Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl:29][C:30]1[CH:35]=[N:34][CH:33]=[C:32](Cl)[N:31]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[Cl:29][C:30]1[N:31]=[C:32]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)[CH:33]=[N:34][CH:35]=1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: Clc1cncc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2cncc(Cl)n2)C3)cc1

Procedure:
1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0499 g, 0.130 mmol) and 2,6-Dichloropyrazine (0.0311 g, 0.209 mmol) were combined then added dry N,N-Dimethylformamide (0.911 mL, 11.8 mmol) followed by N,N-Diisopropylethylamine (0.0456 mL, 0.262 mmol). The reaction was microwaved on 200 watts, 120° C. for 30 minutes on a CEM microwave. The reaction mixture was purified by HPLC. 1H NMR (400 MHz, DMSO) δ 8.65 (s, 1H), 8.40 (s, 1H), 8.22 (d, J=8.8, 2H), 7.90 (s, 1H), 7.49 (d, J=8.8, 2H), 6.17 (t, J=5.5, 1H), 4.69 (d, J=16.4, 2H), 3.86 (t, J=5.1, 2H), 3.79-3.69 (m, 4 H), 3.49 (d, J=4.3, 4H), 3.18-3.06 (m, 2H), 2.80 (s, 2H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+495.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[CH2:11]([O:13][C:14](=[O:24])[CH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18](Br)[CH2:17]1)[CH3:12]>C(O)C>[CH2:11]([O:13][C:14](=[O:24])[CH2:15][CH:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18]([S:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:17]1)[CH3:12]
Reactant: Sc1cccc(Cl)c1
Reactant: CCOC(=O)CC1CCC(=O)C(Br)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CC1CCC(=O)C(Sc2cccc(Cl)c2)C1
Temperature: 25 °C

Procedure:
In a 3-l. three-necked flask, provided with a condenser, nitrogen inlet, dropping funnel and stirrer were placed 23.8 g. of 3-chlorothiophenol and a solution of 10.8 g. of 85% potassium hydroxide in 300 ml. of ethanol. The solution was brought to reflux, and a solution of 43 g. of 3-bromo-4-oxocyclohexaneacetic acid ethyl ester in 250 ml. of ethanol was added over a period of one hour. After the addition, the solution was stirred at reflux for one hour, cooled to room temperature and filtered to remove the potassium bromide. After removal of the ethanol in vacuo on the steam bath, 150 ml. of water was added to the residue, the product extracted three times with 100 ml. of ether, and the ether extract was dried over anhydrous magnesium sulfate. After removal of the ether from a steam bath at atmospheric pressure, the residue was distilled in vacuo. The yield of 3-(3-chlorophenylthio)-4-oxocyclohexaneacetic acid ethyl ester was 12.2 g.; b.p. 195°-225°/2 mm.
Reaction SMILES: Cl[Sn]Cl.O.[Cl:5][C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]([Cl:15])[C:7]=1[CH3:16]>C(O)C>[Cl:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]([Cl:15])[C:7]=1[CH3:16]
Reactant: Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Cc1c(Cl)ccc(N)c1Cl
Yield: 99.4 %

Procedure:
To a solution of SnCl2.H2O (140 g, 0.62 mol) in ethanol (350 mL) was added a solution of 2,6-dichloro-3-nitrotoluene (25 g, 0.12 mol) in ethanol (50 mL). The reaction mixture was refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (100 mL), pH was adjusted to approximately pH 12 with 1N NaOH solution and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over sodium sulfate, and concentrated to afford 2,6-dichloro-3-aminotoluene (21 g, 98%); NMR (CDCl3) 2.42 (s, 3), 6.62 (d, 1), 7.14 (d, 1) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6](=[O:13])[NH:5]2.[N+:14]([O-])([O-:16])=[O:15].[K+]>OS(O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:14]([O-:16])=[O:15])[NH:8][C:7](=[O:12])[C:6](=[O:13])[NH:5]2
Reactant: O=c1[nH]c2ccc(F)cc2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(F)c([N+](=O)[O-])cc2[nH]c1=O
Temperature: 0 °C
Yield: 70 %

