Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1([N:13]([CH3:15])[CH3:14])[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1.[NH2:19]O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1([N:13]([CH3:15])[CH3:14])[CH2:11][CH2:10][CH:9]([NH2:19])[CH2:8][CH2:7]1
Reactant: NO
Reactant: CN(C)C1(Cc2cccc(Cl)c2)CCC(=O)CC1
Product: CN(C)C1(Cc2cccc(Cl)c2)CCC(N)CC1

Procedure:
1.0 g 1-(3-chlorobenzyl)-N,N-dimethylcyclohexane-1,4-diamine, obtained as a cis/trans-mixture from 4-(3-chlorobenzyl)-4-dimethylaminocyclohexanone by reaction with hydroxylamine and reduction of the oxime obtained with lithium aluminium hydride (WO 02090317), dissolved in 5 ml DMF, was added to 0.74 g N-furan-2-yl-methylsuccinic acid at 0° C. and 0.59 ml N,N-diisopropylcarbodiimide followed by 0.5 g 1-hydroxybenzotriazole (HOBt) were added while stirring. After 3 hours in an ice bath, the mixture was stirred overnight at room temperature. For working up, one-molar sodium carbonate solution was added (pH>10) and the crude product (1.75 g) was isolated by extraction with ethyl acetate/THF (V:V=1:1), with subsequent drying over sodium sulphate and evaporation. The main fraction, obtained after column chromatography on silica gel (3.0×20 cm) with 250 ml diethyl ether, diethyl ether/methanol (V:V=4:1) and diethyl ether/methanol (V:V=1:1), of 718 mg was dissolved in 50 ml 2-butanone, 50 ml ethyl acetate and 2 ml methanol and, by adding 29 μl water and 200 μl chlorotrimethylsilane, converted into the corresponding hydrochloride of the N-[4-(3-chlorobenzyl)-4-dimethylaminocyclohexyl]-N′-furan-2-yl-methylsuccinic acid amide (648 mg of white solid, mp. 233-234.5° C.).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl[C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH:32]=3)[CH:25]=2)[CH:21]=[CH:22][CH:23]=1.CCOCC>COCCOCCOC>[O:37]([C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[O:30][C:26]1[CH:25]=[C:24]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([O:14][C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][CH:12]=3)[CH:19]=2)[CH:29]=[CH:28][CH:27]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Clc1cccc(-c2cccc(Oc3cccc(Oc4ccccc4)c3)c2)c1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: COCCOCCOC
Solvent: CCOCC
Product: c1ccc(Oc2ccc(Oc3cccc(-c4cccc(Oc5cccc(Oc6ccccc6)c5)c4)c3)cc2)cc1
Temperature: 150 °C
Reaction time: 0.75 h

Procedure:
A 250 ml. reaction flask equipped with stirrer, dropping funnel, thermometer, and Dean-Stark trap surmounted by a Friedrichs condenser, was charged with 200 g. (1.07 moles) of p-phenoxyphenol, and 34.9 g. (0.567 mole) of potassium hydroxide was added in increments at 90°C. To the resulting melt was added 50 ml. of toluene and the theoretical amount of water azeotroped from the reaction mixture followed by removal of toluene up to 230°C. On cooling to 150°C., the reaction mixture was diluted with 150 ml. of diglyme and 5.0 g. of cuprous chloride and 1.0 g. of copper powder was added. Over a 45 min. period, 20 g. (0.054 mole) of 3-chloro-3'-(m-phenoxyphenoxy)-biphenyl in diglyme was added, and the diglyme was removed by distillation. The stirred reaction mixture was heated at 235°C. for 19 hours. On cooling, an equal volume of ether was added and this mixture centrifuged to remove salts. The ethereal solution was washed with 25 % potassium hydroxide solution to remove excess phenol, water until neutral, and then dried over anhydrous magnesium sulfate. After filtration and concentration to remove ether, the oil obtained was distilled to obtain 17.5 g. of the desired product, bp 297°-302° C./0.05 mm.; nD25 1.6500.
Reaction SMILES: CC([O-])(C)C.[K+].[CH3:7][S:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][NH:18][C:17](=[O:21])[N:16]=2)[CH:12]=[CH:11][N:10]=1.CS(O[CH:27]([C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([F:44])[CH:38]=1)[CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])(=O)=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[Si:30]([O:29][CH2:28][CH:27]([N:18]1[CH:19]=[CH:20][C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([S:8][CH3:7])[N:14]=2)=[N:16][C:17]1=[O:21])[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[C:39]([F:44])[CH:38]=1)([C:33]([CH3:35])([CH3:36])[CH3:34])([CH3:32])[CH3:31]
Reactant: CSc1nccc(-c2cc[nH]c(=O)n2)n1
Reactant: CC(C)(C)[Si](C)(C)OCC(OS(C)(=O)=O)c1ccc(Cl)c(F)c1
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Product: CSc1nccc(-c2ccn(C(CO[Si](C)(C)C(C)(C)C)c3ccc(Cl)c(F)c3)c(=O)n2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.8 %

