Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C2C=CC=CC=2SC=1C(O)=O.B(Br)(Br)Br.C[O:20][C:21]1[CH:32]=[CH:31][C:24]2[S:25][CH:26]=[C:27]([C:28]([OH:30])=[O:29])[C:23]=2[CH:22]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[OH:20][C:21]1[CH:32]=[CH:31][C:24]2[S:25][CH:26]=[C:27]([C:28]([OH:30])=[O:29])[C:23]=2[CH:22]=1
Reactant: COc1ccc2scc(C(=O)O)c2c1
Agent: BrB(Br)Br
Agent: COc1c(C(=O)O)sc2ccccc12
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)c1csc2ccc(O)cc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The methoxybenzo[b]thiophene carboxylic acid from Step 5 was slurried in toluene (35 L) and then warmed to 50° C. To an addition funnel containing toluene (9 L) was added boron tribromide (4.3 kg) and then the solution added over 1 hr to the slurry of 5-methoxy-3-benzo[b]thiophenecarboxylic acid. The mixture was aged for 8 hr. The reaction mixture was cooled to room temperature and 15%NaOH was slowly added (16 kg). To the three phase mixture was added 2 kg Solka Flok (filter aid) and then filtered to remove boric acid. The layers were then cut. To the aqueous layer was added 27 L THF and 4.5 kg NaCl, and then acidified to pH=1-3 with concentrated HCl (2.7 L). The layers were cut and the bottom layer extracted again with 15 L THF. The combined THF layers were then concentrated to a minimum stirred volume and solvent switched into toluene (kf<1000 ug/ml). The slurry was then cooled to 2-5° C., aged one hour and filtered, washing with cold toluene (10 L). The cake was dried on the filter pot with a nitrogen sweep under vacuum.
Reaction SMILES: [O:1]=[C:2]([N:26]1[CH2:31][CH2:30][CH:29]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)[CH2:28][CH2:27]1)[CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18]CC2C=CC=CC=2)[NH:9][N:8]=1)=[O:6]>CO.[Pd]>[O:1]=[C:2]([N:26]1[CH2:31][CH2:30][CH:29]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:40])([F:41])[F:42])[CH:34]=2)[CH2:28][CH2:27]1)[CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[NH:9][N:8]=1)=[O:6]
Reactant: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cc(-c2ccccc2OCc2ccccc2)[nH]n1
Agent: [Pd]
Solvent: CO
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cc(-c2ccccc2O)[nH]n1
Reaction time: 3 h
Yield: 34.9 %

Procedure:
10% Pd/C (50 mg) was added to a stirred solution of 5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide (195 mg, 0.34 mmol) (prepared by method used for the synthesis of Intermediate 45) in methanol (30 mL) under inert atmosphere and stirred under H2 atmosphere with pressure for 3 hrs. The reaction mixture was filtered through celite, the celite was washed with methanol and the filtrate was concentrated under reduced pressure Washing with ethyl acetate afforded 58 mg (35% Yield) of 5-(2-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 489, 91.45%. 1H NMR (300 MHz, DMSO-d6): δ8.2 (m, 1H), 7.64 (d, 1H), 7.5 (t, 1H), 7.26 (t, 2H), 7.1 (m, 2H), 6.94 (m, 1H), 6.84 (t, 1H), 4.8 (m, 1H), 4.2 (d, 2H), 3.9 (m, 1H), 3.7 (m, 1H), 3.4 (m, 2H), 1.9 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][SiH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:14]Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][SiH:11]([Cl:14])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C2CC[SiH2]CC2)cc1
Reactant: ClCl
Solvent: Cc1ccccc1
Product: Fc1ccc(C2CC[SiH](Cl)CC2)cc1