Procedure:
The title compound was prepared using an adaptation of the method of Cheeseman (Cheeseman, G. W. H., J. Chem. Soc. 1171 (1962)). 6-Fluoro-1,4-dihydroquinoxaline-2,3-dione (200 mg, 1.10 mmol) was dissolved in 3 mL of concentrated H2SO4 and the blue green solution was cooled to 0° C. with stirring. To this was added in small portions KNO3 (110 mg, 1.10 mmol). The reaction was allowed to stir 1 h at 0° C. and then was allowed to come to room temperature and stir overnight. The brown-orange reaction mixture was then poured into 10 mL ice/H2O. The product was isolated by vacuum filtration as brown crystals which were rinsed with a small amount of cold H2O and air dried. The crystals were further dried under vacuum (0.1 torr, 25° C.) to yield 173.4 mg (70.0% yield).
Reaction SMILES: [C:1]1([S:11]([N:14]2[C:22]3[C:17](=[C:18]([N+:23]([O-])=O)[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].C(O)C.CO>[C:1]1([S:11]([N:14]2[C:22]3[C:17](=[C:18]([NH2:23])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)(=[O:12])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc2c1ccn2S(=O)(=O)c1cccc2ccccc12
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: Nc1cccc2c1ccn2S(=O)(=O)c1cccc2ccccc12

Procedure:
A mixture of 722 mg (1.97 mmole) 1-(naphthalene-1-sulfonyl)-4-nitro-1H-indole and 100 mg 10% palladium on carbon in 15 mL ethanol and 5 mL methanol was shaken under 40 psi hydrogen at room temperature for 4 hrs. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ether/hexane to provide 1-(naphthalene-1-sulfonyl) -1H-indol-4-ylamine as light yellow-green crystals, 480 mg, m.p. 133-134° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.Cl>[Pt]=O.CO>[CH3:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: Cc1c(-c2ccncc2)cccc1S(C)(=O)=O
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: Cc1c(C2CCNCC2)cccc1S(C)(=O)=O

Procedure:
Preparation according to preparation 9: 4-[2-methyl-3-(methylsulfonyl)phenyl]pyridine (0.4 g, 1.6 mmol), methanol (10 ml), platinum oxide (0.10 g), hydrochloric acid (0.1 ml, cone). Yield: 0.41 g. MS m/z (rel. intensity, 70 eV) 247 (M+, 96), 246 (51), 168 (53), 167 (bp), 139 (51).
Reaction SMILES: CC1C=CC(S(O[N:12]2[CH:23]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)[CH2:22][N:21](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:20][CH2:19][N:18](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)(=O)=O)=CC=1.Br[CH2:57][C:58]([OH:60])=[O:59]>>[N+:31]([C:28]1[CH:27]=[CH:26][C:25]([CH2:24][CH:23]2[CH2:22][N:21]([CH2:57][C:58]([OH:60])=[O:59])[CH2:20][CH2:19][N:18]([CH2:57][C:58]([OH:60])=[O:59])[CH2:17][CH2:16][O:15][CH2:14][CH2:13][N:12]2[CH2:57][C:58]([OH:60])=[O:59])=[CH:30][CH:29]=1)([O-:33])=[O:32]
Reactant: Cc1ccc(S(=O)(=O)ON2CCOCCN(OS(=O)(=O)c3ccc(C)cc3)C(Cc3ccc([N+](=O)[O-])cc3)CN(OS(=O)(=O)c3ccc(C)cc3)CC2)cc1
Reactant: O=C(O)CBr
Product: O=C(O)CN1CCOCCN(CC(=O)O)C(Cc2ccc([N+](=O)[O-])cc2)CN(CC(=O)O)CC1

Procedure:
Scheme 3 illustrates an example of a method that can be used to produce a compound of formula (XVIb). This method involves cyclizing 2,2′-oxybis(ethane-2,1-diyl)bis(4-methylbenzenesulfonate) (XXVIII) with (XXII) in DMF to produce 5-(4-nitrobenzyl)-1-oxa-4,7,10-triazacyclododecane-4,7,10-triyl tris(4-methylbenzenesulfonate) (XXIX), followed by deprotection and alkylation of (XXIX) using bromoacetic acid to yield 2,2′,2″-(5-(4-nitrobenzyl)-1-oxa-4,7,10-triazacyclododecane-4,7,10-triyl)triacetic acid (XXX). Hydrogenation of the nitro group of (XXX) is then achieved using 10% palladium on carbon catalyst at ambient pressure to give aniline intermediate 2,2′,2″-(5-(4-aminobenzyl)-1-oxa-4,7,10-triazacyclododecane-4,7,10-triyl)triacetic acid (XXXI). Conversion of (XXXI) to the reactive electrophilic isothiocyanate 2,2′,2″-(5-(4-isothiocyanatobenzyl)-1-oxa-4,7,10-triazacyclododecane-4,7,10-triyl)triacetic acid (XXXII) is carried out using a 2-phase reaction medium with chloroform/water and thiophosgene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:18][C:19]1[N:20]([CH2:27][C@:28]([OH:32])([CH3:31])[CH2:29][OH:30])[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[N:23]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[O:30][CH2:29][C@@:28]([OH:32])([CH3:31])[CH2:27][N:20]2[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[N:23]=[C:19]2[Cl:18])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@](O)(COC(=O)Nc1ccc(Cl)cc1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 25 °C
Reaction time: 19 h
Yield: 83 %

