Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C@@H:13]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[CH2:16][N:15]([C:28](=[O:43])[CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:14]1.C(N(CC)CC)C>ClCCl>[CH:12]([C@@H:13]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=2)[CH2:16][N:15]([C:28](=[O:43])[CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34])[CH2:14]1)=[O:11]
Reactant: O=C(CCCCC(=O)N1C[C@H](CO)[C@@H](c2cccc(C(F)(F)F)c2)C1)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C[C@H]1CN(C(=O)CCCCC(=O)OCc2ccccc2)C[C@@H]1c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
A 0.30 ml portion of DMSO was dissolved in 5 ml of dichloromethane, and 0.18 ml of oxalyl chloride was added thereto while keeping the internal temperature at −60° C. or less. After 30 minutes of stirring, a dichloromethane solution (5 ml) of 323 mg of benzyl 6-{(3R,4S)-3-(hydroxymethyl)-4-[3-(trifluoromethyl)phenyl]pyrrolidin-1-yl}-6-oxohexanoate was added thereto while keeping the internal temperature at −60° C. or less, successively stirring this for 30 minutes. The reaction solution was mixed with 0.87 ml of triethylamine while keeping the internal temperature at −50° C. or less, and then stirred at −78° C. for 4.5 hours. Thereafter, work-up was carried out in the standard method to obtain benzyl 6-{(3R,4S)-3-formyl-4-[3-(trifluoromethyl)phenyl]pyrrolidin-1-yl}-6-oxohexanoate as a crude product. A mixture of the thus obtained crude product, 143 mg of (R)-(+)-1-(1-naphthyl)ethylamine, acetic acid and 5 ml of 1,2-dichloroethane was stirred for 20 minutes, and then mixed with 443 mg of sodium triacetoxyborohydride at room temperature and stirred at room temperature for 17Hours, successively carrying out work-up and purification in the standard method to obtain 312 mg of benzyl 6-{(3S,4S)-3-({[(1R)-1-(naphthyl)ethyl]amino}methyl)-4-[3-(trifluoromethyl)phenyl]pyrrolidin-1-yl}-6-oxohexanoate.
Reaction SMILES: C([SiH](CC)CC)C.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C(#N)C>[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OC(c1ccc(Cl)cc1)c1ccccc1OCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O
Product: Clc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
In a nitrogen stream, triethylsilane (2.8 mL, 17.6 mmol) and a boron trifluoride-diethyl ether complex (1.84 mL, 14.6 mmol) were added to a solution of (2-benzyloxyphenyl)-(4-chlorophenyl)methanol (4.76 g, 14.6 mmol) in acetonitrile (150 mL) at −40° C. and the reaction mixture was stirred at the same temperature for 2 hours and furthermore at 0° C. for one hour. Water was added thereto and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (3.85 g, 85%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.[N-:18]=[N+:19]=[N-:20].[Na+].CS(C)=O>C1COCC1.C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:18]=[N+:19]=[N-:20])=[CH:12][CH:11]=1
Reactant: [N-]=[N+]=[N-]
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: [N-]=[N+]=NCc1ccc(-c2nc3ccccc3o2)cc1
Reaction time: 24 h

Procedure:
To a solution of 4-(benzoxazol-2-yl)benzyl bromide (0.49 g; 1.7 mmol) in THF (3 ml) is added sodium azide (0.22 g; 3.4 mmol) and dimethylsulfoxide (1 ml). The reaction is stirred for 24 hours and diluted with CH2Cl2, washed with H2O 3× and brine, dried (MgSO4) and concentrated in vacuo. The product is purified by column chromatography using 50% CH2Cl2 /petroleum ether to yield 4-(benzoxazol-2-yl)benzylazide as a white solid which is used directly in Step B.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9](O)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Br[CH2:15][CH2:16][OH:17].CN(C)C=O>O>[Br:1][C:2]1[CH:11]=[C:10]([Br:12])[C:9]([CH2:15][CH2:16][OH:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Oc1c(Br)cc(Br)c2cccnc12
Reactant: OCCBr
Solvent: O
Solvent: CN(C)C=O
Product: OCCc1c(Br)cc(Br)c2cccnc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 76.9 %