Procedure:
In the same manner as in Example 9, 21.0 g of 4-(p-fluorophenyl)-1,1-dichloro-1-silacyclohexane was obtained from 4-(p-fluorophenyl)-1,1-diphenyl-1-silacyclohexane obtained in Preparatory Example 5. A mixture of 50.0 g of methanol and 30 g of triethylamine was added to the solution obtained above, followed by agitation under reflux for 1 hour. The resultant solution was concentrated, to which 200 ml of hexane was added thereby permitting secondarily produced hydrochloride to be precipitated. The precipitate was removed by filtration and the resulting filtrate was concentrated to obtain a mixture of 4-(p-fluorophenyl)-1,1-dimethoxy-1-silacyclohexane and acetophenone. The mixture was subjected to distillation under reduced pressure to remove the acetophenone therefrom. The resultant residue was dissolved in 100 ml of THF and added to a solution of 10.0 g of lithium aluminium hydride in 100 ml of THF. The reaction mixture was agitated under reflux for 1 hour, which was poured into 200 ml of 5% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried and concentrated by a usual manner, followed by purification through silica gel chromatography to obtain 14.7 g of 4-(p-fluorophenyl)-1-silacyclohexane. Subsequently, 14.0 g of 4-(p-fluorophenyl)-1-silacyclohexane was added to 100 ml of toluene, into which chlorine gas was blown to obtain 4-(p-fluorophenyl)-1-chloro-1-silacyclohexane. This solution was dropped in 100 ml of a THF solution of 1 mole/liter of trans-2-(4-n-propylcyclohexyl)ethylmagnesium bromide at room temperature. The reaction mixture was charged into 200 ml of 5% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried and concentrated, followed by purification through silica gel chromatography to obtain 20.8 g of the intended product. The thus obtained product exhibited nematic liquid crystal properties at a temperature between 49.1° C. and 62.9° C. and was found to be very useful as a liquid crystal substance.
Reaction SMILES: [BH4-].[Na+].[CH:3]([CH:6]1[CH2:14][C:13]2[C:8](=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[CH:10]=[CH:11][CH:12]=2)[C:7]1=O)([CH3:5])[CH3:4].C1(C)C=CC=CC=1.S(=O)(=O)(O)O>CO>[CH:3]([C:6]1[CH2:14][C:13]2[C:8]([CH:7]=1)=[C:9]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:17][CH:16]=1)[CH:10]=[CH:11][CH:12]=2)([CH3:5])[CH3:4]
Reactant: CC(C)C1Cc2cccc(-c3ccc(C(C)(C)C)cc3)c2C1=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)C1=Cc2c(cccc2-c2ccc(C(C)(C)C)cc2)C1
Temperature: 50 °C
Reaction time: 6 h
Yield: 96.3 %

Procedure:
4.83 g of sodium borohydride and 39.1 g of 2-isopropyl-7-(4′-tert-butylphenyl)-1-indanone together with 11.8. ml of toluene are placed in a reaction vessel. At 50° C., 22.5 ml of methanol are slowly added and the reaction mixture is stirred for 6 hours at 50° C. After cooling to room temperature, 50 ml of 2N sulfuric acid are added and the mixture is stirred vigorously for another 30 minutes. The mixture is subsequently transferred to a separating funnel, the phases are separated and the aqueous phase is shaken twice with a total of 60 ml of 2N sulfuric acid. The organic phases are combined and dried over magnesium sulfate. The solvent of the reaction mixture is removed virtually completely and 200 ml of toluene and 0.4 g of p-toluenesulfonic acid are subsequently added to the residue. Water is distilled from the reaction mixture by heating for 1.5 hours on a water separator until reaction is complete. The reaction mixture is subsequently washed once with 100 ml of saturated sodium hydrogen carbonate solution and dried over magnesium sulfate. After separating off the magnesium sulfate, the residue is dried in an oil pump vacuum. This gives 35.7 g of 2-isopropyl-4-(4′-tert-butylphenyl)indene (total yield: 96%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[BH4-].[Na+].II>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH2:7][OH:8])[CH:10]=1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1cc(Br)ccc1Cl
Yield: 97.3 %

Procedure:
5-bromo-2-chlorobenzoic acid (20 g, 84.92 mmol) in dry THF (50 mL) was added to a solution of sodium borohydride (8 g, 212.34 mmol) in dry THF (128 mL) in 15 min at r.t. To the resulting reaction mixture a solution of Iodine (26.85 g, 106.15 mmol) in dry THF (170 mL) was added in another 15 min. Stirring was continued till the Iodine color disappeared after which the reaction mixture was heated to reflux temperature for 18 h. After completion of the reaction as confirmed by TLC, volatiles were evaporated in vacuo. The residue obtained was dissolved in ethyl acetate (200 mL), washed with a saturated solution of NaHSO3 (200 mL) and brine (200 mL) successively. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 3:7 Ethyl acetate:Pet. Ether) to afford the title compound (18.3 g, 97%).
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:35][CH3:36])([O:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.[H][H]>CO.O.[C].[Pd]>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:35][CH3:36])([O:27][C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)=[O:26])[C:13]([OH:15])=[O:14]
Reactant: [H][H]
Reactant: COP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1ccc(C)cc1
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COP(=O)(CCC(N)C(=O)O)Oc1ccc(C)cc1
Yield: 50.8 %

