Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][C:8]([NH:10][NH:11][C:12]([N:14]1[CH2:20][C:19]2[CH:21]=[C:22]([O:25]C)[CH:23]=[CH:24][C:18]=2[O:17][C:16]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:15]1=2)=[O:13])=[O:9])(=[O:5])=[O:4])[CH3:2].B(Br)(Br)Br.C(O)C>C(Cl)Cl>[CH2:1]([S:3]([CH2:6][CH2:7][C:8]([NH:10][NH:11][C:12]([N:14]1[CH2:20][C:19]2[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:18]=2[O:17][C:16]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:15]1=2)=[O:13])=[O:9])(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)CCC(=O)NNC(=O)N1Cc2cc(OC)ccc2Oc2ccc(Cl)cc21
Agent: BrB(Br)Br
Solvent: CCO
Solvent: ClCCl
Product: CCS(=O)(=O)CCC(=O)NNC(=O)N1Cc2cc(O)ccc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.4 %

Procedure:
To a stirred suspension of 8-chloro-2-methoxydibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-(ethylsulfonyl)-1-oxopropyl]hydrazide (1.00 g), prepared in the manner described above in Example 3, in methylene chloride (5 mL) at approximately 5° C. (ice water bath) under nitrogen was added dropwise boron tribromide (1.0 M in 6.7 mL of methylene chloride). The ice bath was removed and the reaction stirred at room temperature for 3 hours. The reaction was carefully quenched by the addition of 1 N HCl, and poured into ethyl acetate (100 mL). The solution was washed once with 1 N HCl (100 mL). The 100 mL of 1 N HCl wash was extracted with ethyl acetate (100 mL). The ethyl acetate solutions were combined and washed with 1 N HCl, Water and brine. Evaporation of the solution in vacuo resulted in a semi-solid residue. This was treated With 10 mL of ethanol (3A) and heated on a steam bath for several minutes to break up the solid. Upon cooling, the solidified product Was collected by filtration. Recrystallization from ethanol (3A) yielded 0.44 g (45%) pure product as a white solid. Melting Point: 200°-202° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([Cl:21])[CH:11]=1)=[O:8].[NH:24]1[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]1>>[Br:1][C:2]1[C:3]([N:24]2[CH2:28][CH2:27][C@@H:26]([OH:29])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[C:12]([Cl:21])[CH:11]=1)=[O:8]
Reactant: O[C@@H]1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)c(Cl)c1)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)c(Cl)c1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 33.1 using 5-bromo-6-chloro-N-(3-chloro-4-(trifluoromethoxy)phenyl)nicotinamide (Stage 204.2) and (R)-pyrrolidin-3-ol to afford an off-white crystalline solid. HPLC (Condition 4) tR=6.05 min, UPLC-MS (Condition 3) tR=1.24 min, m/z=480.1/482.1 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16]/[C:17](=[C:24]3\[C:25](=[O:36])[NH:26][C:27]4[C:32]\3=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.[C:37](Cl)(=[O:39])[CH3:38]>ClCCl>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]([C:10]2[CH:11]=[CH:12][C:13]([NH:16]/[C:17](=[C:24]3\[C:25](=[O:36])[NH:26][C:27]4[C:32]\3=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=4)/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:15]=2)[C:37](=[O:39])[CH3:38])[CH2:3][CH2:2]1
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2/C1=C(/Nc1ccc(NCCN2CCOCC2)cc1)c1ccccc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CC(=O)N(CCN1CCOCC1)c1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
486 mg (1.0 mmol) of (Z)-3-{1-[4-(2-morpholinoethylamino)-phenylamino]-1-phenyl-methylidene}-5-nitro-2-indolinone (Example 332) are dissolved in 30 ml of dichloromethane and combined with 1.2 ml (16 mmol) of acetylchloride. The mixture is stirred for 1 hour at ambient temperature. The precipitate is removed by suction filtering and the reaction solution is washed with water. Then the solvent is eliminated in vacuo, the residue is dissolved in 20 ml of methanol and combined with 4 ml of 1 N sodium hydroxide solution. The mixture is stirred for 30 minutes at ambient temperature and then the solvent is eliminated in vacuo. The residue is suspended in water and a little ether. Then the product is suction filtered and dried.
Reaction SMILES: N[C@H](C([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=O)CC(C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1>[CH2:21]([O:20][C:18]([NH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH2:9])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)C[C@H](N)C(=O)NCCCCCCCNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: NCCCCCCCNC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 67 %