Procedure:
A solution of 3.79 g of 5,7-dibromo-8-hydroxyquinoline (12.5 mmol) and 975 mL of 2-bromoethanol (13.75 mmol) in 20 mL of dry dimethylformamide containing 5.18 g anhydrous potassium carbonate (37.5 mmol) was placed under argon atmosphere and heated at 60° C. with vigorous magnetic stirring. After 4 hr a further 220 μL of 2-bromoethanol was added and stirring continued at 60° overnight. After 22 hr another 440 μL of 2-bromoethanol was added. After 4 days the mixture was poured into 150 mL of water while stirring. The precipitated product was collected by filtration, washed with 50 mL of 0.5 M aqueous potassium carbonate, plain water and air dried. The solid was washed through the funnel by dissolving in dichloromethane, and the solvent was removed to yield 3.18 g of 5,7-dibromo-8-(2-hydroxyethyl)quinoline. After recrystallization from methanol/water containing a little triethylamine, the melting point was 128–131° C.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)([F:4])[CH3:3].C([Mg]Cl)(C)C.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[C@@H:26]1[N:30]2[CH:31]=[N:32][CH:33]=[C:29]2[C:28](=[O:34])[CH2:27]1)[C:21]#[N:22]>C1COCC1>[F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C@:28]2([OH:34])[C:29]3[N:30]([CH:31]=[N:32][CH:33]=3)[C@@H:26]([C:25]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=3[F:17])[CH2:27]2)=[CH:7][CH:6]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1ccc(I)cc1
Reactant: N#Cc1ccc([C@H]2CC(=O)c3cncn32)c(F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(F)(F)c1ccc([C@@]2(O)C[C@H](c3ccc(C#N)cc3F)n3cncc32)cc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
To a solution of 1-(1,1-difluoro-ethyl)-4-iodo-benzene, (167 mg, 0.62 mmol) in THF (2 mL) cooled to −40° C. was added a 2 M solution of i-PrMgCl in THF (0.42 mL, 0.83 mmol) dropwise. The crude was stirred at −40° C. for 1 hr. 3-fluoro-4-((R)-7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile (125 mg, 0.52 mmol) in THF (2 mL) was added. The crude was allowed to slowly warm to room temperature over 3 hrs. The crude was quenched with NH4Cl aq. The crude diluted in EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude was purified via preparation plate two times using 2M NH3 in MeOH/CH2Cl2 to give 37 mgs of the entitled product. MS 384.3 (M+H); LCMS condition A, retention time 1.31 min. 1H NMR (400 MHz, CDCl3) δ ppm 1.83 (t, 3H), 2.94 (dd, 1H), 3.24 (dd, 1H), 5.70 (d, 1H), 6.47 (s, 1H), 7.11 (t, 1H), 7.19 (s, 1H), 7.33 (d, 2H), 7.38 (m, 2H), 7.46 (m, 2H).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:31])[C:4]([C@@H:6]1[CH2:10][C@@H:9]([S:11][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][NH:7]1)=[O:5].N1C=CC=CC=1.[CH2:38]([O:42][C:43](Cl)=[O:44])[CH2:39][CH2:40][CH3:41]>C1COCC1>[CH2:38]([O:42][C:43]([N:7]1[CH2:8][C@H:9]([S:11][C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:10][C@H:6]1[C:4](=[O:5])[N:3]([O:2][CH3:1])[CH3:31])=[O:44])[CH2:39][CH2:40][CH3:41]
Reactant: CCCCOC(=O)Cl
Reactant: CON(C)C(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCOC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1C(=O)N(C)OC
Temperature: 25 °C
Yield: 95.7 %

Procedure:
A solution of 17.3 g (40 mmol) (2S,4R)-4-Tritylsulfanyl-pyrrolidine-2-carboxylic acid methoxy-methyl-amide in 120 ml THF was treated at 0° C. with 4 ml (50 mmol) pyridine and 5.59 ml (42 mmol) butylchloroformate. The reaction was warmed up to RT over night, evaporated and partitioned between aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried over Na2SO4. Purification by flash-chromatography on silicagel (Hexane/EtOAc 4:1) gave 20.4 g (96%) of (2S,4R)-2-(Methoxy-methyl-carbamoyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid butyl ester, MS: 533 (MH+).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[Cl-].[Na+]>O1CCCC1>[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][C@@H:22]([O:25][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Reaction time: 0.5 h

