Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[N:16]([CH2:17][CH2:18][OH:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH2:3][CH2:2]1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.S1C=CC=C1.[H][H]>CO.[Pd]>[C:21]1([CH2:20][N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]3[N:16]([CH2:17][CH2:18][OH:19])[C:11]4=[N:12][CH:13]=[CH:14][CH:15]=[C:10]4[N:9]=3)[CH2:5][CH2:6]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [H][H]
Reactant: OCCn1c(NC2CCNCC2)nc2cccnc21
Reactant: O=Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: OCCn1c(NC2CCN(Cc3ccccc3)CC2)nc2cccnc21
Yield: 65.1 %

Procedure:
A mixture of 28 parts of 2-(4-piperidinylamino)-3H-imidazo[4,5-b]pyridine-3-ethanol, 20 parts of benzaldehyde, 2 parts of a solution of thiophene in methanol 4% and 160 parts of methanol was hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in trichloromethane and the whole was extracted with an acidic aqueous solution. The extract was washed three times with trichloromethane and treated with a sodium hydroxide solution. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was stirred in 1,1'-oxybisethane. The solid product was filtered off and dried, yielding 25.2 parts (65.1%) of 2-[[1-(phenylmethyl)-4-piperidinyl]amino]-3H-imidazo[4,5-b]pyridine-3-ethanol; mp. 125.7° C. (compound 120).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]([OH:15])([CH3:14])[CH3:13])[CH2:11][CH2:10][CH2:9]1)(C)(C)C.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[NH2:7][C:8]1([C:12]([OH:15])([CH3:14])[CH3:13])[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(C(C)(C)O)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)C1(N)CCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
In a 25 ml round-bottomed flask, [1-(1-hydroxy-1-methyl-ethyl)-cyclobutyl]-carbamic acid tert-butyl ester (150 mg, 0.65 mmol) was dissolved in dichloromethane (3.8 ml) and trifluoroacetic acid (1.5 ml, 19.5 mmol) was slowly added. The pale yellow reaction mixture was stirred at room temperature for 2.5 h then concentrated to give 2-(1-amino-cyclobutyl)-propan-2-ol trifluoroacetate as a light brown oil which was used without further purification.
Reaction SMILES: [F:1][CH2:2][C:3]([N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])([CH2:8][C:9](Cl)=[O:10])[C:4]([O:6][CH3:7])=[O:5].[N+:23](=[CH2:25])=[N-:24]>CCOCC>[F:1][CH2:2][C:3]([N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22])([CH2:8][C:9](=[O:10])[CH:25]=[N+:23]=[N-:24])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(CF)(CC(=O)Cl)N1C(=O)c2ccccc2C1=O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COC(=O)C(CF)(CC(=O)C=[N+]=[N-])N1C(=O)c2ccccc2C1=O
Reaction time: 0.5 h

Procedure:
A solution of methyl 2-fluoromethyl-2-phthalimido-3-chlorocarbonyl-propionate (2.07 g, 6.33 mmol) in dry ether (24 ml) is slowly added with stirring to a cooled (ice) solution of diazomethane in ether (0.392 mol, 50 ml). After 30 minutes, the solvent is evaporated to give a yellow oil (2.1 g). This is purified by flash chromatography on silica gel (200 g, ethyl acetate/petroleum ether 4:6) to give the pure title compound as a yellow oil (1.7 g);
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:13]Br)=[C:4]([CH2:11]Br)[C:5]([F:10])=[C:6]([F:9])[C:7]=1[F:8].[NH2:15][C@H:16]([C:20]([OH:22])=[O:21])[CH:17]([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[OH-].[K+]>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]2[C:3]=1[CH2:13][N:15]([CH:16]([CH:17]([CH3:19])[CH3:18])[C:20]([OH:22])=[O:21])[CH2:11]2
Reactant: Fc1c(F)c(F)c(CBr)c(CBr)c1F
