Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+].[NH2:9][C@H:10]([C:14]([OH:16])=[O:15])[CH:11]([CH3:13])[CH3:12].Cl[C:18]([O:20][CH3:21])=[O:19]>>[CH3:21][O:20][C:18]([NH:9][C@@H:10]([CH:11]([CH3:13])[CH3:12])[C:14]([OH:16])=[O:15])=[O:19]
Reactant: COC(=O)Cl
Reactant: CC(C)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 3.25 h
Yield: 102.9 %

Procedure:
Na2CO3 (1.83 g, 17.2 mmol) was added to NaOH (33 mL of 1M/H2O, 33 mmol) solution of L-valine (3.9 g, 33.29 mmol) and the resulting solution was cooled with ice-water bath. Methyl chloroformate (2.8 mL, 36.1 mmol) was added dropwise over 15 min, the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 3.25 hr. The reaction mixture was washed with ether (50 mL, 3×), and the aqueous phase was cooled with ice-water bath and acidified with concentrated HCl to a pH region of 1-2, and extracted with CH2Cl2 (50 mL, 3×). The organic phase was dried (MgSO4) and evaporated in vacuo to afford Cap-51 as a white solid (6 g). 1H NMR for the dominant rotamer (DMSO-d6, δ=2.5 ppm, 500 MHz): 12.54 (s, 1H), 7.33 (d, J=8.6, 1H), 3.84 (dd, J=8.4, 6.0, 1H), 3.54 (s, 3H), 2.03 (m, 1H), 0.87 (m, 6H). HRMS: Anal. Calcd. for [M+H]+ C2H14NO4: 176.0923. found 176.0922.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[H-].[Na+].I[CH3:34]>CN(C=O)C>[CH3:34][N:21]([C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:29])[F:30])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86.9 %

Procedure:
tert-Butyl (4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)carbamate (120 mg, 0.286 mmol) was dissolved in anhydrous DMF (2.0 mL) under N2 and cooled to 0° C. NaH (60% suspension in mineral oil; 15 mg, 0.372 mmol) was added, and the mixture was stirred for 10 min at 0° C. Iodomethane (23 μL, 0.372 mmol) was added, and the mixture was warmed to ambient temperature and stirred for 1 h. The mixture was quenched with aqueous NH4Cl and extracted with 80% EtOAc/hexanes (×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude product was applied to a silica gel column, and elution with a 15% to 40% to 80% EtOAc/hexanes gradient provided the title compound (108.0 mg, 87%) as a white solid: mp 125-128° C.; 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.14 (d, J=8.6 Hz, 2H), 7.79 (d, J=8.9 Hz, 2H), 7.38 (d, J=9.8 Hz, 2H), 7.35 (d, J=8.8 Hz, 2H), 3.31 (s, 3H), 1.47 (s, 9H); HRMS-FAB (m/z) [M+H]+ calcd for C21H21F3N4O3, 434.156. found, 434.157.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].S(Cl)([Cl:15])(=O)=O>>[Cl:15][CH:5]([C:4](=[O:11])[CH2:3][O:2][CH3:1])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(=O)COC
Reactant: O=S(=O)(Cl)Cl
Product: CCOC(=O)C(Cl)C(=O)COC