Procedure:
Potassium 2-methylpropan-2-olate (0.026 g, 0.24 mmol) and tetrabutylammonium iodide (0.0067 g, 0.018 mmol) were added to 4-(2-(methylthio)pyrimidin-4-yl)pyrimidin-2(1H)-one (0.040 g, 0.18 mmol) suspended in THF (4 mL) cooled in ice. After 10 minutes, a solution of 2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl methanesulfonate (0.10 g, 0.27 mmol) in THF (1 mL) was added. The mixture was stirred at room temperature overnight and then heated at 90° C. for 3 days. Due to incomplete reaction, the material was transferred to a microwave vial and heated in a microwave at 130° C. for 1 hour. The reaction mixture was evaporated, and the residue was chromatographed on a 10 g Biotage SNAP column with 1:1 hexane/EtOAc. Fractions 8-13 contained the desired 1-(2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-(methylthio)pyrimidin-4-yl)pyrimidin-2(1H)-one (0.030 g, 0.059 mmol, 33% yield) as a film.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[CH2:15][NH:14][CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[C:24]1[N:29]([CH3:30])[C:28](=[O:31])[CH:27]=[C:26]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[N:25]=1.ClC1C=CNC(=O)N=1>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]2[CH2:15][N:14]([C:24]3[N:29]([CH3:30])[C:28](=[O:31])[CH:27]=[C:26]([C:32]4[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=4)[N:25]=3)[CH2:13][CH2:12][NH:11]2)=[CH:8][CH:9]=1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: Clc1ccc([C@@H]2CNCCN2)cc1
Agent: Cl
Agent: O=c1nc(Cl)cc[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCN[C@H](c3ccc(Cl)cc3)C2)nc(-c2ccncc2)cc1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.3 %

Procedure:
To a suspension of (R)-2-(4-chlorophenyl)piperazine dihydrochloride (1.09 g, 4.05 mmol) in tetrahydrofuran (24 ml) was added triethylamine (2.82 ml, 20.3 mmol). After stirring for 15 min at room temperature, 2-chloro-3-methyl-6-(4-pyridyl)-3H-pyrimidin-4-one (748 mg, 3.38 mmol) was added portionwise. Upon disappearance of the chloropyrimidone, the reaction mixture was condensed under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give pale yellow solid, which was recrystallized from ethanol to afford (R)-2-(2-(4-chlorophenyl)piperazin-4-yl)-3-methyl-6-(4-pyridyl)-pyrimidin-4-one (998 mg, 77.4%) as white crystals. The enantiomer excess was determined by HPLC (>99% ee). The crystals were converted into its dihydrochloride salt.
Reaction SMILES: [CH3:1][CH:2]([NH:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[CH:14][N:13]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl:20]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:20][C:17]1[C:12]([NH:11][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:1])=[N:13][CH:14]=[N:15][C:16]=1[O:18][CH3:19]
Reactant: CCCCCCCCC(C)Nc1cc(OC)ncn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCC(C)Nc1ncnc(OC)c1Cl
Yield: 84.5 %