Reactant: CC(C)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)C(C(=O)O)N1Cc2c(F)c(F)c(F)c(F)c2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3,4,5,6-tetrafluoro-1,2-bis(bromomethyl)benzene (3 g, 9 mmol), valine (1 g, 9 mmol), potassium carbonate (2.8 g) and 25 ml THF/HMPT (1:1) is stirred for about 24 hours at RT (the reaction is followed by TLC). The reaction mixture is then diluted with 100 ml aqueous 10% KOH and extracted three times with ether. The aqueous phase is acidified to about pH 3 with aqueous HCl and extracted thoroughly with ether. The organic layer is washed with water, dried and solvent removed under vacuum to give 2-(4,5,6,7-tetrafluoro-2-isoindolinyl)-3-methylbutanoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:16](S(C)(=O)=O)[S:17]([CH3:20])(=[O:19])=[O:18])[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.CN(C)CCN>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)cc1N(S(C)(=O)=O)S(C)(=O)=O
Agent: CN(C)CCN
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ncc(Br)cc1NS(C)(=O)=O
Yield: 100 %

Procedure:
A solution of tert-butyl 5-bromo-3-(N-(methylsulfonyl)methylsulfonamido)pyridin-2-ylcarbamate (68 mg, 0.15 mmol) and N,N-dimethylethylenediamine (169 uL, 1.5 mmol) in dioxane (1 mL) was stirred at rt for 70 min. After diluting with ethyl acetate, the mixture was washed with aqueous citric acid (10%) followed by water. The organic phase was then dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was then diluted with dichloromethane which was then washed with 1 N HCl. After partitioning, the organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo to provide tert-butyl 5-bromo-3-(methylsulfonamido)pyridin-2-ylcarbamate (57 mg, 0.15 mmol, quantitative yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.24 (d, 1H), 8.07 (d, 1H), 2.98 (s, 3H), 1.54 (s, 9H); MS (EI) for C10H16BrN3O4S: 310, 312 (Br isotopes, MH+-t-butyl).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(O)C.ClCCl>[O:8]=[C:6]1[NH:7][C@H:3]([CH2:2][O:1][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:4][CH2:5]1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: CS(=O)(=O)Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
To a solution of commercially available (S)-(+)-5-(hydroxymethyl)pyrrolidin-2-one (2 g, 17.36 mmol) in ethanol-free CHCl3 (60 ml), triethylamine (TEA) (2.63 g, 26.04 mmol) and methanesulfonyl chloride (2.38 g, 20.84 mmol) were added dropwise at 0° C. The mixture was left stirring at room temperature for 3 hours, then it was diluted with dichloromethane (DCM) (60 ml) and washed with a saturated aqueous solution of NaHCO3 (3×30 ml). After drying (Na2SO4) the solvent was removed under reduced pressure and the residue was purified by flash chromatography (DCM/MeOH 9/1 respectively) to give the title compound as a pale yellow solid (2.2 g, 65% yield).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[F:16].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:9])=[CH:4][C:3]=1[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][C:11]=1[F:16]
Reactant: Cn1ncc(F)c1-c1cc(C(=O)O)sc1Cl
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(F)c1-c1cc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 63.5 %

Procedure:
