Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([CH2:12]O)[CH:3]=1.S(Cl)([Cl:16])=O>C(Cl)Cl>[Cl:16][CH2:12][C:4]1[CH:5]=[C:6]2[C:11]([CH2:10][CH2:9][CH2:8][CH2:7]2)=[C:2]([CH3:1])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(CO)cc2c1CCCC2
Solvent: ClCCl
Product: Cc1cc(CCl)cc2c1CCCC2

Procedure:
Alcohol 46.5 (1.0 g, 5.7 mmol) is dissolved in anhydrous DCM (50 mL). Thionyl chloride (619 μL, 8.5 mmol) is slowly added dropwise to the solution. The resulting mixture is stirred until TLC confirms consumption of the starting material. The organic solvent is removed in vacuo. The residue is purified by column chromatography (silica, EtOAc/Hexane), to afford chloride 46.6.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C:11](Cl)(Cl)Cl)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[CH3:16].C1C[O:26]CC1>>[CH2:15]([N:17]1[CH2:22][CH2:21][N:20]([C:11]([C:8]2[NH:7][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:10]=3[N:9]=2)=[O:26])[CH2:19][CH2:18]1)[CH3:16]
Reactant: Cc1cccc2[nH]c(C(Cl)(Cl)Cl)nc12
Reactant: C1CCOC1
Reactant: CCN1CCNCC1
Product: CCN1CCN(C(=O)c2nc3c(C)cccc3[nH]2)CC1
Yield: 62 %

Procedure:
The reaction was carried out as described in General Procedure 2 using 4-methyl-2-trichloromethyl-1H-benzoimidazole (Example 20, Step A, 100 mg, 0.40 mmol) and N-ethylpiperazine (0.10 mL, 0.80 mmol) in THF (3 mL). Purification afforded 67 mg (62%) of the title compound. MS (ESI): mass calculated for C15H20N4O, 272.16; m/z found, 273.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 10.89 (s, 1H), 7.64 (d, J=8.6 Hz, 0.5H), 7.33 (d, J=8.6 Hz, 0.5H), 7.22-7.18 (m, 1H), 7.13 (d, J=7.4 Hz, 0.5H), 7.10 (d, J=7.4 Hz, 0.5H), 4.86-4.84 (m, 1H), 4.80-4.78 (m, 1H), 3.93-3.90 (m, 2H), 2.66 (s, 1.5H), 2.63-2.56 (m, 4H), 2.52 (s, 1.5H), 2.48 (q, J=7.3 Hz, 2H), 1.14 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:21])[CH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:24](OC)[CH2:25][Br:26].B(F)(F)F.CCOCC.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:11][C:12]2[C:13]([O:19][CH3:20])=[CH:14][CH:15]=[C:16]([CH3:18])[C:17]=2[C@H:24]([CH2:25][Br:26])[O:21]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(CBr)OC
Reactant: COc1ccc(C)cc1CC(O)COCc1ccccc1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(C)c2c1C[C@@H](COCc1ccccc1)O[C@H]2CBr
Reaction time: 1.5 h