Procedure:
4.0 g (0.015 mol) of 4-(2-decylamino)-6-methoxypyrimidine were refluxed for 1 hour together with 2.2 g (0.016 mol) of N-chlorosuccinimide in 25 ml of chloroform. After cooling, the mixture was extracted by stirring with 2N sodium hydroxide solution, and the organic phase was dried and concentrated. 3.8 g (84.3% of theory) of 5-chloro-4-(2-decylamino)-6-methoxypyrimidine were obtained in the form of a yellow oil.
Reaction SMILES: Cl[C:2]1([NH:24][C:25]2[CH:30]=[CH:29][C:28]3[O:31][CH2:32][CH2:33][O:34][C:27]=3[CH:26]=2)[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:18](OCC)=[O:19])([CH3:17])[CH3:16])=[CH:11][CH:10]=2)[C:5]([F:23])=[CH:4][NH:3]1.CC(C[AlH]CC(C)C)C>ClCCl>[CH2:33]1[CH2:32][O:31][C:28]2[CH:29]=[CH:30][C:25]([NH:24][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:14]=[CH:13][C:12]([C:15]([CH3:16])([CH3:17])[CH2:18][OH:19])=[CH:11][CH:10]=4)[C:5]([F:23])=[CH:4][N:3]=3)=[CH:26][C:27]=2[O:34]1
Reactant: CCOC(=O)C(C)(C)c1ccc(NC2=NC(Cl)(Nc3ccc4c(c3)OCCO4)NC=C2F)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(CO)c1ccc(Nc2nc(Nc3ccc4c(c3)OCCO4)ncc2F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-5-fluoro-N4-[4-[ethoxycarbonyl(dimethyl)methyl]phenyl]-N2-(3,4-ethylenedioxyphenyl)-2,4-pyrimidinediamine was reduced with 10 eq. DIBALH (1.0 M in toluene) at 0° C. in dichloromethane. Reaction was quenched with methanol, diluted with ethylacetate followed by the addition of aqueous Rochelle's salt solution, stirred at room temperature for 30 minutes followed by the addition of anhydrous sodium sulfate. The solution was filtered through Celite, concentrated and purified the concentrated by silica gel column chromatography to furnish the N2-(3,4-ethylenedioxyphenyl)-N4-[4-(2-hydroxy-1,1-dimethylethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.01 (br s, 1H), 9.6 (br s, 1H), 8.13 (d, 1H, J=4.7 Hz), 7.58 (d, 2H, J=8.2 Hz), 7.31 (d, 2H, J=8.8 Hz), 7.18 (d, 1H, J=2.3 Hz), 6.88 (dd, 1H, J=2.3 and 8.8 Hz), 6.73 (d, 1H, J=8.8 Hz), 4.21–4.19 (m, 4H), 3.56 (br s, 2H), 1.20 (s, 6H); LCMS: ret. time: 20.34 min.; purity: 98%; MS (m/e): 411 (MH+).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[N:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.[C:19](=O)(O)[O-:20].[Na+]>CN(C)C=O>[Cl:6][C:7]1[N:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:9]([CH:19]=[O:20])=[CH:10][CH:11]=1
Reactant: Cc1ccc(-n2cccc2Cl)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-n2c(Cl)ccc2C=O)cc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
Phosphoryl chloride (747 μl) was added dropwise to N,N-dimethylformamide (7 ml) at 5° C. The mixture was stirred at 5° C. for 15 minutes and at ambient temperature for 15 minutes. To the mixture was added a solution of 2-chloro-1-(4-methylphenyl)pyrrole (1.2 g) in N,N-dimethylformamide (7 ml) at ambient temperature. The mixture was stirred at the same temperature for one hour and at 50° C. for 2.5 hours. After cooled to ambient temperature, the mixture was treated with saturated aqueous sodium bicarbonate solution. The separated oil was extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated in vacuo. The residue was column chromatographed on silica gel to yield 5-chloro-1-(4-methylphenyl)pyrrole-2-carbaldehyde (377 mg) as a solid.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[CH:17][CH:16]=1.[CH3:25][C:26]1[N:27]=[C:28]([N:36]2[C:40](=[O:41])[NH:39][N:38]=[CH:37]2)[S:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[F:23][CH:22]([F:24])[O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:39]2[C:40](=[O:41])[N:36]([C:28]3[S:29][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:26]([CH3:25])[N:27]=3)[CH:37]=[N:38]2)=[CH:16][CH:17]=1
Reactant: FC(F)Oc1ccc(CBr)cc1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(-n2cnn(Cc3ccc(OC(F)F)cc3)c2=O)nc1C
Yield: 79 %

Procedure:
Following the procedure as described in Example 19, making variation as required to replace 4-(trifluoromethyl)benzyl bromide with 1-(bromomethyl)-4-(difluoromethoxy)benzene to react with ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate, the title compound was obtained as a white solid in 79% yield:
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:29][Si](C)(C)C>CC(CC)=O>[ClH:29].[CH3:28][N:2]([CH3:1])[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:4][CH2:5][C:6](=[CH:9][C:10]([NH:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:11])[CH2:7][CH2:8]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccn2)CCC(=CC(=O)NCCCc2ccccc2)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
2-(4-Dimethylamino-4-pyridin-2-ylcyclohexylidene)-N-(3-phenylpropyl)acetamide (203 mg, 0.537 mmol was dissolved in ethyl methyl ketone (5 ml), and chlorotrimethylsilane (0.2 ml, 1.6 mmol) was added. After 1.5 h the hydrochloride was isolated as a colourless solid with an m.p. of 173-176° C. in a yield of 86% (190 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>CN(C)C=O>[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2ccc([N+](=O)[O-])n2)cc1
Yield: 81.6 %