Procedure:
The title compound was prepared in a manner analogous to Intermediate 124 starting from ethyl 4-methoxy-3-oxobutanoate (Intermediate 5) and sulfuryl chloride.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[C:8]([C:12]1[CH:38]=[CH:37][C:15]([CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:34]=[CH:35][CH:36]=2)[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30](=[O:33])(=[O:32])[NH2:31])=[O:22])=[CH:14][CH:13]=1)([CH3:11])([CH3:10])[CH3:9]>CN(C)C1C=CN=CC=1.O1CCCC1>[C:8]([C:12]1[CH:38]=[CH:37][C:15]([CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:34]=[CH:35][CH:36]=2)[C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[S:30]([NH:31][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])(=[O:32])=[O:33])=[O:22])=[CH:14][CH:13]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)c1ccc(COc2cccc(C(=O)Nc3ccccc3S(N)(=O)=O)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
In a stream of nitrogen and at 0° C., 0.09 ml (0.75 mmol) of pivaloyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 300 mg (0.68 mmol) of 3-(4-t-butylbenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 2 and 167 mg (1.36 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 284 mg (yield: 80.0%) of the title compound.
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:11]([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)C1C=CC=CC=1.C(O)C.Cl>CO>[Cl:25][C:23]1[CH:24]=[C:19]([S:18][C:12]2[N:11]([CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:10]([CH2:9][OH:8])=[N:14][C:13]=2[CH:15]([CH3:17])[CH3:16])[CH:20]=[C:21]([Cl:26])[CH:22]=1
Reactant: CC(C)c1nc(COCc2ccccc2)n(CCCc2ccccn2)c1Sc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CC(C)c1nc(CO)n(CCCc2ccccn2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
To 300 mg of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(3-(2-pyridyl)propyl)imidazole was added 10 ml of ethanol and 20 ml of 36% hydrochloric acid, and the mixture was stirred at 90° C. for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, an aqueous sodium hydrogen carbonate solution was added, and extracted with ethyl acetate. The extract was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:methanol=10:1)to give 127 mg of 5-(3,5-dichlorophenylthio)-4-isopropyl-2-hydroxymethyl-1-(3-(2-pyridyl)propyl)-1H-imidazole (yield 51%).
Reaction SMILES: [OH-].[Na+].[C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]([CH2:14][CH3:15])[C:11](O)=[O:12].S(Cl)([Cl:24])=O>>[C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]([CH2:14][CH3:15])[C:11]([Cl:24])=[O:12]
Reactant: CCC(Cc1ccccc1-c1ccccc1)C(=O)O
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCC(Cc1ccccc1-c1ccccc1)C(=O)Cl
Yield: 106.3 %

Procedure:
To a 100-ml three-necked round flask (equipped with a stirrer tip, a Dimroth condenser, a thermometer and a trap of NaOH) were introduced 13.3 g (52.4 mmol) of 3-(2-biphenylyl)-2-ethylpropionic acid and 25.9 ml (355 mmol) of thionyl chloride, and they were refluxed for 2.5 hours with heating in a nitrogen atmosphere. After the reaction was completed, the unreacted thionyl chloride was distilled off under reduced pressure to obtain 15.2 g of a crude product as a yellow orange liquid. This acid chloride was used for the next reaction without further purification. The properties of the product thus obtained are described below.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:14]([Sn](CCCC)(CCCC)CCCC)[CH:15]=[CH2:16].[F-].[K+]>CN(C=O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:16]([C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:3]=1[NH2:4])[CH:15]=[CH2:14]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: Nc1ccc(OC(F)(F)F)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCc1cc(OC(F)(F)F)ccc1N
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of 2-bromo-4-(trifluoromethoxy)aniline (75 g, 293 mmol) in DMF (1000 ml) was added Pd(PPh3)4 (13.5 g, 11.7 mmol) and allyltributyltin (116 g, 351 mmol) and the reaction mixture was stirred at 80° C. for 16 h. The mixture was cooled to room temperature and saturated aqueous KF solution was added. The mixture was diluted with ethyl acetate (1500 mL) and washed with 1:1 H2O: saturated aqueous NaCl solution (2×750 mL) and saturated aqueous KF (1×). The aqueous layers were combined and extracted with ethyl acetate (250 mL). The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure to give the crude product, which was absorbed onto silica and purified by chromatography eluting with 1% ethyl acetate in petroleum ether to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:17])[C:10]3[CH:11]=[CH:12][CH:13]=[N:14][C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C@H:19]([C@H:21]1[CH2:25][N:24]([C@@H](C2C=CC=CC=2)C)[C:23](=[O:34])[CH2:22]1)[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>C(Cl)Cl>[C:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[N:14]3)=[C:9]([O:17][C@@H:19]([C@H:21]3[CH2:25][NH:24][C:23](=[O:34])[CH2:22]3)[CH3:20])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](O)[C@@H]1CC(=O)N([C@H](C)c2ccccc2)C1
Reactant: Oc1cc(-c2ccccc2)cc2ncccc12
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-c2ccccc2)cc2ncccc12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Reaction time: 21 h
Yield: 17.8 %

