Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][OH:26])[CH:20]=4)[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[F-].[K+].I[CH3:30].[OH-].[K+]>CS(C)=O>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][CH3:30])[CH:20]=4)[CH2:17][CH2:18]3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CI
Reactant: OCc1cccc(N2CCN(CCC3CCC4(CC3)OCCO4)CC2)c1
Agent: [F-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COCc1cccc(N2CCN(CCC3CCC4(CC3)OCCO4)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.4 %

Procedure:
To a solution of 1.2 g (3.42 mmol) of 1-[2-(1,4-dioxaspiro[4.5]dec-8-yl)ethyl]-4-(3-hydroxymethylphenyl)piperazine (preparation A) in 15 mL of dimethyl sulfoxide are added, at room temperature, 1.0 g (17.2 mmol) of potassium fluoride, 0.52 g (3.66 mmol) of iodomethane and 0.68 g (10.3 mmol) of potassium hydroxide. The mixture is stirred overnight at room temperature, partitioned between with ethyl acetate and water. The aqueous phase is separated and the organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated. The oily residue is purified by chromatography over silica gel (eluant hetane/ethyl acetate 1/1) to give 0.3 g of 1-[2-(1,4-dioxaspiro[4.5]dec-8-yl)ethyl]-4-(3-methoxymethylphenyl)piperazine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][S:27][CH2:26]1)=[O:24])[C:5]([NH:7][CH:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6].ClC1C=C(C=CC=1)C(OO)=[O:35].ClCCl.CO.ClCl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([N:25]1[CH2:29][CH2:28][S:27](=[O:35])[CH2:26]1)=[O:24])[C:5]([NH:7][CH:8]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:12]=2[N:11]=1)[CH3:9])=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(NC(=O)c1ccc(C(=O)N2CCSC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: ClCCl
Solvent: CO
Product: CC(NC(=O)c1ccc(C(=O)N2CCS(=O)C2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 46 %

Procedure:
Prepared analogously to Example 85 from rac.-3-chloro-N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]4-(thiazolidin-3-ylcarbonyl)benzamide and 3-chloroperoxybenzoic acid in dichloromethane/glacial acetic acid. Yield: 46%; Rf value: 0.20 (silica gel; dichloromethane/methanol=9:1); C20H18Cl2N4O3S (465.36); mass spectrum: (M+H)+=465/467 (chlorine isotope) and (M−H)−=463/465 (chlorine isotope).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][C:51]2[O:54][N:55]=[C:56]([C:57](O)=[O:58])[C:50]=2[CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]>CN(C)C=O>[N:1]1([C:57]([C:56]2[C:50]3[CH2:49][N:48]([C:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:47])[CH2:53][CH2:52][C:51]=3[O:54][N:55]=2)=[O:58])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCc2onc(C(=O)O)c2C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCc2onc(C(=O)N3CCCCC3)c2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Piperidine (1.1 ml, 11.18 mmol), N-methylmorpholine (3.68 ml, 33.54 mmol) and BOP reagent (6.42 g, 14.53 mmol) were added to a solution of 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-carboxylic acid (3 g, 11.18 mmol) in dry dimethylformamide (100 ml) and the reaction mixture was stirred at room temperature for 16 hours. The solution was then concentrated in vacuo, the residue was taken up in ethyl acetate and the mixture was washed with NaHCO3 solution and NaCl solution. The combined organic phases were dried with Na2SO4, filtered and concentrated in vacuo. Purification was carried out by chromatography on silica gel (100-200 mesh silica gel, 30% ethyl acetate in hexane). The yield was (71%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].S(Cl)([Cl:16])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].Cl>C1(C)C=CC=CC=1.O>[Cl:16][C:8]1[CH:7]=[CH:6][C:5]([OH:10])=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:9]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Oc1ccccc1OC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Oc1ccc(Cl)cc1OC(F)(F)F
Temperature: 30 °C
Reaction time: 0.33 h