Procedure:
In 80 ml of the tetrahydrofuran were dissolved 1.00 g of DL-trans-benzylhydrogenepoxysuccinate, 1.70 g of N-L-leucyl-N'-benzyloxycarbonyl-1,7-diaminoheptane, 0.73 g of 1-hydroxybenzotriazole and 0.55 g of N-methylmorpholine. To the solution was slowly added 0.95 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride under ice-cooling with stirring. The mixture was stirred for 2 hours under ice-cooling and then for 2 hours at room temperature. The solution was concentrated under reduced pressure and admixed with 100 ml of ethyl acetate and 100 ml of water and the mixture was shaken vigorously. The ethyl acetate layer was separated and washed successively with a 10% aqueous hydrochloric acid solution, an aqueous saturated bicarbonate solution and an aqueous saturated sodium chloride solution and concentrated to dryness. The resulting residue was purified by column chromatography on silica gel (chloroform:acetone=10:1) and recrystallized from ethyl acetate-n-hexane to give 1.50 g of N-[N-DL-3-trans-benzyloxycarboxyloxirane-2-carbonyl)-L-leucyl]-N'-benzyloxycarbonyl-1,7-diaminoheptane m.p. 134° C. Yield: 67%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].[CH3:20][O:21]C(Cl)Cl>ClCCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:12]([C:11]1[CH:16]=[CH:17][CH:18]=[CH:19][C:10]=1[S:9][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH:20]=[O:21])([O:14][CH3:15])=[O:13]
Reactant: COC(Cl)Cl
Reactant: COC(=O)c1ccccc1Sc1ccccc1OC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Product: COC(=O)c1ccccc1Sc1cc(C=O)ccc1OC

Procedure:
Dissolve 117 g (0.427 mole) of the ester of Step B in 1500 ml of 1,2-dichloroethane and cool with stirring in an ice-bath. Add 200 ml (345 g, 1.82 mole) of titanium tetrachloride at a rapid dropwise rate. Add also fairly rapidly 154 g (1.34 mole) of dichloromethyl methyl ether. Stir the mixture under a nitrogen atmosphere overnight then pour into ice. After shaking, separate the organic phase and extract the aqueous phase twice with methylene chloride. Wash the combined organic phases twice with water, dry and strip to an oil which crystallizes. (m.p. 99°-104° C.).
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:6]1)(=[O:3])[CH3:2].ClS([N:32]=[C:33]=[O:34])(=O)=O.O>C(#N)C>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([CH2:23][O:24][CH2:25][CH2:26][O:27][C:33](=[O:34])[NH2:32])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)S[C@H]1C[C@@H](COCCO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CC#N
Solvent: O
Product: CC(=O)S[C@H]1C[C@@H](COCCOC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-4-acetylthio-2-(2-hydroxyethyloxymethyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.1 g) in acetonitrile (20 ml) was added chlorosulfonyl isocyanate (0.32 ml) at 0°-5° C. and the mixture was stirred at 20°-25° C. for 1 hour. Water (3 ml) was added to the solution at the same temperature and the mixture was stirred for 20 hours. After the solvent was evaporated, the residue was dissolved in ethyl acetate, washed with water, saturated sodium bicarbonate and brine successively. The dried organic layer was evaporated to give (2S,4S)-4-acetylthio-2-(2-carbamoyloxyethyloxymethyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.19 g).
Reaction SMILES: [C:1]1([C:7]([SH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[C:24]([CH3:28])([CH3:27])[CH:25]=[O:26]>C1COCC1.C1(C)C=CC=CC=1>[CH3:27][C:24]([S:20][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:28])[CH:25]=[O:26]
Reactant: CC(C)(Br)C=O
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C=O)SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 58.7 %