Procedure:
16.91 ml of triethylamine and 9.36 ml of methanesulfonyl chloride were added, in that order, whilst ice-cooling, to a solution of 25 g of (3R)-1-t-butoxycarbonyl-3-hydroxypyrrolidine dissolved in 250 ml of dry tetrahydrofuran, and the mixture was stirred at 0° to 5° C. for 30 minutes and then at 15° C. for 30 minutes. At the end of this time, the mixture was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to give 3.10 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]([N:9]1[CH2:12][CH:11]([OH:13])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].[H-].[Na+].[F:18][C:19]([F:28])([F:27])[C:20]1[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=1>CN(C)C=O.C1C=CC=CC=1>[CH3:1][CH:2]([N:9]1[CH2:12][CH:11]([O:13][C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:28])([F:27])[F:18])=[CH:21][CH:22]=2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(c1ccccc1)N1CC(O)C1
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(c1ccccc1)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 90 °C

Procedure:
The maleate salt of 1-(α-methylbenzyl)-3-hydroxyazetidine (78.6 g., 0.20 mole) was partitioned between benzene and dilute sodium hydroxide, the benzene layer dried, filtered, and concentrated at reduced pressure. The residue was dissolved in 100 ml. of dry dimethylformamide and added at a rapid dropwise rate, to a stirring suspension of 10.1 g. (0.22 mole) of sodium hydride (50% in mineral oil) in 150 ml. of dry dimethylformamide at 90° C. The solution was heated at 90° C. for one hour and then treated dropwise with 32.0 g. (0.20 mole) of 4-trifluoromethylfluorobenzene. The solution was refluxed for three hours. The cooled solution was partitioned between water and isopropyl ether, and the ether layer extracted with dilute hydrochloric acid. The aqueous acid layer was made basic with concentrated sodium hydroxide and ice, and extracted with isopropyl ether. The ether layer was concentrated and the residue distilled at 150°-160° C./0.2 mm. to give 25.6 g. of product.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=2)=[CH:8][N:9]=1)(=O)C.Cl>C(O)(=O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[N:12]([CH3:16])[CH:13]=[CH:14][N:15]=2)=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2nccn2C)s1
Agent: Cl
Solvent: CC(=O)O
Product: Cn1ccnc1Sc1cnc(N)s1
Yield: 83.9 %

Procedure:
A solution of 2-acetylamino-5-(1-methylimidazol-2-ylthio)thiazole (7.0 g) in a mixture of acetic acid (100 ml) and aqueous 6N-hydrochloric acid (20 ml) was refluxed for 3.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was adjusted to pH 8 using aqueous sodium bicarbonate under ice cooling. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-amino-5-(1-methylimidazol-2-ylthio)thiazole (4.9 g, yield: 83.9%). mp: 180°-190° C. (dec.) IR (Nujol): 3300, 3150, 1620, 1530, 1280, 1220 cm-1
Reaction SMILES: [C:1]1([C:7]2[N:8]([CH2:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:27][OH:28].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>N1C=CC=CC=1>[OH:28][NH:27][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:17]([CH2:16][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:15]=[C:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:18][CH:19]=1
Reactant: NO
Reactant: O=C(O)c1ccc(Cn2c(-c3ccccc3)cc3ccccc32)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C(NO)c1ccc(Cn2c(-c3ccccc3)cc3ccccc32)cc1
Yield: 16.7 %

Procedure:
Title compound 496 (332 mg, 1.014 mmol), hydroxylamine hydrochloride (85 mg, 1.217 mmol), BOP (583 mg, 1.318 mmol), triethylamine (0.424 mL, 3.04 mmol) and pyridine (7 mL) were stirred together at room temperature for 1 hour. All solvents were then removed under reduced pressure, and the residue was diluted with ethyl acetate and brine. Following extraction with ethyl acetate, the combined organic layers were dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was then purified by column chromatography on silica gel using 50-100% EtOAc/hexanes as the eluent to afford title compound 497 (0.058 g, 17%) as a white solid. 1H NMR (CD3OD) δ (ppm): 7.66-7.62 (m, 3H), 7.50-7.38 (m, 5H), 7.28-7.23 (m, 1H), 7.17-7.08 (m, 2H), 7.03 (d, J=8.4 Hz, 2H), 6.65 (d, J=0.6 Hz, 1H), 5.51 (s, 2H). MS (m/z): 343.5 (M+H).
Reaction SMILES: [C:1]([O:14]C)(=[O:13])/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:8](OC)=[C:6](O)[CH:5]=1.[H-].[Na+].C1OC1CO.Cl>CS(C)=O>[C:1]([OH:14])(=[O:13])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:8]=[CH:11][CH:12]=1
Reactant: COC(=O)/C=C/c1ccc(OC)c(O)c1
Agent: Cl
Agent: OCC1CO1
Agent: [H-]
Solvent: CS(C)=O
Product: O=C(O)C=Cc1ccccc1
Reaction time: 0.5 h