Procedure:
A THF solution (15 ml) of 4-chlorophenylisocyanate (1.3 g, 85 mmol) and triethylamine (0.1 ml) were added to a suspension of (R)-2-chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 10 (1.5 g, 6.5 mmol) in THF (30 ml) followed by stirring at room temperature for 19 hours. Insoluble matters were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford (R)-3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl 4-chlorophenylcarbamate (2.1 g, yield 83%) as a white solid.
Reaction SMILES: [Na].C([CH:4]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:6])#N.Br>C(O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:4][C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[O:6])=[CH:14][CH:15]=1
Reactant: N#CC(C(=O)c1ccncc1)c1ccc(F)cc1
Agent: Br
Agent: [Na]
Solvent: CCO
Product: O=C(Cc1ccc(F)cc1)c1ccncc1

Procedure:
The starting materials are converted in a condensation reaction with the aid of metallic sodium in an alcohol, for example ethanol, into 2-cyano-2-(4-fluorophenyl)-1-(4-pyridyl)ethanone (IIIa). The cyano group is then removed by hydrolysis, for example with hydrobromic acid, and decarboxylation, giving 2-(4-fluorophenyl)-1-(4-pyridyl)ethanone (IVa). In the next step, IVa is converted by treatment with ammonium chloride/sodium acetate in an alcoholic solvent, such as methanol, into the oxime (Va). By reaction with p-toluenesulfonyl chloride in pyridine, the latter is converted into the tosylate (VIa). From the tosylate, the thione compound (IIa) is obtained by treatment with sodium ethoxide and reaction of the azirene intermediate formed with potassium thiocyanate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](O)=[N:9][CH:8]=[N:7][C:6]=2[N:12]=1.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)[Cl:24]>ClCCCl>[Cl:24][C:10]1[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[N:12][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Cc1ccc2c(O)ncnc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1ccc2c(Cl)ncnc2n1
Yield: 75.9 %

Procedure:
To a solution of 7-Methyl-pyrido[2,3-d]pyrimidin-4-ol (0.78 g, 4.84 mmol) in DCE (30 mL) was added DIEA (1.0 mL, 1.19 mmol), followed by POCl3 (2.4 mL, 26.1 mmol). The mixture was refluxed overnight. After cooling, the solvent was removed and the residue was dissolved in water (50 mL) and extracted with ethyl acetate (3×100 mL). The organic phase was dried and concentrated. The residue was subject to column chromatography, eluted by hexane/ethyl acetate (2:1) to give 4-Chloro-7-methyl-pyrido[2,3-d]pyrimidine (0.66 g, 76%). 1H NMR (CDCl3, 400 MHz) δ 9.22 (s, 1H), 8.49 (d, J=8.8 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 2.88 (s, 3H). MS (APCI+) [M+H]+180.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[CH2:35]([N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[NH:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)[CH:36]=[CH:37][CH3:38]>>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:52]2[CH2:53][CH2:54][CH:49]([NH:48][C:40]3[N:39]([CH2:35][CH:36]=[CH:37][CH3:38])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:50][CH2:51]2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)=[O:6]
Reactant: CC=CCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Agent: I
Product: CC=CCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 99.1 using 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and (1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydriodic acid salt to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19](O)(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].Cl.[CH3:39][O:40][NH2:41]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:41][O:40][CH3:39])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:26][CH2:27][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:29][CH2:30]1)=[O:24]
Reactant: O=C(c1cnc2c(S(=O)(=O)O)cnn2c1Nc1cc(Cl)ccc1Cl)N1CCC(c2ccc(F)cc2)CC1
Reactant: CON
Agent: Cl
Product: CONS(=O)(=O)c1cnn2c(Nc3cc(Cl)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 43.1 %