Procedure:
30 mg of 7-Phenylquinolin-5-ol, 32.5 mg of (R)-4-((S)-1-hydroxyethyl)-1-((R)-1-phenylethyl)pyrrolidin-2-one and 150 mg of triphenylphosphine were dissolved in 3 mL of DCM. 125.5 mg of Di-tertbutyl-azodicarboxylate (DBAD) was added and the mixture stirred for 21 h at room temperature. The mixture was diluted with DCM and extracted with 1N NaOH and water. The organic phase was concentrated in vacuo and purified via flash column chromatography (FCC) (20 SiO2; cyclohexane→cyclohexane:ethylacetate:MeOH 58:40:2). Product containing fractions were concentrated, dissolved in 2 mL of trifluoroacetic acid (TFA) and heated 45 min at 150° C. in the microwave. The mixture was purified with rpHPLC (XbridgeC18, MeOH/water, TFA) to yield after lyophilisation 8 mg of Example 1 as solid. Analysis: HPLC-MS: Rt=1.21 min (method D), M+H=333.
Reaction SMILES: O1CCOCC1.[CH3:7][C:8]1[N:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:10](=[O:17])[C:11]2[S:16][CH:15]=[CH:14][C:12]=2[N:13]=1.C(OC(=O)C)(=O)C.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH:38]=O>C(=O)(O)[O-].[Na+]>[CH3:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:9]1[C:10](=[O:17])[C:11]2[S:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:8]1[CH:7]=[CH:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=1
Reactant: O=Cc1ccccn1
Reactant: Cc1ccccc1-n1c(C)nc2ccsc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: Cc1ccccc1-n1c(C=Cc2ccccn2)nc2ccsc2c1=O
Temperature: 25 °C
Yield: 70.4 %

Procedure:
To a mixture of fused zinc chloride (2.13 g, 15.6 mmol) and dioxane (75 mL), 2-methyl-3-(2-methylphenyl)-3H-thieno[3,2-d]pyrimidin-4-one (2.0 g, 7.81 mmol, preparation 2), and acetic anhydride (2.2 mL, 23.4 mmol) was added 2-pyridine carboxaldehyde (2.2 mL, 23.4 mmol). The reaction was refluxed 1.5 hours, cooled to ambient temperature, and diluted with aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the organic extracts were washed with water and brine, dried over sodium sulfate and concentrated to leave a dark residue. This material was flash chromatographed on silica gel (45×125 mm). Elution with 20% ethyl acetate/hexane removed an unweighed impurity. Continued elution with 40% ethyl acetate/hexane gave a sticky yellow foam. The foam was triturated with 5% ethyl acetate/hexane to yield 1.9 g (70%) of 3-(2-methyl-phenyl)-2-[2-pyrid-2-yl-vinyl]-3H-thieno[3,2-d]pyrimidin-4-one as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[N:23][CH:22]=[CH:21]2>CC(N(C)C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[N:23][CH:22]=[CH:21]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Fc1ccc2cnccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cnccc3c2)CC1
Temperature: 80 °C
Yield: 76.4 %