Procedure:
3 g of methyl isoferulate was dissolved in 600 ml of DMSO, and 370 mg of sodium hydride was added. The system was heated to 90° C. under N2 gas flow and 7 g of glycidol was added gradually. Heating and agitation was carried out for 0.5 hours. The system was cooled, neutralized by adding hydrochloric acid, solvent was removed and adduct of cinnamic acid and glycerin was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].C([O:13][C:14](=O)[C:15](Br)([CH3:17])[CH3:16])C>C1(C)C=CC=CC=1.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[CH3:16][C:15]1([CH3:17])[C:14](=[O:13])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8]1
Reactant: Nc1ccccc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC1(C)Oc2ccccc2NC1=O
Reaction time: 2 h

Procedure:
3 g of 2-aminophenol is mixed in 23 ml of toluene with 1.8 g of sodium hydride with the addition of 50 mg of TEBA (triethylbenzylammonium chloride), and 4.4 ml of 2-bromo-2-methylpropionic acid ethyl ester is added drop by drop at ice bath temperature. After 2 hours at room temperature, it is poured onto ice water, extracted with ethyl acetate, washed with brine, the organic phase is dried with magnesium sulfate and concentrated by evaporation. After recrystallization from isopropyl ether, 278 mg of crystals results.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH:32]=O)[CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:32][C:28]2[CH:27]=[C:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:31]=[CH:30][N:29]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cc(-c2ccccc2)ccn1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cc(-c2ccccc2)ccn1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 4-phenylpicolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.65 min.; [M+H]+: 403.16 g/mol.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][C:3]=1[C:7]([NH2:9])=[O:8].[H-].[Na+].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:16]Cl.O>CN(C)C=O.C(O)(=O)C>[NH2:1][C:2]1[N:6]([CH2:16][C:15]2[CH:18]=[CH:19][C:20]([Cl:21])=[C:13]([Cl:12])[CH:14]=2)[N:5]=[N:4][C:3]=1[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1nn[nH]c1N
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1nnn(Cc2ccc(Cl)c(Cl)c2)c1N
Reaction time: 1 h

Procedure:
A stirred, ambient temperature solution of 5-amino-1,2,3-triazole-4-carboxamide (635 mg, 5.00 mmole) in dry dimethylformamide (20ml) is treated in one portion with sodium hydride (240 mg of a 5% dispersion in mineral oil, 120 mg NaH, 5.0 mmol). After 15 min 3,4-dichlorobenzyl chloride (0.977 g, 5.00 mmol) is added. The mixture is stirred 1 hour, poured into water (20 ml), acidified to pH 6 with glacial acetic acid, and filtered. The solid is washed with water, dried, and chromatographed to provide 5-amino-1-(3,4-dichlorobenzyl)-1,2,3-triazole-4-carboxamide.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16](OS(C(F)(F)F)(=O)=O)[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[Cl:31])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3cccc(OS(=O)(=O)C(F)(F)F)c3O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)OCC2CCc3cccc(-c4ccccc4Cl)c3O2)cc1
Temperature: 100 °C
Yield: 88.8 %