To a solution of 5-chloro-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (53 mg, 0.203 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (78 mg, 0.203 mmol)[prepared according to Preparation 6] and diisopropylethylamine (0.18 ml, 1.02 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (95 mg, 0.203 mmol) in one portion. The solution stirred at 25° C. over 12 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 40% EtOAc in hexanes) yielding 5-chloro-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-4-(4-fluoro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (106 mg, 0.129 mmol, 63.5% yield) as a clear oil; LCMS (ES) m/e 591, 593 (M, M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([NH:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[N:15]=[CH:14][CH:13]=2)=[N:3]1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[N:17]=[C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])[N:15]=[CH:14][CH:13]=2)=[N:3]1
Reactant: CC(C)(C)OC(=O)CNc1nccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: O=C(O)CNc1nccc(-c2nc(=O)c3ccccc3s2)n1
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
tert-Butyl {[6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyrimidinyl]amino}acetate (0.20 g, 0.54 mmol) was dissolved in trifluoroacetic acid (5 ml), and the mixture was stirred for 0.5 hr. Diisopropyl ether was added thereto. The obtained precipitates were recrystallized from ethanol to give the titled compound (0.13 g, 75%) as pale yellow crystals
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C(O)(=O)C(O)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.[C:44]12([C:54](Cl)=[O:55])[CH2:53][CH:48]3[CH2:49][CH:50]([CH2:52][CH:46]([CH2:47]3)[CH2:45]1)[CH2:51]2>O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:44]12([C:54]([NH:13][CH:14]3[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=4)=[O:24])[CH2:18][CH2:19]3)=[O:55])[CH2:51][CH:50]3[CH2:49][CH:48]([CH2:47][CH:46]([CH2:52]3)[CH2:45]1)[CH2:53]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)n1nc(C(=O)NCCN2CCC(NC(=O)C34CC5CC(CC(C5)C3)C4)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 23, as the free base (0.330 g, 1 mmol) and triethylamine (0.15 mL, 1.05 mmol) were stirred in 10.0 mL tetrahydrofuran and cooled briefly in an ice bath. To the mixture was added, in portions, 1-adamantanecarbonyl chloride (0.199 g, 1 mmol) and the resulting mixture was stirred 18 h at room temperature and filtered, and the filtrate was evaporated to 0.565 g oil. Crystallization as the oxalate salt from ethyl acetate/methanol provided 0.267 g colorless crystals. Mp 228° C. Mass spectrum, m+ =491. Anal (C31H43N5O6) theory C, 64.01; H, 7.45; N, 12.04; found C, 63.89; H, 7.53; N, 12.12.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:15][CH2:14][C:5]2([C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][O:6]2)[CH2:4][C:3]1=O.CSC.B.[OH-:21].[Na+].[O-:23]O>O1CCCC1.O>[OH:21][CH2:1][CH:2]1[CH2:15][CH2:14][C:5]2([C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:23])[O:6]2)[CH2:4][CH2:3]1
Reactant: C=C1CCC2(CC1=O)OCc1ccccc12
Reactant: [O-]O
Reactant: [OH-]
Agent: B
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CSC
Solvent: O
Product: O=C1OC2(CCC(CO)CC2)c2ccccc21
Reaction time: 1.5 h

Procedure:
A solution of 4-methylenespiro[cyclohexane-1,1′(3′H)-isobenzofuran]-3-one (196 mg) in anhydrous tetrahydrofuran (5.0 mL) was cooled to 0° C., to which borane-dimethyl sulfide complex (2M tetrahydrofuran solution, 690 μL) was added and the mixture was stirred at that temperature for 1.5 hours, then additional 20 minutes together with aqueous 2M sodium hydroxide (5.0 mL) and aqueous 30% hydroperoxide (5.0 mL). The reaction mixture was diluted with water, extracted with ethyl acetate, washed with saturated saline solution, then dried over anhydrous Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give the subject compound (190 mg) as diastereomers.