Procedure:
1.78 g of o-trifluoromethoxyphenol was dissolved in 5 mL of toluene, and the mixture was stirred in an ice water bath for 20 min. 1.485 g of sulfonyl chloride was added dropwise to the reaction system within 10 min, which was then stirred for 20 min. The solution was moved to a water bath maintained at 30° C., and allowed to stir at this temperature for 1 h. 200 mL of 5% sodium carbonate aqueous solution and 50 mL of toluene were added to the system, which was then violently vibrated and isolated (pH of water layer was 10 upon determination). The pH of water layer was adjusted to 2 with 2 N of hydrochloric acid aqueous solution. The solution was extracted with 50 mL of toluene once again. The toluene layers were combined, successively washed with 100 mL of water and 100 mL of saturated sodium chloride aqueous solution, dried over 5 g of anh. MgSO4 for 30 min, and concentrated via a rotary evaporator to obtain a white granular solid. MS anion peak (M-H: 213).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([S:2]([C:5]2[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=2)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3])[CH2:17][CH2:16]1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCN(S(=O)(=O)c2cccc(C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 35.3 %

Procedure:
3-(chlorosulfonyl)benzoic acid (200 mg, 0.906 mmol) was added to the 1-methylpiperazine (100 mg, 0.997 mmol) in presence of potassium carbonate (251 mg, 1.813 mmol) in THF (Volume: 5 ml) at room temperature and the reaction mixture was stirred for 12 h at room temperature. Reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by column chromatography (3% CH3OH/CH2Cl2) afforded the product 3-((4-methylpiperazin-1-yl)sulfonyl)benzoic acid (100 mg, 0.320 mmol, 35.3% yield) as a solid. 1H NMR (CDCl3, 400 MHz): δ 7.77 (m, 2H), 7.63-7.55 (m, 2H), 3.04 (m, 4H), 2.46 (m 4H), 2.31 (s, 3H). Mass [M+H]+:285.1
Reaction SMILES: [C:1]([O:4][CH2:5]/[CH:6]=[CH:7]\[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:26]([O:28][CH2:29][CH3:30])=[CH2:27]>CCOCC>[C:1]([O:4][CH2:5]/[CH:6]=[CH:7]\[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:26]([O:28][CH2:29][CH3:30])[CH3:27])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC/C=C\c1ccc(O)cc1
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: CCOC(C)Oc1ccc(/C=C\COC(C)=O)cc1

Procedure:
To 50 ml of methanol solution containing 10 g of 3-[4-(1-ethoxyethoxy)phenyl]propargyl acetate, were added 1.5 g of 5%-Pd-BaSO4 and 10 drops of quinoline, and the mixture was catalytically reduced. After the reaction was finished, the reaction mixture was filtered, and the filtrate was allowed to evaporation, the residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane and dichloromethane:methanol=100:1) to obtain 3 g of 4(Z)-(1-ethoxyethoxy)cinnamyl acetate and 4 g of 4(Z)-hydroxycinnamyl acetate. Thus obtained 4 g of 4(Z)-hydroxycinnamyl acetate was dissolved in 20 ml of anhydrous ether, to this solution was added 50 mg of p-toluenesulfonic acid and 10 ml of ethyl vinyl ether, and the whole mixture was refluxed for 3 hours. The reaction mixture was then washed with 5%-sodium hydroxide aqueous solution and water in this order, and dried. The solvent was removed by evaporation to yield 4.8 g of 4(Z)-(1-ethoxyethoxy)cinnamyl acetate.
Reaction SMILES: [Na].[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]=[CH:9][CH:8]=[C:7]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[O:24])=[C:18]([F:33])[CH:17]=1)#[N:3].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:41][CH2:42][CH2:43][N:44]([CH2:47][CH3:48])[CH2:45][CH3:46].O>CN(C)C=O>[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:41][CH2:42][CH2:43][N:44]([CH2:47][CH3:48])[CH2:45][CH3:46])[N:10]=[CH:9][CH:8]=[C:7]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[O:24])=[C:18]([F:33])[CH:17]=1)#[N:3]
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)ccnc2cc1O
Reactant: CCN(CC)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(F)cc4)c(F)c3)c2cc1C#N
Temperature: 65 °C
Reaction time: 7 h
Yield: 23.5 %