Procedure:
A solution of 1-benzyloxy-3-(2'-methoxy-5'-methylphenyl)-2-propanol (3.4 g, 12 mmol), from Step 1, and bromoacetaldehyde dimethyl acetal (1.7 mL, 14 mmol) in 25 mL of methylene chloride is cooled to 0° C. Boron trifluoride etherate (3.6 mL, 29 mmol) is added dropwise and the reaction mixture is stirred for 1.5 h. The resultant dark brown solution is poured into 50 mL of 10% aqueous sodium carbonate solution and the aqueous solution is extracted with 3×50 mL of diethyl ether. The combined ether extracts are washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[C:22](Cl)(=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26].O>C1COCC1>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]([C:22](=[O:27])[CH2:23][CH2:24][CH2:25][CH3:26])[C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: CCCCC(=O)Cl
Reactant: CC(C)[C@H](NCc1ccc(Br)cc1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(=O)N(Cc1ccc(Br)cc1)[C@H](C(=O)O)C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
A mixture made up of 5 g (17.47 mmol) of N-(4-bromobenzyl)-L-valine and 5.9 g (70.24 mmol) of sodium bicarbonate in 50 mL of dry THF is left under stirring and under nitrogen atmosphere for one hour. The preceding suspension is cooled to 0° C. and to it is added over a period of 15 min. 4.2 mL (35.41 mmol) of valeroyl chloride. The mixture is then left to react at 20-25° C. for 3 h, 50 mL of water is added and the THF is distilled at low pressure. The resulting solution is taken to pH 2 with HCl 35% and the remains of THF distilled off completely. The solid obtained is filtered, washed with 50 mL of water and dried in a vacuum over to provide 5.9 g (91.2%) of N-(4-bromobenzyl)-N-valeryl-L-valine. The solid is recrystallised from a mixture of EtOH/H2O 2:1. M.p.=123° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6]C=1.CC1C=C(C=C(C)C=1)[NH2:23].N1C=CC=CC=1C=O>>[N:23]1[CH:6]=[CH:5][C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)=[CH:3][CH:2]=1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Reactant: Cc1cc(C)cc(N)c1
Agent: O=Cc1ccccn1
Product: c1ccc(-c2nnn(-c3ccncc3)n2)nc1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3,5-dimethylaniline (72.7 mg, 0.6 mmol) and 2-pyridinecarboxaldehyde (64.2 mg, 0.6 mmol) were employed to obtain 2-[2-(4-pyridyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: [CH2:1]([N:5]([CH2:34][CH2:35][CH2:36][CH3:37])[C:6]([C:8]1[N:9]=[C:10]([C:21]2[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][C:22]=2[C:23](O)=[O:24])[N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:62]1[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[CH2:65][C@@H:64]([CH2:72][OH:73])[NH:63]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH2:34]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:21]2[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][C:22]=2[C:23]([N:63]2[C@H:64]([CH2:72][OH:73])[CH2:65][C:66]3[C:71](=[CH:70][CH:69]=[CH:68][CH:67]=3)[CH2:62]2)=[O:24])[N:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=1)=[O:7])[CH2:35][CH2:36][CH3:37]
Reactant: OC[C@@H]1Cc2ccccc2CN1
Reactant: CCCCN(CCCC)C(=O)c1cn(CCc2ccccc2)c(-c2ccc(C(=O)OC)cc2C(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(CCCC)C(=O)c1cn(CCc2ccccc2)c(-c2ccc(C(=O)OC)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
To a solution of 2-(4-(dibutylcarbamoyl)-1-phenethyl-1H-imidazol-2-yl)-5-(methoxycarbonyl)benzoic acid (130 mg, 0.25 mmol) in DMF (5 mL) was added HATU (293 mg, 0.77 mmol), (S)-1,2,3,4-tetrahydroisoquinoline-3-yl-methanol (84 mg, 0.51 mmol) and diisopropylethylamine (269 μL, 1.54 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with water and extracted with MTBE (3×). The combined organic layer was dried over Na2SO4 and concentrated to give crude product. The crude material was purified by flash chromatography (gradient from 0% to 50% EtOAc/hexanes) to provide the title compound (113 mg, 61%) as a light yellow oil. 1H NMR (DMSO-d6, 1:1 mixture amide rotamers) δ 8.14-8.01 (m, 2H), 7.64 (s, 1H), 7.34 (d, J=7.2 Hz, 1H), 7.26-7.21 (m, 3H), 7.17-7.03 (m, 5.5H), 6.98 (d, J=6.8 Hz, 0.5H), 5.03 (d, J=18.4 Hz, 0.5H), 4.91 (br s, 1H), 4.39 (br s, 0.5H), 4.24 (d, J=18.4 Hz, 0.5H), 4.16-4.07 (m, 2.5H), 3.91 (s, 3H), 3.88-3.85 (m, 0.5H), 3.76-3.73 (m, 0.5H), 3.65-3.55 (m, 1H), 3.39-3.34 (m, 2H), 3.24-3.00 (m, 2H), 2.96-2.85 (m, 3H), 2.70-2.65 (m, 2H), 1.50-1.11 (m, 8H), 0.88-0.76 (m, 6H); MS(ESI+) m/z 651.4 (M+H)+.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[N:10]=[CH:9][N:8]=[C:7]([N:11]2[CH2:14][CH:13]([OH:15])[CH2:12]2)[CH:6]=1>C(O)C>[NH:2]([C:5]1[N:10]=[CH:9][N:8]=[C:7]([N:11]2[CH2:14][CH:13]([OH:15])[CH2:12]2)[CH:6]=1)[NH2:3]
Reactant: NN
Reactant: OC1CN(c2cc(Cl)ncn2)C1
Solvent: CCO
Solvent: O
Product: NNc1cc(N2CC(O)C2)ncn1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
At RT, 27.2 ml (27.9 g, 279.1 mmol) of hydrazine hydrate are added dropwise with stirring to a solution of 10.4 g (55.8 mmol) of 1-(6-chloropyrimidin-4-yl)azetidin-3-ol in 100 ml of ethanol. The reaction solution is stirred at 80° C. for 16 h. For work-up, the mixture is concentrated under reduced pressure, and the precipitate is filtered off and washed twice with in each case 10 ml of ethanol. Yield: 2.0 g (19% of theory)
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:15]C)[CH2:6]1)[CH2:2][CH3:3].[CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1CC(O)=O.B(Br)(Br)Br.[C:35]1(C)C(C)=CC=C[CH:40]=1>>[CH2:1]([N:4]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[OH:15])[CH2:6]1)[CH2:35][CH2:40][C:25]1[C:26]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][CH:24]=1)[CH2:2][CH3:3]
Reactant: Cc1ccccc1C
Reactant: CCCNC1CCc2c(cccc2OC)C1
Reactant: O=C(O)Cc1ccc2ccccc2c1
Agent: BrB(Br)Br
Product: CCCN(CCc1cccc2ccccc12)C1CCc2c(O)cccc2C1