Procedure:
Triphenylmethylmercaptan (362.94 g, 1.31 mol, 100 mol %) dissolved in anhydrous THF (2 L) was cooled in an ice bath under argon. Sodium hydride (60% in oil; 54.39 g, 1.35 mol, 104 mol %) was added in portions over 20 min. 2-bromo-2-methylpropanal (206.06 g, 1.36 mol, 104 mol %; see Stevens & Gillis, 1957, J. Amer. Chem. Soc. 79: 3448-51) was then added slowly over 20 min. The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction was quenched with water (1 L) and extracted with diethyl ether (3×1 L). The ether extracts were combined, washed with saturated NaCl solution (500 mL), dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to afford a thick orange oil. The crude oil was dissolved in toluene (200 mL) and diluted to 2 L with hot hexanes. The mixture was filtered through a sintered glass funnel and cooled at -5° C. for 12 hours. The white crystalline solid which formed was removed by filtration to afford 266.36 g (59% yield) of the title compound. The melting point of the resulting compound was determined to be 83-85° C. Nuclear magnetic resonance characterization experiments yielded the following molecular signature:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[C:6]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])[CH:7]=1.[C:17](O)(=[O:23])[CH2:18][CH2:19][C:20](O)=[O:21]>>[C:14]([C:4]1[CH:3]=[C:2]([N:1]2[C:20](=[O:21])[CH2:19][CH2:18][C:17]2=[O:23])[CH:7]=[C:6]([S:8]([F:13])([F:9])([F:10])([F:11])[F:12])[CH:5]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)c1cc(N)cc(S(F)(F)(F)(F)F)c1
Reactant: O=C(O)CCC(=O)O
Product: CC(=O)c1cc(N2C(=O)CCC2=O)cc(S(F)(F)(F)(F)F)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 16.1 %

Procedure:
1-[3-Amino-5-(pentafluorosulfanyl)phenyl]ethanone (200 mg) was mixed with succinic acid (90 mg) in a flask, and then polyphosphoric acid (10 ml) was added. The mixture was heated to 130° C. for 8 h while stirring and, after leaving to stand overnight, further succinic acid (50 mg) was added and the mixture was heated to 130° C. for a further 4 h. After cooling, the mixture was stirred into ice-water and the aqueous solution was extracted five times with ethyl acetate. The combined extracts were washed with saturated sodium hydrogencarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC. The product-containing fractions were combined, freed of the acetonitrile, admixed with saturated sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 42 mg of the desired compound were obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]([F:18])([F:17])[F:16])[CH:9]=2)[C:5]([CH3:19])=[CH:4][N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[CH2:23][CH2:22]1>C(Cl)Cl.CO>[CH3:19][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]([F:18])([F:17])[F:16])[CH:9]=2)=[N:7][C:2]([NH:32][C:31]2[CH:30]=[CH:29][C:28]([CH2:27][N:24]3[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]3)=[CH:34][CH:33]=2)=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)nc1-c1cccc(OC(F)(F)F)c1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(CN3CCN(C)CC3)cc2)nc1-c1cccc(OC(F)(F)F)c1
Yield: 79 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-5-methyl-4-(3-(trifluoromethoxy)phenyl)pyrimidine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 79% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 8.32 (s, 1H), 7.57 (d, 3H, J=8.5 Hz), 7.52 (s, 1H), 7.50 (t, 1H, J=7.9 Hz), 7.29 (d, 1H, J=7.9 Hz), 7.25 (d, 2H, J: not calculated due to overlapping peaks), 3.45 (s, 2H), 2.47 (bs, 8H), 2.28 (s, 3H), 2.26 (s, 3H); MS (ESI): 458.3 [M+H]+, 229.7 [M+2H]2+.
Reaction SMILES: [Al](C)(C)C.CO[C:7]([C:9]1[S:10][C:11]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:12][C:13]=1[C:14]#[C:15][Si](C)(C)C)=[O:8].[C:27]([O:31][C:32]([N:34]1[CH2:37][CH:36]([O:38][C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][C:40]=2[F:46])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1(C)C=CC=CC=1.CCOC(C)=O>[C:27]([O:31][C:32]([N:34]1[CH2:35][CH:36]([O:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH:15]=[CH:14][C:13]4[CH:12]=[C:11]([C:20]5[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=5)[S:10][C:9]=4[C:7]3=[O:8])=[CH:41][C:40]=2[F:46])[CH2:37]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(N)cc2F)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Al](C)C
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(-n3ccc4cc(-c5ccc(Cl)cc5)sc4c3=O)cc2F)C1
Temperature: 0 °C
Yield: 80.1 %