Procedure:
After dissolving 480 mg of 6-cyano-4-{4-[4-fluoroanilinocarbonyl]amino-3-fluorophenoxy}quinolin-7-ol sodium salt in 5 ml of dimethylformamide, 350 mg of potassium carbonate and 204 mg of 3-chloropropyldiethylamine were added and the mixture was heated and stirred at 65° C. for 7 hours. After standing to cool, water was added and extraction was performed with ethyl acetate and tetrahydrofuran, after which the solvent was distilled off under reduced pressure and the residue was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to obtain 135 mg of the title compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[N:14]=[C:13]([CH3:15])[C:12]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19]C)=[O:18])=[C:11]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[N:10]=2)[CH2:3]1.[OH-].[Na+]>CO>[CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[N:14]=[C:13]([CH3:15])[C:12]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([OH:19])=[O:18])=[C:11]([C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[N:10]=2)[CH2:3]1
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CC(C)CC(C)C2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CC(C)CC(C)C2)nc1-c1ccc(C)cc1
Yield: 74.6 %

Procedure:
To a solution of methyl 2-(2-(3,5-dimethylpiperidin-1-yl)-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.090 g; 0.227 mmol) in methanol (3 mL) was added a solution of sodium hydroxide 5N (0.488 mL; 2.44 mmol) and the reaction mixture was heated to reflux for 18 h. The volatiles were removed under reduced pressure, the residue was dissolved in water and the pH of the solution was adjusted between 2 and 3 by addition of a solution of hydrochloric acid 6N. The formed precipitate was collected by filtration and dried under reduced pressure over P2O5 to give 0.067 g (69%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][OH:12])[N:8]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[S:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[O:16][N:15]=2)[N:7]=1)=[O:5])[CH3:2].Br[CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][O:12][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32])[N:8]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[S:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[O:16][N:15]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: COCCOCCBr
Reactant: CCOC(=O)c1cc(CO)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(COCCOCCOC)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Reaction time: 0.17 h

Procedure:
To a solution of 100 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-hydroxymethyl-1H-pyrazole-3-carboxylic acid ethyl ester in 2 ml DMF 11 mg NaH (60% in mineral oil) were added at RT and stirred for 10 min. Then 100 mg 1-Bromo-2-(2-methoxy-ethoxy)-ethane were added and the mixture was stirred for 16 h. After addition of 5 ml of water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The crude residue was directly subjected to the next reaction step. Yield: 130 mg.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:46])[CH2:10][C:11]1[CH:45]=[CH:44][CH:43]=[CH:42][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([CH:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)=[N:27][CH:28]=2)[N:16]=1>C(Cl)Cl>[CH3:21][C:20]1[C:15]([CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[CH2:10][C:9]([NH2:8])=[O:46])=[N:16][C:17]([NH:22][C:23]2[CH:28]=[N:27][C:26]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:25][CH:24]=2)=[N:18][CH:19]=1
Reactant: Cc1cnc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)nc1CCc1ccccc1CC(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(C3CCNCC3)nc2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
TFA (0.5 mL) was added to a solution of tert-butyl 4-(5-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate (A20) (70 mg, 0.13 mmol) in DCM (5 mL) and the resulting mixture stirred for 18 hours at room temperature. The volatiles were removed in vacuo and the residue partitioned between 2 M aqueous NaOH (10 mL) and EtOAc (25 mL). The organic layer was separated then washed with water (25 mL), brine (25 mL), dried (Na2SO4) and concentrated under reduced pressure to give the title compound 4 as an off white solid (45 mg, 79%); 1H NMR (400 MHz, d4-MeOH) δ 8.79 (dd, J=2.6, 0.5 Hz, 1H), 8.15 (dd, J=8.6, 2.7 Hz, 1H), 8.13 (d, J=0.6 Hz, 1H), 7.28-7.22 (m, 2H), 7.21-7.14 (m, 3H), 3.64 (s, 2H), 3.20-3.10 (m, 4H), 3.02-2.95 (m, 2H), 2.88-2.68 (m, 3H), 2.11 (s, 3H), 1.95-1.84 (m, 2H), 1.71 (qd, J=12.7, 4.0 Hz, 2H). LCMS-A: rt 4.241 min; m/z 431 [M+H]+.
Reaction SMILES: [O:1]([CH:8]([OH:10])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:11][PH:12]([OH:14])=[O:13].O>C1(C)C(C)=CC=CC=1>[P:12]([O:10][CH:8]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:9])([OH:14])([OH:13])=[O:11]
Reactant: O=[PH](O)O
Reactant: CC(O)Oc1ccccc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CC(Oc1ccccc1)OP(=O)(O)O