Procedure:
7.49 g of 4-hydroxy-piperidine-1-carboxylic acid-tert-butylester were dissolved in 20 mL of dry dimethyl acetamide. 1.49 g of sodium hydride (60%) were added. Then a solution of 3.65 g of 6-fluoroisoquinoline (3) in dimethyl acetamide was added dropwise. The solution was heated at 80° C. for 2 hours, then the solvent was removed and the residue was taken up in dichloromethane. The organic layer was extracted twice with water and then with brine, dried over magnesium sulfate and evaporated to dryness. The crude product was purified by silica gel chromatography to yield 6.22 g of 4-(isoquinolin-6-yloxy)-piperidine-1-carboxylic acid-tert-butylester (7). Rt=1.32 min (Method B). Detected mass: 329.1 (M+H+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=3[CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=1.B.[Na]>CO>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:19]=[CH:18][C:6]2[S:7][C:8]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=3[CH2:10][CH:11]([OH:12])[C:5]=2[CH:4]=1
Reactant: O=C1Cc2c(Cl)cccc2Sc2ccc(C(F)(F)F)cc21
Agent: B
Agent: [Na]
Solvent: CO
Product: OC1Cc2c(Cl)cccc2Sc2ccc(C(F)(F)F)cc21

Procedure:
To the mixture of 2-trifluoromethyl-9-chloro-10,11-dihydrodibenzo[b,f]thiepin-11-one obtained in Example 40 and 10ml of methanol was gradually added 0.2g of sodium boron hydride with ice-cooling over a period of 5 minutes and the mixture was reacted at room temperature for 30 minutes and refluxed for 15 minutes. After the completion of the reaction, methanol was distilled off. After cooling, to the mixture was added water and the mixture was extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate and freed of the solvent to obtain 0.5g of 2-trifluoromethyl-9-chloro-10,11-dihydrodibenzo[b,f]thiepin-11-ol as colorless crystals having a melting point of 130°-132° C.
Reaction SMILES: [NH+]1C=CC=CC=1.[OH:7][C@H:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@:14]3([OH:29])[CH2:15][CH2:16][C@@H:17]2[CH:27]=[O:28])[CH2:9]1>ClCCl.C(OCC)C>[O:7]=[C:8]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@:14]3([OH:29])[CH2:15][CH2:16][C@@H:17]2[CH:27]=[O:28])[CH2:9]1
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@]12O
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@]12CCC(=O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C=O)CC[C@]12O
Yield: 60.4 %

Procedure:
To a suspension of 0.88 g of pyridinium dicromate in 2.2 ml of dichloromethane a solution of 0.50 g of 3β,14β-dihydroxy-5β-androstane-17β-carboxaldehyde (Boutagy J. and Thomas R., Aust. J. Chem., 1971, 24, 2723) in 2.5 ml of dichloromethane was added at room temperature. After 20 hrs the mixture was diluted with diethyl ether and filtered through celite; the filtrate was evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 6/4 as eluant; the fractions containing the title compound were collected and evaporated to give 0.30 g of the title compound (II-e) as a white foam.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].P(Cl)(Cl)(Cl)(Cl)[Cl:24]>C1C=CC=CC=1>[CH2:1]([O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([Cl:24])=[O:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Yield: 103.4 %