Procedure:
Add 2.0 M Al(CH3)3 (1.28 mL, 2.56 mmol) to a suspension of 5-(4-chloro-phenyl)-3-trimethylsilanylethynyl-thiophene-2-carboxylic acid methyl ester (0.851 g, 2.44 mmol) and 3-(4-amino-2-fluoro-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.688 g, 2.44 mmol) in toluene (20 mL). Stir the reaction at 60° C. for 4 h. Cool the mixture to 0° C., quench with 2.0 M NaOH (5 mL) and water (20 mL) and then extract with CHCl3 (3×50 mL). Dry with Na2SO4, filter, and concentrate. Dissolve the crude material in THF (50 mL), treat with 1.0 M TBAF (2.93 mL, 2.93 mmol) and stir at RT overnight. Dilute with EtOAc (100 mL), wash with water (3×40 mL), dry with Na2SO4, filter, and concentrate. Purify the crude material by chromatography, eluting with 5% CH3OH/CHCl3 to give 1.03 g (80%) of the title compound. LC-MS/ES m/z (35Cl) 526.9 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:27]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(O)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(OCc3ccccc3)c2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a mixture of tert-butyl 5,6-dihydro-4-(3-hydroxyphenyl)pyridine-1(2H)-carboxylate (crude, 100 mg) and potassium carbonate (300 mg) in DMF was added benzyl bromide (60 μL) at room temperature. The resulting mixture was stirred at 80° C. for 16 h. The mixture was cooled down, diluted with ethyl acetate, washed with water, brine, dried and concentrated. The product (60 mg) was purified by combiflash using hexane/ethyl acetate (max. EtOAc 10%) to afford tert-butyl 4-(3-(benzyloxy)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate which was then converted to the final compound using procedures analogous to those for example 1. MS(ESI): (M+H)+=462.2
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[Br:22][CH2:23][CH2:24]O>C(Cl)Cl>[F:7][C:8]([F:21])([F:20])[S:9]([O:12][CH2:24][CH2:23][Br:22])(=[O:11])=[O:10]
Reactant: OCCBr
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(OCCBr)C(F)(F)F
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 82.5 %

Procedure:
Anhydrous pyridine (8.5 mL, 105 mmol) and dry DCM (100 mL) were added to a 3-necked round-bottomed flask under a nitrogen atmosphere. The reaction flask was then cooled to about −20° C. with a dry ice/ethylene glycol bath. Trifluoromethanesulfonic anhydride (17 mL, 100 mmol) was added, whereupon a white/pink precipitate formed immediately. 2-Bromoethanol (7.1 mL, 100 mmol) was added after 5 minutes. The precipitate disappeared and then after a few minutes a new white precipitate formed. The reaction mixture was stirred for 20 minutes during which time it gradually warmed to r.t. The reaction mixture was then filtered through a phase separator and the residue was washed with 1:1 DCM/hexane (2×10 mL). The filtrate was run through a 4 cm silica plug with 1:1 DCM/hexane solution (300 mL). The solvent was removed in vacuo to give the title compound as a brown oil (21.2 g, 87%). δH (CDCl3) 4.76 (2H, t, J 6.4 Hz), 3.62 (2H, t, J 6.4 Hz).
Reaction SMILES: [Li]CCCC.C([Mg]Cl)CCC.Br[C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Br:19])[CH:18]=1.[O:20]=[C:21]1[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22]1>[NH4+].C1(C)C=CC=CC=1.C1COCC1>[Br:19][C:17]1[CH:18]=[C:13]([C:21]2([OH:20])[CH2:25][CH2:24][CH:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22]2)[CH:14]=[N:15][CH:16]=1
Reactant: Brc1cncc(Br)c1
Reactant: CCOC(=O)C1CCC(=O)C1
Agent: CCCC[Mg]Cl
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(O)(c2cncc(Br)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of THF:toluene (2.11 mL:2.11 mL) and n-BuLi (0.923 ml, 1.48 mmol) was cooled to −10° C. The reaction mixture was purged/filled with argon (3×). n-Butyl magnesium chloride (0.369 ml, 0.739 mmol) was added to the reaction mixture and stirred for 30 minutes. 3,5-Dibromopyridine (0.5 g, 2.111 mmol) was added to the reaction mixture over the course of 30 minutes, keeping bath below −10° C. and stirred for 1 hour. Ethyl 3-oxocyclopentanecarboxylate (0.330 g, 2.111 mmol) was added to the reaction mixture and stirred at −10° C. for ˜5 minutes. The reaction mixture was warmed to room temperature, diluted with saturated ammonium, extracted DCM (3×), and combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to afford ethyl 3-(5-bromopyridin-3-yl)-3-hydroxycyclopentanecarboxylate. MS ESI calc'd for C13H17BrNO3 [M+H]+ 314 and 316. found 314 and 316.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:16][CH2:17][CH2:18][CH2:19]Cl)=[CH:11][CH:12]=2)[CH:7]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>CS(C)=O>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][C:10]([O:16][CH2:17][CH2:18][CH2:19][NH:29][C:26]4[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=4)=[CH:11][CH:12]=3)[CH:7]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(N)cc1
Reactant: ClCCCOc1ccc2ccc(OCCCCl)cc2c1
Solvent: CS(C)=O
Product: COc1ccc(NCCCOc2ccc3ccc(OCCCNc4ccc(OC)cc4)cc3c2)cc1
Temperature: 140 °C