Procedure:
A mixture of (8-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (0.49 g, 1.05 mmol), 2-chlorophenylboronic acid (0.33 g, 2.1 mmol), potassium carbonate (0.44 g, 3.2 mmol) and lithium chloride (0.13 g, 3.1 mmol) in dioxane (3.75 ml) and water (1.25 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)palladium(0) (60 mg, 0.052 mmol) was added and the reaction mixture heated at 100° C. for 1 hour. The cooled reaction mixture was then partitioned between ethyl acetate (50 mL) and 1 M aqueous sodium hydroxide (50 mL). The organic layer was separated, washed with water (50 mL) dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford an orange oil. Purification by flash chromatography using a solvent gradient of 5 to 10% ethyl acetate in hexane gave 400 mg (89%) of [8-(2-chlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate as a white solid. HRMS: calcd for C23H21ClO4S+NH4+, 446.11873. found (ESI, [M+NH4]+), 446.1179.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:13][C:14]1[C:19]([CH3:20])=[C:18]([S:21][CH2:22][CH2:23][CH2:24][S:25][C:26]2[CH:27]=[CH:28][C:29]3[N:30]([C:32]([N+:35]([O-:37])=[O:36])=[CH:33][N:34]=3)[N:31]=2)[CH:17]=[CH:16][N:15]=1.O>CN(C)C=O>[C:1]([S:3][CH2:13][C:14]1[C:19]([CH3:20])=[C:18]([S:21][CH2:22][CH2:23][CH2:24][S:25][C:26]2[CH:27]=[CH:28][C:29]3[N:30]([C:32]([N+:35]([O-:37])=[O:36])=[CH:33][N:34]=3)[N:31]=2)[CH:17]=[CH:16][N:15]=1)(=[O:4])[CH3:2]
Reactant: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CCl
Reactant: CC([O-])=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)SCc1nccc(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
A suspension of potassium thioacetate (0.44 g, 3.75 mmol) and potassium carbonate (0.87 g, 6.25 mmol) in 10 ml of dimethylformamide is stirred at room temperature for 30 min and then treated with a solution of 1.03 g (2.5 mmol) of 6-[3-(2-chloromethyl-3-methylpyridin-4-ylsulfanyl)propylsulfanyl]-3-nitroimidazo[1,2-b]pyridazine in 10 ml of dimethylformamide. The suspension is stirred at room temperature for a further 18 h. Water (100 ml) is then added, and the mixture is cooled to 0° C. and filtered. After drying the solid in vacuo at 40° C., it is additionally suspended in hot diisopropyl ether. After cooling to room temperature, the solid is again filtered and dried. 1.02 g (98%) of the title compound are isolated as a pale beige solid. M.p.: 138-140° C.
Reaction SMILES: [F:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.S(=O)(=O)(O)O.[CH3:20]O>>[F:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([O:8][CH3:20])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1cc(O)c(F)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(O)c(F)cc1[N+](=O)[O-]
Temperature: 12.5 °C
Reaction time: 13.5 h
Yield: 85 %

Procedure:
Starting material 4-fluoro-5-hydroxy-2-nitrobenzoic acid, 68 g, 0.34 mol, 1.0 eq) and methanol (140 mL) were charging into a reactor under nitrogen. The solution was cooled to 10-15° C. Sulfuric acid (120 g, 1.2 mol, 3.5 eq) was added at a rate that the internal temperature was below 30° C. The reaction mixture was'refluxed at 65-75° C. for 12-15 hour until HPLC sample showed the conversion was higher than 96%. The mixture was concentrated to minimum volume and the residue was charged into cold water (400 mL) slowly so that the batch was kept below 25° C. The resulting suspension was stirred at 10-15° C. for about 2 hours. The slurry was filtered. The desired product, methyl 4-fluoro-5-hydroxy-2-nitrobenzoate, was obtained as a light brown solid after drying under vacuum (62 g, 85% yield). 1H NMR (CDCl3, 400 MHz) δ 7.84 (d, J=9.7 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 6.66 (s, 1H), 3.93 (s, 3H). 13C NMR (DMSO-4, 100 MHz) δ 165.3, 157.6, 151.9, 151.0, 150.8, 149.4, 138.0, 137.9, 125.9, 117.4, 114.1, 113.8, 53.3.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:21])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19]C)=[CH:4][CH:3]=1.B(Br)(Br)Br.C(Cl)Cl.O>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:21])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=[CH:4][CH:3]=1
Reactant: COc1ccccc1CCC(=O)NCCOc1ccc(Cl)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(CCc1ccccc1O)NCCOc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(4-Chlorophenoxyethyl)-3-(2-methoxyphenyl)propanamide (12.8 g, 38.3 mmol) was dissolved in methylene chloride (10.0 mL). Subsequently, a 1.0M-boron tribromide/methylene chloride solution (49.8 mL, 49.8 mmol) was slowly added dropwise thereto under ice-cooling, followed by stirring for 1 hour at room temperature. Subsequently, water was slowly added dropwise thereto under ice-cooling, followed by stirring for 30 minutes. The resultant mixture was extracted with chloroform. The organic layer was washed with brine, and the resultant mixture was subjected to drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification by column chromatography (n-hexane/ethyl acetate=20/1), whereby a white solid was obtained (11.6 g, 95%).