Procedure:
A mixture of 2-(N-n-propylamino)-5-methoxytetralin, 2-naphthylacetic acid and trimethylaminoborohydride in dry xylene was refluxed under an atmosphere of nitrogen as described by Horn et al. Pharm. Weekbld. Sci. Ed. 7 208-211, 1985. The resulting methoxy intermediate was demethylated using boron tribromide as described in the above article to yield the desired product.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([CH2:15][O:16]C(=O)C)[O:8][C@H:7]([O:20][C:21]2[CH:26]=[CH:25][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:23][CH:22]=2)[C@H:6]1CC([O-])=O)(=O)C.Br[C:41]1[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=1)[C:46]([O:48][CH3:49])=[O:47].C(=O)([O-])[O-:52].[Cs+].[Cs+]>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>[OH:52][C@H:6]1[C@@H:5]([OH:4])[C@H:10]([OH:11])[C@@H:9]([CH2:15][OH:16])[O:8][C@@H:7]1[O:20][C:21]1[CH:22]=[CH:23][C:24]([C:41]2[CH:50]=[C:45]([C:46]([O:48][CH3:49])=[O:47])[CH:44]=[N:43][CH:42]=2)=[CH:25][CH:26]=1
Reactant: CC(=O)OC[C@H]1O[C@H](Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@@H](CC(=O)[O-])[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: COC(=O)c1cncc(Br)c1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cncc(-c2ccc(O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]3O)cc2)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 39.6 %

Procedure:
Under nitrogen atmosphere, the mixture of [(2R,3S,4S,5R,6R)-4,5-diacetoxy-6-(acetoxymethyl)-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]tetrahydropyran-3-yl]acetate (0.132 g, 0.24 mmol), methyl 5-bromonicotinate (0.043 g, 0.2 mmol), cesium carbonate (0.196 g, 0.6 mmol) and tetrakis(triphenylphosphine)palladium (0.023 g, 0.02 mmol) in dioxane/water (5 mL/1 mL) was heated at 80° C. with stirring for 1 h. After cooling down, the mixture was filtered through silica gel column to remove the metal catalyst and salts with hexane/ethyl acetate (2/1) containing 2% triethylamine as eluent. The filtrate was concentrated, then dried in vacuo. Into the residue, 6 mL of methanol with catalytic amount of sodium methoxide (0.02 M) was added and the mixture was stirred at room temperature overnight. The solvent was removed. The resulting residue was purified by silica gel chromography with CH2Cl2/MeOH combinations containing 2% NH3/H2O as eluent, giving rise to 12b (0.031 g) in 40% yield. 1H NMR (300 MHz, CD3OD) δ ppm 3.53-3.65 (m, 1H) 3.67-3.83 (m, 3H) 3.89-3.96 (m, 1H) 3.99 (s, 3H) 4.04 (dd, J=3.43, 1.79 Hz, 1H) 5.57 (d, J=1.92 Hz, 1H) 7.22-7.37 (m, 2H) 7.58-7.73 (m, 2H) 8.54 (t, J=2.06 Hz, 1H) 8.97 (d, J=2.20 Hz, 1H) 9.04 (d, J=1.92 Hz, 1H). MS (ESI): found: [M+H]+, 392.1.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]2=[O:14])([CH3:3])[CH3:2].[Br:15]Br>C(O)(=O)C>[Br:15][C:6]1[CH:7]=[C:8]2[C:12](=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=1)[NH:11][C:10](=[O:13])[C:9]2=[O:14]
Reactant: BrBr
Reactant: CC(C)c1cccc2c1NC(=O)C2=O
Solvent: CC(=O)O
Product: CC(C)c1cc(Br)cc2c1NC(=O)C2=O
Temperature: 75 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
7-isopropylindoline-2,3-dione (23.8 g, 0.12 mol) was added to a stirred solution of glacial acetic acid (700 ml). To this solution was added, via additional funnel bromine (7.8 ml, 0.15 mol) in glacial acetic acid (300 ml) during 30 min. After the addition, the combined mixture was stirred at 75° C. for 3 hr, cooled, and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, and evaporated in vacuo; air dried to give (31.8 g, 94%) of crude product. 1H NMR (300 MHz, CDCl3) δ 8.04 (b, NH), 7.59 (dd 2H), 2.84 (m, 1H), 1.31 (d, 6H); ESI (+) MS m/e=269 (MH+), ESI (−) MS m/e=267 (MH−).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][O:10][S:19]([CH3:18])(=[O:21])=[O:20]
Reactant: OCCc1ccccc1F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.5 %