Procedure:
A mixture of 2,7-bis(3-chloropropyloxy)naphthalene (1 gm, 0.003 mole) and p-anisidine (1.17 gm, 0.005 mole) were taken in 60 ml dry DMSO. It was refluxed at 140° C. for 12 hrs the completion of the reaction was checked by TLC. The reaction mixture was poured into distilled water (80 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was further crystallized by benzene hexane to get the desired compound as solid, m.p. 127° C., (yield 1.34 gm, 89%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([I:12])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.I[CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCOCC>[Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([I:12])[C:5]([O:11][CH2:15][CH3:16])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CCI
Reactant: CC(=O)c1cc(Cl)c(C)c(I)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOc1c(C(C)=O)cc(Cl)c(C)c1I
Temperature: 60 °C
Yield: 91.7 %

Procedure:
1-(5-Chloro-2-hydroxy-3-iodo-4-methylphenyl)ethanone (18.9 g, 60.9 mmol) (from Example 1, Step 1) was dissolved in N,N-dimethylformamide (60.8 mL). Iodoethane (7.3 mL, 91 mmol) was added followed by potassium carbonate (17 g, 120 mmol). The reaction was heated at 60° C. for 1 hour. The mixture was cooled to room temperature, diluted with ether. The organic layers were combined, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0-10% EtOAc in hexanes) to give the desired product (18.9 g, 91.7%). LCMS calculated for C11H13ClIO2 (M+H)+: m/z=339.0; Found: 339.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[N:6][CH:7]=1.[Cl:10][C:11]1[C:12]([C:17](O)=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][C:17](=[O:18])[C:12]2[C:11]([Cl:10])=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)c1ncccc1Cl
Reactant: NCc1cncc(Br)c1
Product: O=C(NCc1cncc(Br)c1)c1ncccc1Cl

Procedure:
In analogy to the procedure described for the preparation of example 75, coupling of (5-bromopyridin-3-yl)methanamine with 3-chloro-pyridine-2-carboxylic acid gave the title compound as off-white solid. MS: 326.2 and 328.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13].O[CH:15](S([O-])(=O)=O)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Na+]>C(O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)ccc1NCCCO
Reactant: O=S(=O)([O-])C(O)Cc1ccccc1
Agent: [Na+]
Solvent: CCO
Product: OCCCn1c(Cc2ccccc2)nc2cc(Cl)ccc21

Procedure:
A mixture of 30 parts of 3-[(2-amino-4-chlorophenyl)amino]-1-propanol, 44.8 parts of sodium α-hydroxybenzeneethanesulfonate and 120 parts of ethanol is stirred and refluxed for 30 minutes. The reaction mixture is evaporated and the residue is taken up in water. The oily product is extracted with trichloromaethane. The extract is dried, filtered and evaporated, yielding 5-chloro-2-(phenylmethyl)-1H-benzimidazole-1-propanol as a residue.