Reaction SMILES: C(OC(C)(C)C)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[C:12]([CH2:14][CH2:15][C:16](Cl)=[O:17])#[N:13]>CCOCC>[O:17]=[C:16]([CH2:2][C:3](=[O:4])[CH3:5])[CH2:15][CH2:14][C:12]#[N:13]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: N#CCCC(=O)Cl
Solvent: CCOCC
Product: CC(=O)CC(=O)CCC#N

Procedure:
The magnesium complex of t-butyl acetoacetate (135 gm; 635 mmole) is suspended in 250 ml of anhydrous ether in a three-neck one liter round bottom flask and beta-cyano propionyl chloride (78.05 gm; 664 mmole) added dropwise over fifteen minutes while the mixture is stirred from overhead. The dropping funnel is removed and the mixture refluxed for thirty minutes. The mixture is cooled and 250 ml of 2 N aqueous sulfuric acid is slowly added. The mixture is transferred to a one liter separatory funnel and the layers separated. The aqueous layer is extracted with ether (2×150 ml) and the combined ether extracts washed with water (4×100 ml). The ether is evaporated and to the residual red oil is added 800 mg of toluene sulfonic acid monohydrate. The mixture is heated in an oil bath (with reflux condenser) to 175 degrees until evolution of gas has ceased. The mixture is cooled and taken up in 500 ml of ether. The ether is extracted with ice-cold 2 M aqueous sodium hydroxide (175, 90, 50, and 35 ml). The extracts were run from the separatory funnel directly into 250 ml of ice-cold 1.8 M aqueous sulfuric acid. The acidic suspension is extracted with methylene chloride (3×150 ml) and the combined organic extracts washed with 5% aqueous sodium bicarbonate (2×100 ml) and brine (100 ml). The residue after evaporation of the methylene chloride may be purified by silica gel flash column chromatography using ethyl acetate:hexane 1:4 as eluant.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=O)[C:12]([C:21](OCC)=[O:22])=[CH:11]1.P(Cl)(Cl)(Cl)=O.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH:38][NH2:39].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[CH2:9][N:10]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2=[N:39][N:38]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[F:31])[C:21](=[O:22])[C:12]2=[CH:11]1
Reactant: CCOC(=O)c1cn(Cc2ccc(I)cc2F)c2ccccc2c1=O
Reactant: NNc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1c2cn(Cc3ccc(I)cc3F)c3ccccc3c-2nn1-c1ccccc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Ethyl 1-[(2-fluoro-4-iodophenyl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate (1.4 g, 3.1 mmol) was dissovled in phosphorus oxychloride (6.0 mL, 64 mmol, 21 equiv) and stirred for 2.5 hours at ambient temperature. The mixture was diluted with toluene (10 mL) and concentrated in vacuo. The residue was dissolved in dioxane (17 mL), treated with 2-fluorophenylhydrazine (0.87 g, 6.8 mmol, 2.2 equiv) and potassium carbonate (1.3 g, 9.4 mmol, 3 equiv) and stirred at ambient temperature for 5 minutes. The mixture was placed into a preheated oil bath at 80° C. for 1 hour, cooled to ambient temperature and diluted with chloroform (150 mL). The organic mixture was washed once with water (50 mL) and brine (50 mL), dried with sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a chloroform:methanol (95:5) solution (30 mL). The solid was filtered and dried in vacuo, providing the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Cl:12][C:4]1[CH:3]=[C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(N)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(NS(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5 g of methyl 2-chloro-4-nitrobenzoate in 100 mL of EtOH was added 20 g of Tin (II) Chloride in portions. The reaction was heated to 55° C. and monitored by TLC until complete. Solvent was concentrated and extraction was performed in Ethyl Acetate and water with TEA to reduce emulsions. The organic layer was dried over Magnesium Sulfate, filtered and concentrated to give 3.9 g of methyl 4-amino-2-chlorobenzoate. 1 g of methyl 4-amino-2-chlorobenzoate was cooled to 0° C. in DCM with 485 μL of Pyridine before Methanesulfonyl Chloride was added dropwise. The reaction was allowed to warm to room temperature and stir overnight. Solvent was concentrated and the crude material was dissolved in Ethyl Acetate and extracted with saturated bicarbonate solution and then brine. The crude material was dried over Magnesium Sulfate, filtered and concentrated to give 1.54 g of methyl 2-chloro-4-(methylsulfonamido)benzoate. 