Procedure:
Using 7-(2,5-dichlorophenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonic acid (0.15 g, 0.27 mmol) obtained in step 1 and O-methylhydroxylamine hydrochloride (0.089 g, 1.06 mmol) instead of tert-butylamine, and in the same manner as in Example 1 step 3, the title compound (0.069 g, 44%) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:16][O:17]S(C)(=O)=O)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[Cl:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1>>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([O:17][CH2:16][CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:8][CH:9]=2)=[O:33])=[CH:37][CH:36]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(F)cc2)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2ccc(Cl)cc2)NS(=O)(=O)c2ccc(F)cc2)cc1
Yield: 74 %

Procedure:
The procedure described in Example 125 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (300 mg) was reacted with 4-chlorophenol (153 mg) to obtain (RS)-3-(4-chlorophenoxy)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)propanamide (236.25 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](O)=[O:6].CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([Cl:20])=[O:6]
Reactant: O=C(O)c1cc(F)cc(Br)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 1.67 h

Procedure:
10 g of 3-bromo-5-fluoro-benzoic acid are suspended in 100 ml of DCM, 0.5 ml DMF and 4.5 ml oxalyl chloride (1.15 Eq) are added and the resulting mixture is stirred for 100 minutes at RT. The solvent is removed by vacuo and the benzoic acid chloride is isolated by distillation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:11]=[N+:12]([O-:36])[CH:13]=[CH:14][C:15]=1[C:16]([N:18]1[CH2:21][C:20]([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2C(OC(C)(C)C)=O)([OH:22])[CH2:19]1)=[O:17].Cl.[O:38]1CCO[CH2:40][CH2:39]1>CO>[C:39]([O:22][C:20]1([C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][NH:24]2)[CH2:21][N:18]([C:16]([C:15]2[CH:14]=[CH:13][N+:12]([O-:36])=[CH:11][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[O:17])[CH2:19]1)(=[O:38])[CH3:40]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C1(O)CN(C(=O)c2cc[n+]([O-])cc2Nc2ccc(I)cc2F)C1
Agent: Cl
Solvent: CO
Product: CC(=O)OC1([C@@H]2CCCCN2)CN(C(=O)c2cc[n+]([O-])cc2Nc2ccc(I)cc2F)C1
Yield: 65.6 %

Procedure:
1,1-Dimethylethyl (2S)-2-[1-({3-[(2-fluoro-4-iodophenyl)amino]-1-oxidopyridin-4-yl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (57 mg, 0.093 mmol) was dissolved in methanol (2 mL) and treated with 4N hydrochloric acid in dioxane (0.25 mL, 1 mmol) at 50° C. for 2.25 hours. The mixture was concentrated in vacuo and was purified by reverse-phase HPLC followed by lyophilization of the pure fractions to afford 1-({3-[(2-fluoro-4-iodophenyl)amino]-1-oxidopyridin-4-yl}carbonyl)-3-[(2S)-piperidin-2-yl]azetidin-3-ol acetate (35 mg, 0.061 mmol, 66% yield): 1H NMR (400 MHz, d6-DMSO): 7.83 (s, 1H), 7.72 (dt, 2H), 7.55-7.51 (m, 1H), 7.47-7.41 (m, 1H), 7.24 (t, 1H), 4.45-4.32 (m, 1H), 4.14-3.95 (m, 2H), 3.72 (d, 1H), 2.97 (d, 1H), 2.58-2.43 (m, 2H), 1.80-1.73 (m, 1H), 1.67-1.55 (m, 1H), 1.49 (br d, 1H), 1.38-1.16 (m, 2H), 1.16-1.01 (m, 1H); MS (EI) for C20H22FIN4O3: 513 (MH+).
Reaction SMILES: [C:1]([Si:5]([CH3:28])([CH3:27])[O:6][CH:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[CH2:8][CH2:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:39][O:40][C:41](=[O:52])[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][CH2:50]Br)=[CH:44][CH:43]=1>>[CH3:39][O:40][C:41](=[O:52])[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][CH2:50][N:14]2[C:13](=[O:15])[CH2:12][CH2:11][CH:10]2[CH2:9][CH2:8][CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:28])[CH3:27])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=2)=[CH:44][CH:43]=1
Reactant: COC(=O)c1ccc(CCCBr)cc1
Reactant: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(Cc2cccc(C(F)(F)F)c2)O[Si](C)(C)C(C)(C)C)cc1
Yield: 84.2 %