Procedure:
1 mol of phenoxyethanol is esterified azeotropically in the presence of 1.1 mol of H3PO3 in xylene on a water separator. The reaction product which precipitates on cooling is filtered off, washed with petroleum ether and dried to give a white powder. The amount of the phosphoric diester (2-phenoxyethanol hydrogensulphate, 0-50%) which may be formed in this reaction in addition to phenoxyethanol phosphate (phenoxyethanol dihydrogenphosphate) does not interfere in the polycondensation which subsequently takes place; it is also incorporated into the polycondensate.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([S:13](Cl)(=[O:15])=[O:14])[CH2:11][CH3:12].[C:17]1([S:23]([N:26]2[C:30]3=[N:31][CH:32]=[C:33]([NH:42][C:43](=[O:47])[CH2:44][C:45]#[N:46])[C:34]([NH:35][CH:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[C:29]3[CH:28]=[CH:27]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[C:17]1([S:23]([N:26]2[C:30]3=[N:31][CH:32]=[C:33]([NH:42][C:43](=[O:47])[CH2:44][C:45]#[N:46])[C:34]([NH:35][CH:36]4[CH2:41][CH2:40][N:39]([S:13]([CH2:10][CH2:11][CH3:12])(=[O:15])=[O:14])[CH2:38][CH2:37]4)=[C:29]3[CH:28]=[CH:27]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: N#CCC(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CCC(Nc2c(NC(=O)CC#N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Diisopropylethylamine (0.107 ml, 0.615 mmol) and 1-propanesulfonyl chloride (0.035 ml, 0.308 mmol) were added sequentially to a solution of N-[1-benzenesulfonyl-4-(piperidin-4-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-cyano-acetamide (hydrochloride salt) (0.205 mmol) in CH2Cl2 (2 ml) at 25° C. The reaction mixture was stirred for 3 h at 25° C., then was partitioned between saturated NaHCO3 (6 ml) and CH2Cl2 (2 ml). The phases were separated using a phase separation column (Biotage) and the organic layer was concentrated under reduced pressure to give crude N-{1-benzenesulfonyl-4-[1-(propane-1-sulfonyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-yl}-2-cyano-acetamide as a brown oil/solid. LCMS (Method G, ESI): RT=0.88 min, m+H=545.3. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [H-].[Na+].[C:3](OCC)(=O)[CH2:4][C:5]([CH3:7])=[O:6].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=C(F)[C:14]=1[F:23]>C1COCC1>[C:5]([CH2:4][C:3]1[C:14]([F:23])=[C:13]([F:12])[CH:18]=[CH:17][C:16]=1[N+:19]([O-:21])=[O:20])(=[O:6])[CH3:7]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(F)c1F
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
To a suspension of sodium hydride (5.42 g, 226 mmol) (prewashed with pentane) in THF (100 ml) cooled at 10° C. was added ethyl acetoacetate (29.4 g, 226 mmol) while keeping the temperature below 15° C. After completion of addition, the mixture was further stirred for 15 minutes and cooled to 5° C. A solution of 1,2,3-trifluoro-4-nitrobenzene (20 g, 113 mmol) in THF (150 ml) was added while keeping the temperature below 5° C. The mixture was then left to warm up to ambient temperature and stirred for 24 hours. The volatiles were removed under vacuum and the residue was partitioned between ethyl acetate and 2N aqueous hydrochloric acid. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. The residue was dissolved in concentrated hydrochloric acid (650 ml) and acetic acid (600 ml) and the mixture was refluxed for 15 hours. After cooling, the volatiles were removed under vacuum and the residue was partitioned between aqueous sodium hydrogen carbonate (5%) and ethyl acetate. The organic layer was washed with sodium hydrogen carbonate, water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with ethylacetate/petroleum ether (75/25) to give 3-acetylmethyl-1,2-difluoro-4-nitrobenzene (17.5 g, 72%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[CH2:14]([N:17]([CH2:25][C:26](N(OC)C)=[O:27])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=[CH2:16].Cl>O1CCCC1.C(OCC)(=O)C>[CH2:14]([N:17]([CH2:25][C:26]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1)=[O:27])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:15]=[CH2:16]
Reactant: Fc1ccc(Br)nc1
Reactant: C=CCN(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCN(CC(=O)c1ccc(F)cn1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 32.8 %