107 μL of 1-bromo-2-methoxyethane and 556 mg of Cesium Carbonate were added to 150 mg of methyl 2-chloro-4-(methylsulfonamido)benzoate in DMF and stirred at room temperature for 16 hours. The reaction mixture was extracted in Ethyl Acetate twice with saturated bicarbonate and once with brine, dried over Magnesium Sulfate, filtered and concentrated to give methyl 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoate. 182 mg of methyl 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoate was hydrolyzed via Procedure M to yield 169 mg of crude 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoic acid. 65 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-methoxyethyl)methylsulfonamido)benzamide. MS (Q1) 494 (M)+.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[NH:11][S:12]([C:15]1[CH:16]=[N:17][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:19][CH:20]=1)(=[O:14])=[O:13].C([O-])([O-])=O.[Na+].[Na+].[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][C:35]=1[C:42]([F:45])([F:44])[F:43]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[N:11]([CH2:38][C:37]1[CH:40]=[CH:41][C:34]([F:33])=[C:35]([C:42]([F:45])([F:43])[F:44])[CH:36]=1)[S:12]([C:15]1[CH:16]=[N:17][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:19][CH:20]=1)(=[O:14])=[O:13]
Reactant: O=S(=O)(Nc1nc2ccccn2c1Cl)c1ccc(N2CCOCC2)nc1
Reactant: Fc1ccc(CBr)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(N2CCOCC2)nc1)N(Cc1ccc(F)c(C(F)(F)F)c1)c1nc2ccccn2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To a solution of compound 11-E (0.030 g, 0.049 mmol) in DMF (1 mL) was added Na2CO3 (0.015 g, 0.15 mmol) and 4-fluoro-3-trifluoromethylbenzyl bromide (0.014 g, 0.053 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography, eluting with a hexanes-EtOAc gradient to give Compound 90 as a yellow solid (0.008 g, 29%); MS m/z (M+H+) 570.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:25][S:26]([O:11][C@H:10]([C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](O)c1ccncc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H](OS(C)(=O)=O)c1ccncc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of (R)-2-(tert-butyldimethylsilyloxy)-1-(pyridin-4-yl)ethanol (80 mg, 0.316 mmol), triethylamine (97 μL, 0.695 mmol) and 4-(dimethylamino)pyridine (3.85 mg, 0.032 mmol) in DCM was added methanesulfonyl chloride (36.8 μL, 0.474 mmol) at 0° C. The reaction was stirred at 0° C. for 20 min, then at room temperature overnight. The mixture was washed with a NaHCO3 solution, water and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to give the title compound without further purification. LCMS m/z=332.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Br:8])=[C:5]([Br:7])[N:6]=1.[H-].[Na+].[CH3:11][Si:12]([CH2:15][CH2:16][O:17][CH2:18]Cl)([CH3:14])[CH3:13]>CN(C=O)C>[Br:1][C:2]1[N:3]([CH2:18][O:17][CH2:16][CH2:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[C:4]([Br:8])=[C:5]([Br:7])[N:6]=1
Reactant: Brc1nc(Br)c(Br)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(Br)nc(Br)c1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
A dried 500 mL round bottom flask was charged with 2,4,5-tribromoimidazole (20.0 g, 65.62 mmol) and anhydrous DMF (100 mL), the resulting solution was cooled to 0° C. To this cold solution was added NaH (60% in mineral oil, 2.80 g, 70.0 mmol) portionwise with gas evolution under control and an internal temperature maintained below 10° C. After addition, the cold bath was removed and the resulting mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was cooled back to 0° C., and SEM chloride (12.2 mL, 69.5 mmol) was added to the reaction via syringe pump over 30 minutes. The reaction was stirred at 0° C. for an additional 30 minutes and at ambient temperature for another 30 minutes. The reaction was deemed complete by LCMS and the mixture was partitioned between EtOAc (150 mL) and water (300 mL), and the layers separated. The organic phase was sequentially washed with dilute aqueous NaCl (5% w/w, 2×), then brine (100 mL), dried (Na2SO4), concentrated and a light yellow solid was obtained. The crude material was recrystallized from hot petroleum ether (30 mL) and the solids were harvested from the mother liquor at 0° C. The product was washed with cold petroleum ether (30 mL) and dried under vacuum to afford 2,4,5-tribromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole (26.3 g, 92% yield): 1H NMR (400 MHz, CDCl3) δ 5.31 (s, 2H), 3.59 (t, J=7.2 Hz, 2H), 0.92 (t, J=7.2 Hz, 2H), −0.01 (s, 9H, —Si(CH3)3).