Procedure:
Analogous to the procedure described for Example 1A, Step D, 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-trifluoromethyl-phenyl)-butyl]-pyrrolidin-2-one (250 mg, 0.602 mmol) was alkylated with NaHMDS (1M in THF, 0.72 mL, 0.72 mmol) and 4-(3-bromo-propyl)-benzoic acid methyl ester (170 mg, 0.663 mmol) to yield 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-trifluoromethyl-phenyl)-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (300 mg). MS 592.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[Br:10][CH2:11][CH2:12]Br.[OH-].[Na+]>O>[Br:10][CH2:11][CH2:12][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:9])[CH:4]=1
Reactant: BrCCBr
Reactant: Cc1cc(O)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(OCCBr)ccc1Cl

Procedure:
A mixture of 4-chloro-3-methylphenol (100 g.) and 1,2-dibromoethane (158.2 g.) in water (160 ml.) was stirred and heated to reflux during the slow dropwise addition of a solution of sodium hydroxide (30.8 g.) in water (140 ml.). Stirring and heating were continued for a total of 6 hours and the mixture was cooled and extracted exhaustively with ether. The ethereal extract was washed exhaustively with 5N-sodium hydroxide, dried over potassium carbonate, filtered and evaporated. The residual oil was distilled under reduced pressure to give 1-bromo-2-(4-chloro-3-methylphenoxy)ethane, b.p. 106°-112° 10.65 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=1[C:35]([F:38])([F:37])[F:36].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([NH:32][C:31]3[CH:33]=[CH:34][C:28]([F:27])=[C:29]([C:35]([F:38])([F:36])[F:37])[CH:30]=3)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)ccc1C(=O)Nc1ccc(F)c(C(F)(F)F)c1
Yield: 36.9 %

Procedure:
The title compound was prepared by following the procedure as described for Example-31 by using methyl 4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-21, 0.100 g, 0.25 mmol), 4-fluoro-3-(trifluoromethyl)aniline (0.069 g, 0.38 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL) and dry toluene (5.0 mL) to afford 0.050 g of desired product. 1H NMR (DMSO-d6): δ 4.09 (s, 3H), 7.52 (t, J=9.6 Hz, 1H), 7.88-7.68 (m, 6H), 8.25 (s, 8.25 (d, J=6.9 Hz, 1H), 10.37 (s, 1H), 12.74 (s, 1H); MS (m/z): 540.91[M]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1)#[N:27]>>[C:26]([C:28]1[CH:29]=[CH:30][C:31]([NH:34][C:35](=[O:36])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]4=[O:17])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)=[CH:32][CH:33]=1)#[N:27]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: N#Cc1ccc(N=C=O)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(C#N)cc4)cc3)cc2C1=O

Procedure:
The compound of example 39 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 4-cyanophenyl isocyanate. The compound of example 39 was used directly without isolation for the preparation of compound of example 40.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][CH2:9][CH:10]1[O:14][CH2:13][CH2:12][O:11]1.CN(C)C=O.[F:20][C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[N:25][C:26]=1[F:27]>O>[O:11]1[CH2:12][CH2:13][O:14][CH:10]1[CH2:9][CH2:8][O:28][C:23]1[CH:22]=[C:21]([F:20])[C:26]([F:27])=[N:25][CH:24]=1
Reactant: Oc1cnc(F)c(F)c1
Reactant: BrCCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cc(OCCC2OCCO2)cnc1F
Temperature: 100 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
Cesium carbonate (33 g, 100 mmol) and 2-(2-bromoethyl)-1,3-dioxolane (12 g, 67 mmol) were added to an N,N-dimethylformamide suspension (30 ml) of 5,6-difluoropyridin-3-ol (8.8 g, 67 mmol), and stirred at 100° C. for 1 hour. The reaction solution was cooled to room temperature, water was added, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:chloroform=1:1 to 0:1) to obtain 5-[2-(1,3-dioxolan-2-yl)ethoxy]-2,3-difluoropyridine (5.9 g, yield: 38%) as a pale yellow oil.