Procedure:
To a solution of 3-nitro-1H-pyrazole (prepared in example 3, 200 mg, 1.77 mmol) in anhydrous N,N-dimethylformamide (2 mL), a 60% dispersion of sodium hydride in mineral oil (92 mg, 2.30 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for additional 20 min, 4-methyoxybenzylchloride (312 μL, 2.30 mmol) was added. The mixture was continued to stir under nitrogen for an additional 2 h. The solvent was removed in vacuo and purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 2% methanol/methylene chloride to 5% methanol/methylene chloride) afforded 1-(4-methoxy-benzyl)-3-nitro-1H-pyrazole (337 mg, 82%) as a white solid: H1-NMR (400 MHz, CDCl3) δ: 3.77 (3H, s), 5.27 (2H, s), 6.83 (1H, d, J=2.3 Hz), 6.86 (2H, d, J=8.6 Hz), 7.22 (2H, d, J=8.5 Hz), 7.35 (1H, d, J=2.3 Hz).
Reaction SMILES: [CH:1]([C:3]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([C:13]([O:15]CC)=[O:14])[CH2:9][CH2:8]1)=[O:2].[OH-].[Na+].Cl>C1COCC1>[CH:1]([C:3]1[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:4]=1[CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][CH:10]([C:13]([OH:15])=[O:14])[CH2:11][CH2:12]1)=[O:2]
Reactant: CCOC(=O)C1CCN(CCc2cccc(O)c2C=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=Cc1c(O)cccc1CCN1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
To ethyl 1-(2-formyl-3-hydroxyphenethyl)piperidine-4-carboxylate (80 mg, crude above) in THF (5.0 mL) was added NaOH (3 N, 1.0 mL). The mixture was stirred at rt for 2 h and acidified to pH 3-4 using HCl (2 N). The mixture was concentrated and purified on RP-HPLC (Gemini 21.2 mm×150 mm) using a mixture of CH3CN and water (0.1% HCOOH) as eluent to give 1-(2-formyl-3-hydroxyphenethyl)piperidine-4-carboxylic acid (40 mg, 29% for three steps) as a yellow solid. 1H NMR (400 MHz, DMSO) δ 10.26 (s, 1H), 8.65 (s, 2H), 6.91 (dd, J=8.7, 6.9 Hz, 1H), 6.16 (d, J=7.9 Hz, 1H), 5.76 (d, J=6.7 Hz, 1H), 3.01-2.89 (m, 4H), 2.50-2.36 (m, 2H), 2.03 (t, J=10.3 Hz, 2H), 1.92-1.76 (m, 3H), 1.69-1.49 (m, 2H). LRMS (M+H+) m/z 278.4. 1H NMR (400 MHz, DMSO-d6) δ 10.1 (s, 1H), 8.55 (s, 2H), 6.75 (dd, J=Hz, 1H), 6.05 (d, J=Hz, 1H), 5.6 (d, J=Hz, 1H), 2.7 (m, 4H), 2.3 (m, 2H), 1.85 (m, 2H), 1.7 (m, 3H), 1.5 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:32][C:33]([O:42][CH2:43][C@H:44]1[CH2:46][O:45]1)([CH3:41])[CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:41][C:33]([O:42][CH2:43][C@H:44]1[CH2:46][O:45]1)([CH3:32])[CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH:40][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[N:36]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(Cn1ccc(N)n1)OC[C@H]1CO1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.56 g, 1.2 mmol), 1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3ylamine (0.27 g, 1.12 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 0.912 g, 2.4 mmol) and iPr2NEt (1.5 mL, 8.4 mmol) in CH2Cl2 (50 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by column chromatography (25-80 g Analgix column, 1-100% ethyl acetate/heptane) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((R)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (222 mg, 28%) as an off-white solid. HRMS (ES+) m/z Calcd for C33H37Cl2F2N5O3S+H [(M+H)+]: 660.2315. found: 660.2312.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH:14]([OH:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]([F:27])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:24]=[CH:23][C:11]([O:12][CH:13]([CH3:22])[CH:14]([O:21][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)CC(O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(OC(=O)c1ccccc1)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Yield: 92 %