Procedure:
Next, 0.70 g (1.37 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-[methyl(4-methylphenyl)phosphono]butanoate was dissolved in 30 mL of a solvent mixture of methanol and water at 2:1 and mixed with 270 mg of 5% palladium-carbon and hydrogen gas was introduced for 2 hours. The palladium-carbon was removed by Celite filtration and the filtrate was concentrated under a reduced pressure. The residue was purified by medium pressure reversed-phase column chromatography ODS-S-50B (Yamazen Co., Ltd., Osaka). The column was eluted with a linear gradient of 30 to 60% methanol (6 mL/min flow rate) and the fractions of the compound eluted with 60% methanol were collected. After the elution and purity of the compound were confirmed by TLC (BuOH/AcOH/H2O=5:2:2, ninhydrin coloration), vacuum concentration and freeze drying were carried out to obtain 2-amino-4-[methyl(4-methylphenyl)phosphono]butanoic acid (0.20 g, yield 51%) as a colorless solid.
Reaction SMILES: [N:1]1([C:11]([O:13][CH2:14][CH:15]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:12])[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7](OC)=[O:8].[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1.ClCCl>[CH:7]([CH:2]1[CH2:3][O:4][CH2:5][CH2:6][N:1]1[C:11]([O:13][CH2:14][CH:15]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[C:22]2[C:27]1=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:12])=[O:8]
Reactant: COC(=O)C1COCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=CC1COCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 4-(9H-fluoren-9-ylmethyl) 3-methyl 3,4-morpholinedicarboxylate (0.6 g, 1.633 mmol) in anhydrous toluene (80 mL) cooled to −78° C. in a dry-ice acetone bath under nitrogen was added dropwise 1.0 M diisobutylaluminium hydride in hexanes (6.53 mL, 6.53 mmol) over 4 minutes. The solution was stirred at −78° C. for 1.5 hours. The reaction was quenched at −78° C. with methanol (1.5 mL) and then aqueous HCl (1 M, 50 mL). The mixture was allowed to warm to ambient temperature and the phases separated. The aqueous was washed with ethyl acetate (2×50 mL). The combined organic extracts were dried (MgSO4), filtered and the solvent removed in vacuo to leave an oil. The residue was loaded in dichloromethane and purified by flash chromatography (Si) using 0-100% ethyl acetate-cyclohexane over 30 minutes. The appropriate fractions were combined and evaporated in vacuo to give the required product as a white foam, 329 mg. LCMS [LCMS4] Rt 2.43 min, m/z (ES+) 338 (M+H).
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([O:13][CH3:14])=[O:12])[CH:4](O)[CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:14][O:13][C:11]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[S:1][CH2:2][CH:3]=[CH:4]2)=[O:12]
Reactant: COC(=O)c1cccc2c1SCCC2O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2c1SCC=C2
Reaction time: 2 h
Yield: 87.3 %

Procedure:
Methyl thiochroman-4-ol-8-carboxylate (0.337 g, 1.50 mmol) was dissolved in toluene (25 ml) and was treated with p-toluenesulphonic acid (0.028 g, 0.15 mmol). The mixture was then heated to reflux with stirring. After 2 h, the reaction mixture was allowed to cool and was washed with sodium hydrogen carbonate solution. The aqueous layer was then extracted with EtOAc (1×), and the combined organic layers were dried (Na2SO4) and evaporated under reduced pressure to give a pale yellow oil which was purified by silica-gel chromatography (pentane: Et2O 2:1 as eluant) to give the title compound (D2b) as a pale yellow oil (0.270 g, 87%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[C:14]([CH:27]=[CH:28][CH:29]=1)[C:15]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)=[O:16])(=[O:10])=[O:9].F[C:31]1C=CC=C[C:32]=1S(Cl)(=O)=O>>[CH2:31]([O:23][C:22](=[O:24])[C:21]1[CH:25]=[CH:26][C:18]([NH:17][C:15](=[O:16])[C:14]2[CH:27]=[CH:28][CH:29]=[C:12]([NH:11][S:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])(=[O:9])=[O:10])[CH:13]=2)=[CH:19][CH:20]=1)[CH3:32]
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: O=C(O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccccc3F)c2)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3ccccc3F)c2)cc1