Procedure:
4.0 g (1.31×10-2 mol) of p-dodecyloxybenzoic acid was dissolved in 15 ml of benzene, and 2.79 g (1.31×10-2 mol) of PCl5 was slowly added thereto under stirring at room temperature. Thereafter, 3 hours of heat-refluxing was effected, followed by distilling-off the solvent to obtain 4.4 g of p-dodecyloxybenzoic acid chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[F:28][C:29]([F:40])([F:39])[C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:33]4[CH:32]=[N:31][C:30]([C:29]([F:40])([F:39])[F:28])=[CH:35][CH:34]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: OB(O)c1cccnc1C(F)(F)F
Product: C[C@@H](c1ccc(-c2ccc(C(F)(F)F)nc2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one and 2-trifluoromethylpyridine-3-boronic acid following a procedure analogous to that described in Example 64. LC-MS Method 3 tR=1.36 min, m/z=459.3; 1H NMR (CDCl3) 1.40 (m, 1H), 1.51 (m, 3H), 1.63 (m, 1H), 1.70-1.98 (m, 3H), 2.11-2.33 (m, 3H), 2.95 (m, 1H), 3.50-3.63 (m, 2H), 5.66 (m, 1H), 6.97 (m, 4H), 7.20 (m, 2H), 7.29 (m, 2H), 7.67 (m, 1H), 7.87-7.90 (m, 1H), 8.78 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([F:20])[CH:19]=1)[NH2:16].CC(C)([O-])C.[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[NH:16][C:15]1[CH:14]=[C:13]([F:12])[CH:19]=[C:18]([F:20])[CH:17]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)cc1Nc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-2-fluoro-1-nitrobenzene (2.500 g, 14.24 mmol) and 3,5-difluoroaniline (2.206 g, 17.09 mmol) in DMF (22.61 mL) was added potassium tert-butoxide (3.20 g, 28.5 mmol) under argon and the solution was stirred at rt overnight. The solution was poured into water and extracted with DCM, and the organic extracts were purified by column chromatography on a silica gel column using 5 to 10% gradient of EtOAc in hexane as eluent to give 5-chloro-N-(3,5-difluorophenyl)-2-nitroaniline as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 6.98 (tt, J=9.34, 2.20 Hz, 1H) 7.02-7.11 (m, 3H) 7.35 (d, J=2.15 Hz, 1H) 8.14 (d, J=9.00 Hz, 1H) 9.40 (s, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)(=[O:4])=[O:3].[CH3:13][NH:14][CH2:15][CH:16]=[O:17]>C1C=CC=CC=1>[CH3:13][N:14]([CH2:15][CH:16]=[O:17])[C:11]([NH:10][C:8]1[S:9][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6][N:7]=1)=[O:12]
Reactant: CNCC=O
Reactant: CS(=O)(=O)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: CN(CC=O)C(=O)Nc1nnc(S(C)(=O)=O)s1

Procedure:
A mixture of 5-methylsulfonyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-methylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product dimethyl acetal of 2-[1-methyl-3-(5-methylsulfonyl-1,3,4-thiadiazol-2 -yl)ureido]acetaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)\[CH:10](C(OC2C(C(C)C)CCC(C)C2)C([O-])=O)[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[OH-:35].[K+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](/[N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)\[CH:10]([OH:35])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC1CCC(C(C)C)C(OC(C(=O)[O-])C(/C(=C\c2ccc(Cl)cc2)n2cncn2)C(C)(C)C)C1
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)C(O)/C(=C\c1ccc(Cl)cc1)n1cncn1
Yield: 69.6 %

Procedure:
Similarly, 1.2 g of (+)-[(E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-yl]-(-)-menthoxyacetate was treated with 20 cc of a 95% aqueous ethanol solution containing 0.2 g of potassium hydroxide and the resulting crude crystals were recrystallized from a carbon tetrachloride-n-hexane mixture to obtain 0.5 g of (+)-(E)-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol: [α]D24 +14.0 (c=1.0, CHCl3); m.p. 169°-170° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)[CH3:2].Br[C:13]1[S:21][C:20]2[C:19]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][CH:27]=[CH:26]4)=[N:18][CH:17]=[N:16][C:15]=2[CH:14]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:13]2[S:21][C:20]3[C:19]([NH:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[NH:28][CH:27]=[CH:26]5)=[N:18][CH:17]=[N:16][C:15]=3[CH:14]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(B(O)O)cc1
Reactant: Brc1cc2ncnc(Nc3ccc4[nH]ccc4c3)c2s1
Product: CCc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 4-ethylbenzeneboronic acid and (6-bromo-thieno[3,2-d]pyrimidin-4-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 2. M.P. 171-182° C.; LC-MS: 371 (MH+); HPLC RT: 5.13 minutes.