Procedure:
2.5 g of ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-hydroxypentanoate were refluxed with 1.2 min. of benzoyl chloride in 60 ml of methylene chloride in the presence of 1.3 ml of triethylamine for 1(1/2) hours. The product was diluted with methylene chloride washed with water, 1M HCl and brine and dried over MgSO4. The product was purified by silica gel chromatography (total yield 92%) and was identified as a mixture of two stereoisomers of the above ethyl benzoyloxypentanoate.
Reaction SMILES: O=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]#[N:13])[CH:9]=2)[N:4]=[CH:3]1.P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]#[N:13])=[CH:7][CH:6]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1ccc2ncc(=O)[nH]c2c1
Product: N#Cc1ccc2ncc(Cl)nc2c1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
A solution of 3-oxo-3,4-dihydro-quinoxaline-6-carbonitrile (5.99 g, 35 mmol, 1.0 eq) in phosphorus oxychloride (26 mL, 280 mmol, 8.0 eq) is heated under reflux for 1 hour. Then the reaction mixture is cooled down to room temperature and the solvent is evaporated. The residue is poured into ice water, the resulting mixture is neutralized with sodium carbonate and extracted with ethyl acetate (3×50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: dichloromethane 100%) to afford 3-chloro-quinoxaline-6-carbonitrile as a white solid (5.27 g, 79% yield).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C[O-].[Na+].[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH2:28]Cl)[C:23]=1[CH3:30])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>CO.C(OCC)(=O)C>[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH2:28][S:1][C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[C:23]=1[CH3:30])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCCCCCCOc1ccnc(CCl)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Yield: 38.7 %

Procedure:
To a liquid prepared by dissolving with stirring 8.7 g (0.058 mol, 0.95 eq.) of 2-mercaptobenzimidazole and 68.2 g (0.354 mol, 5.8 eq.) of a 28% sodium methoxide solution in 400 mL of methanol, a liquid prepared by dissolving the whole amount of 4-heptyloxy-2-chloromethyl-3-methylpyridine in 210 mL of methanol was added at 28° C. Subsequently, the mixture was heated to reflux for one hour and cooled, and then methanol was solid dried under reduced pressure. A yellow brown oily residue resulting therefrom was dissolved in 250 mL of ethyl acetate, and then the organic layer was washed with 100 mL of water. The organic layer was dried over anhydrous magnesium sulfate, and then concentrated to dryness. The resulting residue was purified by silica gel column chromatography, and then was concentrated to dryness, to obtain 17.8 g of an orange-colored oily matter. The orange-colored oily matter was recrystallized from ethyl acetate (7 vol.), to obtain 8.7 g of colorless crystals (HPLC: 99.0 Area %, yield 38.7%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]([OH:35])[C:31]([O:33][CH3:34])=[O:32])=[CH:26][CH:25]=1>C(Cl)Cl>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](=[O:35])[C:31]([O:33][CH3:34])=[O:32])=[CH:28][CH:29]=1
Reactant: COC(=O)C(O)c1ccc(Br)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dess-Martin periodinane (7.6 g, 17.96 mmol) was added to an ambient temperature solution of methyl (4-bromophenyl)(hydroxy)acetate (4 g, 16.33 mmol) in methylene chloride (100 mL). After stirring at ambient temperature for 2 h, the reaction mixture was quenched with saturated aqueous sodium thiosulfate/saturated aqueous sodium bicarbonate (1:1) and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded methyl (4-bromophenyl)(oxo)acetate.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].C([O-])([O-])=O.[Na+].[Na+].F[C:19]1[CH:20]=[N+:21]([O-:28])[CH:22]=[CH:23][C:24]=1[N+:25]([O-:27])=[O:26].O>CN(C=O)C>[N+:25]([C:24]1[CH:23]=[CH:22][N+:21]([O-:28])=[CH:20][C:19]=1[O:11][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:1]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1F
Reactant: Oc1ccc2c(c1)CCCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc[n+]([O-])cc1Oc1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5,6,7,8-tetrahydro-2-naphthol in 50 ml of DMF was added Na2CO3 (10 g) portionwise and this mixture was stirred for 15 minutes at room temperature. A solution of 3-fluoro-4-nitropyridine-N-oxide in 50 ml DMF was added dropwise and the reaction was allowed to proceed for four hours at room temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (sat NaCl, anhy MgSO4).