Procedure:
4-[3-(2-Fluoro-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=413.1 (M−H), was prepared in analogy to example 1, steps A to D. Step C was performed using 2-fluoro-benzensulfonyl chloride and yielded 4-[3-(2-fluoro-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: O1CCCCC1[O:7][CH:8]([CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:9][O:10][N:11]=[C:12]([Cl:19])[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[CH2:27]([NH2:31])[CH2:28][CH2:29][CH3:30].Cl>C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)(C)C>[ClH:19].[OH:7][CH:8]([CH2:20][N:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[CH2:9][O:10][NH:11][C:12]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[N:31][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCN
Reactant: ClC(=NOCC(CN1CCCCC1)OC1CCCCO1)c1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: CC(C)O
Product: CCCCN=C(NOCC(O)CN1CCCCC1)c1cccnc1
Temperature: 60 °C

Procedure:
A mixture of 3.7 g (9.68 mmol) of N-[2-[(2-tetrahydropyranyl)oxy]-3-(1-piperidinyl)propoxy]-3-pyridinecarboximidoyl chloride and 40 ml (0.41 mol) n-butylamine was refluxed for 3 hours. The excess of amine was evaporated in vacuum affording dark-brown oil, which was dissolved in 40 ml of ethanol containing 3.0 g of 4-toluenesulphonic acid and the mixture was heated at 60° C. for one hour. The solvent was removed under reduced pressure, the residue was made alkaline (pH 10) with 2 N of sodium hydroxide solution then extracted three times with chloroform. The organic solution was dried over sodium sulfate, filtered and the solvent was evaporated in vacuum. The dark oily residue was purified by chromatography to give the pure base, which was dissolved in 20 ml of ethanol and acidified with equivalent amount of dry hydrochloric acid dissolved in isopropyl alcohol to give the title compound as a pale-yellow crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([S:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:30]([O:32][CH2:33]Cl)[CH3:31]>O1CCCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:33][O:32][CH2:30][CH3:31])[C:10]([S:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)=[CH:11][C:12]=2[C:13]#[N:14])=[CH:6][CH:7]=1
Reactant: N#Cc1cc(Sc2ccc(Cl)c(Cl)c2)[nH]c1-c1ccc(Cl)cc1
Reactant: CCOCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOCn1c(Sc2ccc(Cl)c(Cl)c2)cc(C#N)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
A mixture of 2-(p-chlorophenyl)-5-[(3,4-dichlorophenyl)thio]pyrrole-3-carbonitrile (820 mg, 2.16 mmol) and potassium tert-butoxide (266 mg, 2.37 mmol) in tetrahydrofuran is stirred at room temperature for 30 minutes, treated with chloromethyl ethyl ether (225 mg, 2.37 mmol), stirred at room temperature for 4 hours, and diluted with water and ethyl acetate. The phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phase and extracts are combined, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a syrup. The syrup is crystallized from an ethyl acetate/hexanes solution to give the title product as a solid (780 mg, mp 95°-97° C.).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[CH:12]=[C:11]([C:14]([O:16]CC)=O)[CH:10]=[CH:9]2.[CH3:19][S:20][CH2:21][S:22]([CH3:24])=[O:23]>CN(C)C=O>[O:16]=[C:14]([C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[C:4]([Cl:3])[CH:5]=[CH:6][CH:7]=2)[CH:12]=1)[CH:21]([S:20][CH3:19])[S:22]([CH3:24])=[O:23]
Reactant: CCOC(=O)c1ccc2cccc(Cl)c2c1
Reactant: CSCS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSC(C(=O)c1ccc2cccc(Cl)c2c1)S(C)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.4 %

Procedure:
A suspension of 9.2 g sodium hydride in 50 ml of N,N-dimethylformamide was added in one portion to a stirred solution of 5.6 g (24 mM) of ethyl 8-chloro-2-naphthylformate and 4.4 g (36 mM) of methyl methylthiomethyl sulfoxide in 10 ml of N,N-dimethylformamide. The reaction mixture was stirred for four hours at 25° C., and then concentrated to dryness. The product was dissolved in 250 ml of ethyl acetate and the solution was washed with 5% hydrochloric acid, saturated sodium bicarbonate and brine. The solution was dried and the solvent was removed by evaporation to give 4.73 g (63% yield) of 1-oxo-1-(8-chloro-2-naphthyl)-2-methylthio-2-methylsulfinylethane. A solution of 3.12 g (10 mM) of the product in 150 ml of formic acid and 12 ml of acetic anhydride was stirred at 65° C. for thirty minutes. To the reaction mixture were added 856 mg (4 mM) of sodium periodate and stirring was continued for an additional fifteen minutes. The reaction mixture was cooled and concentrated to dryness, and the product was dissolved in ethyl acetate, washed with sodium bicarbonate and brine, and the solvent was removed to give 1.2 g (46% yield) of methylthio α-oxo-α-(8-chloro-2-naphthyl)acetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][NH2:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][C:37]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:41])[C:38](O)=[O:39].CCN(CC)CC.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:34][NH:35][C:38](=[O:39])[C:37]([CH3:36])([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH3:41])[C@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN)C(C)C)ccc1OC
Reactant: CC(C)(C(=O)O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC(=O)C(C)(C)c2ccccc2)C(C)C)ccc1OC
Reaction time: 8 h

