CH3:35])[CH3:34]>>[NH2:61][C:54]([C:49]1[CH:48]=[CH:47][C:46]2[C:51](=[CH:52][CH:53]=[C:44]([O:43][C@H:40]3[CH2:41][CH2:42][C@H:37]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:38][CH2:39]3)[CH:45]=2)[CH:50]=1)([CH3:60])[CH2:55][CH2:56][C:57]([OH:59])=[O:58]
Reactant: CC(CCC(=O)O)(c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]
Agent: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C(N)CCC(=O)O)ccc3c2C(F)(F)F)CC1
Product: CC(N)(CCC(=O)O)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1

Procedure:
4-amino-4-(6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)pentanoic acid was synthesized as per 4-amino-4-(6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)naphthalen-2-yl)butanoic acid (Example 203) in 3% yield using 4-(6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)-4-nitropentanoic acid as starting material. MS: m/z=381.53 [M−NH2]+. 1H NMR (MeOD) δ: 7.91 (d, J=8.7 Hz, 1H), 7.83-7.88 (m, 2H), 7.55 (dd, J=8.7, 1.9 Hz, 1H), 7.31 (d, J=2.3 Hz, 1H), 7.21 (dd, J=9.1, 2.3 Hz, 1H), 4.34-4.47 (m, 1H), 2.69 (s, 3H), 2.40-2.57 (m, 2H), 2.23-2.39 (m, 3H), 2.06-2.19 (m, 1H), 1.91-2.01 (m, 2H), 1.88 (s, 2H), 1.39-1.55 (m, 2H), 1.11-1.39 (m, 3H), 0.96 (s, 9H)
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH:21]([CH3:23])[CH3:22])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.Cl>[CH:21]([C:7]1[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][CH:12]=2)[O:10][C:6]=1[CH2:4][OH:3])([CH3:23])[CH3:22]
Reactant: CCOC(=O)c1oc(-c2ccc(C(F)(F)F)cc2)nc1C(C)C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)oc1CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazole-5-carboxylic acid ethyl ester (0.53 g, 1.62 mmol) is stirred in tetrahydrofuran (25 mL) at 0° C. Lithium aluminum hydride (0.122 g, 3.23 mmol) is added and the mixture is stirred 18 hr at room temperature. The mixture is diluted carefully with 1M aqueous hydrochloric acid (10 mL), and the product is extracted with ethyl acetate (three 75 mL portions). The extracts are combined, dried over anhydrous magnesium sulfate, filtered, and concentrated to afford [4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-methanol as a white solid, 0.46 g, 100%. MS (M++1) 286.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)(=[O:27])=[O:26])[CH2:23][CH2:22]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13]2)(=[O:27])=[O:26])[CH2:23][CH2:22]1
Reactant: O=S(=O)(CCCCCCBr)NC1CC1
Reactant: Clc1cccc(C(c2ccccc2)N2CCNCC2)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccccc2)c2cccc(Cl)c2)CC1)NC1CC1
Yield: 67 %

Procedure:
1-[(3-Chlorophenyl)phenylmethyl]piperazine (435.2 mg, 1.52 mmol) and N-cyclopropyl-6-bromohexanesulfonamide (474.5 mg, 1.67 mmol) were refluxed in toluene (15 ml) in the presence of triethylamine (169 mg, 1.67 mmol) for 42 hours. The reaction mixture was washed with water, and the organic layer was dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfonamide (499.0 mg) as an oil (yield based on 1-[(3-chlorophenyl)phenylmethyl]piperazine: 67.1%).