Procedure:
2-Bromo-5-fluoro-pyridine (2.46 g, 13.98 mmol) in tetrahydrofuran (20 mL) is added drop wise to isopropylmagnesium chloride (15 mL, 30.00 mmol of a 2M solution in tetrahydrofuran) with stirring under nitrogen at room temperature. The resulting reaction mixture is stirred at room temperature for 2 hours. tert-Butyl N-allyl-N-[2-[methoxy(methyl)amino]-2-oxo-ethyl]carbamate (3.4 g, 13.16 mmol) in tetrahydrofuran (15 mL) is then added drop wise at room temperature and the resulting mixture is stirred overnight. Dilute aqueous hydrochloric acid is added followed by ethyl acetate. The layers are separated and the aqueous phase is re-extracted with ethyl acetate. The combined organic extracts are dried over magnesium sulfate, filtered, and concentrated to dryness under reduced pressure. The resulting residue is purified by silica gel column chromatography using a 0-40% gradient of acetone in iso-hexane to give the title compound (1.27 g, 33%). ES/MS (m/e): 317 (M+23).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].C([N-]C(C)C)(C)C.[Li+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>O1CCCC1>[CH2:16]([CH:4]([CH2:3][CH2:2][CH3:1])[C:5]([OH:7])=[O:6])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: CCCCC(=O)O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC(Cc1ccccc1)C(=O)O
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 87 %

Procedure:
N-Valeric acid (1 g) was dissolved in 75 ml of tetrahydrofuran and treated with 2 equivalents of lithium diisopropylamide at room temperature. The solution was then heated to 40° C. for 30 minutes followed by the addition of 1.1 ml of benzyl chloride. After 1.5 hours at 40° C., the reaction mixture was cooled to room temperature, poured into 300 ml of water and extracted with diethyl ether (2×200 ml). The aqueous solution was then acidified with 1M hydrochloric acid and extracted with diethyl ether (2×300 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. The residue was purified by radial chromatography (40-50% ethyl acetate in hexane, 2 mm plate) to yield 1.63 g of 2-benzylpentanoic acid (87% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[N:3]=1.Cl.[Cl:14][C:15]1[C:19]([Cl:20])=[C:18]([CH3:21])[NH:17][C:16]=1[C:22]([NH:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:23].O>CN(C=O)C>[Cl:1][C:2]1[NH:3][C:4]([N:28]2[CH2:27][CH2:26][CH:25]([NH:24][C:22]([C:16]3[NH:17][C:18]([CH3:21])=[C:19]([Cl:20])[C:15]=3[Cl:14])=[O:23])[CH2:30][CH2:29]2)([C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][N:7]=1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)c(Cl)c1Cl
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)C=CN=C(Cl)N1

Procedure:
A solution of methyl 2,4-dichloropyrimidine-6-carboxylate (commercially available) (0.95 g, 4.6 mmol) in DMF (5 ml) was added dropwise to a solution of 3,4-dichloro-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 1, 0.43 g, 4.6 mmol) and TEA (0.92 g, 9.2 mmol) in DMF (10 ml) under nitrogen. The resultant mixture was stirred for 1 h at room temperature. Water (50 ml) was added to the stirred reaction mixture and the material that precipitated was collected and washed with water/acetonitrile (1:1, 15 ml) to give 1.9 g of the title compound. An analytical sample was purified by reversed-phase HPLC (water/acetonitrile gradient, 20-95%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].[CH:14]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH:5][C:20]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:21]
Reactant: O=C(Cl)C1CCCCC1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)C1CCCCC1
Reaction time: 2 h

Procedure:
Phenylalanine methyl ester (1 g., 0.0046 moles) is dissolved in pyridine 5 mL. Cyclohexanoyl chloride (0.62 mL) is added and the mixture is stirred for 2 hours. The reaction mixture is poured onto hydrochloric acid (1N) and crushed ice. The aqueous mixture is extracted twice with toluene. The combined toluene extracts are concentrated in vacuo to give 1.1 g of crude N-cyclohexanoylphenylalanine methyl ester.