Procedure:
To a solution of (3R,4R)-3-aminomethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.405 mmol) and α,α-dimethylphenylacetic acid (101 mg, 0.608 mmol) in CH2Cl2 (3 mL) is subsequently added Et3N (0.085 mL, 0.608 mmol), 1-hydroxy-7-azabenzotriazole (84 mg, 0.608 mmol; commercially available from ABCR, AV24631) and N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide HCl (118 mg, 0.608 mmol). Stirring is continued overnight at room temperature, the mixture is then diluted with CH2Cl2, and the organic layer is subsequently washed with 2N HCl, saturated aqueous NaHCO3 and brine, dried (MgSO4) and concentrated. Purification by RP-HPLC on a PrepC18 OBD column (dimensions: 30×100 mm; 5 μM particle size, SunFire Ltd) and using a 95-5% gradient of MeCN/H2O 5:95 (containing 0.1% TFA) to MeCN/H2O 95:5 (containing 0.1% TFA) over 20 min gives the title compound as colorless oil. MS [M]+=640.2. tR (HPLC, Nucleosil C18HD column, 20-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 5.2 min.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Li])CCC.[CH2:20]([O:22]C=O)C>C1COCC1>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]([CH:20]=[O:22])=[CH:7][N:6]=1
Reactant: CCOC=O
Reactant: CC(C)(C)CNc1nc(Cl)ncc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)CNc1nc(Cl)ncc1C=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of (5-bromo-2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine (30 g, 108 mmol) in THF (500 ml) is added n-butyllithium (1.6 mol/l in n-hexane, 148 ml, 237 mmol) dropwise at −78° C. and the mixture is stirred for 10 min. Ethylformate (19 ml, 230 mol) is added dropwise to the mixture at −78° C., and the reaction mixture is allowed to warm to ambient temperature. After being stirred for 1 hour, the reaction mixture is quenched with saturated NH4Cl at −78° C. and then extracted with AcOEt. The combined extracts are washed with water, brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent:n-hexane:AcOEt=4:1) give 2-chloro-4-(2,2-dimethyl-propylamino)-pyrimidine-5-carbaldehyde. Rf=0.56 (n-hexane:AcOEt=1:1). 1H NMR (400 MHz, DMSO-d6) δ 1.00 (s, 9H), 3.41 (d, 2H), 8.40 (s, 1H), 8.88 (brs, 1H), 9.84 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH2:10])[S:9][C:5]=2[CH:4]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[C:36]([N:39]1[CH:43]([C:44]2[CH:45]=[CH:46][C:47]([O:55][CH3:56])=[C:48]([CH:54]=2)[O:49][CH2:50][C:51](O)=[O:52])[CH2:42][C:41]([C:57]2[CH:62]=[C:61]([O:63][CH3:64])[C:60]([O:65][CH3:66])=[C:59]([O:67][CH3:68])[CH:58]=2)=[N:40]1)(=[O:38])[CH3:37]>ClCCl.O>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH:10][C:51](=[O:52])[CH2:50][O:49][C:48]3[CH:54]=[C:44]([CH:43]4[N:39]([C:36](=[O:38])[CH3:37])[N:40]=[C:41]([C:57]5[CH:62]=[C:61]([O:63][CH3:64])[C:60]([O:65][CH3:66])=[C:59]([O:67][CH3:68])[CH:58]=5)[CH2:42]4)[CH:45]=[CH:46][C:47]=3[O:55][CH3:56])[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc(C2CC(c3cc(OC)c(OC)c(OC)c3)=NN2C(C)=O)cc1OCC(=O)O
Reactant: Nc1nc2ccc(C(F)(F)F)cc2s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C2CC(c3cc(OC)c(OC)c(OC)c3)=NN2C(C)=O)cc1OCC(=O)Nc1nc2ccc(C(F)(F)F)cc2s1
Yield: 801.6 %

Procedure:
To a solution of 6-(trifluoromethyl)-2-aminobenzothiazole (218 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetic acid (3) (458 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (10i) (528 mg, 80% yield).