Procedure:
To a solution of 2-(2-fluorophenyl)-ethanol (4.00 g, 28.5 mmol) and triethylamine (6.36 mL, 45.7 mmol) in dichloromethane (15 mL) was added methanesulfonyl chloride (2.88 mL, 37.1 mmol) at −5° C. The mixture was stirred for 4 hours and was allowed to slowly warm to room temperature. The mixture was diluted with dichloromethane and extracted with 1 M HCl and water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography, using dichloromethane as eluent, to afford 5.88 g (94.4%) the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[NH:16]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][N:16]([C:7](=[O:8])[C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=1)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:22]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CCOC(=O)CNCC(=O)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CN(CC(=O)OCC)C(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reaction time: 21 h
Yield: 71.5 %

Procedure:
A solution of 5.0 g (21.7 mmol) of 3,5-dinitrobenzoyl chloride in 75 ml of methylene chloride was added dropwise with stirring to an ice bath cooled mixture of 4.7 ml (27 mmol) of diethyl iminodiacetate and 6.0 ml (43 mmol) of triethylamine in 25 ml of methylene chloride. The reaction mixture was stirred in the cooling bath for 30 minutes and then was left at room temperature for 21 hours. After washing with NaHCO3 solution, the organic layer was dried and concentrated to an oil which was chromatographed on 150 g of silica gel using 20-30% ethyl acetate-hexane. The combined pure fractions were recrystallized from methanol to give 5.95 g (72% yield, 79°-80°) of N-(3,5-dinitrobenzoyl)-N-(2-ethoxy-2-oxoethyl)glycine ethyl ester. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][C@H:14]2[C@@H:18]3[O:19][C:20]([CH3:23])([CH3:22])[O:21][C@@H:17]3[C@@H:16]([O:24][CH2:25][CH2:26][OH:27])[CH2:15]2)=[N:4][C:5]([S:9][CH2:10][CH2:11][CH3:12])=[N:6][C:7]=1[Cl:8].C(O)(=O)C.[N:32]([O-])=O.[Na+]>O.C(OCC)(=O)C>[Cl:8][C:7]1[C:2]2[N:1]=[N:32][N:13]([C@H:14]3[C@@H:18]4[O:19][C:20]([CH3:22])([CH3:23])[O:21][C@@H:17]4[C@@H:16]([O:24][CH2:25][CH2:26][OH:27])[CH2:15]3)[C:3]=2[N:4]=[C:5]([S:9][CH2:10][CH2:11][CH3:12])[N:6]=1
Reactant: O=N[O-]
Reactant: CCCSc1nc(Cl)c(N)c(N[C@@H]2C[C@H](OCCO)[C@H]3OC(C)(C)O[C@H]32)n1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCCSc1nc(Cl)c2nnn([C@@H]3C[C@H](OCCO)[C@H]4OC(C)(C)O[C@H]43)c2n1
Temperature: 2.5 °C

Procedure:
A flask was charged with 2-(((3aR,4S,6R,6aS)-6-((5-amino-6-chloro-2-(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)oxy)ethan-1-ol (50 g), acetic acid (265 mL) and water (50 mL). The mixture was stirred and cooled to 0-5° C. followed by addition of aqueous sodium nitrite solution (8.65 g in 50 mL) over a period of about 1 hour. The mixture was stirred at the same temperature for about 2 hours followed by addition of ethyl acetate (250 mL) and water (250 mL). The mixture was further stirred at room temperature for about 45 minutes at which point water (250 mL) was added. The mixture was stirred and layers were separated, aqueous layer was extracted with ethyl acetate (250 mL). Total organic layer was separated and washed with aqueous potassium carbonate solution (20%, 2×250 mL). The organic layer (˜500 mL) was used for subsequent step.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.C(N(C(C)C)CC)(C)C.[CH2:29]([O:36][C:37]1[C:45]([O:46][CH3:47])=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][C:38]=1[Cl:48])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH2:29]([O:36][C:37]1[C:45]([O:46][CH3:47])=[CH:44][C:40]([C:41]([N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][CH2:2]2)=[O:42])=[CH:39][C:38]=1[Cl:48])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1cc(C(=O)Cl)cc(Cl)c1OCc1ccccc1
Reactant: c1ccc2c(c1)NCS2
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)N2CSc3ccccc32)cc(Cl)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (347 mg) and 37% formalin (0.23 mL) in the same manner as in Example 1 was dissolved in dichloromethane (3 mL), and diisopropylethylamine (0.63 mL) and 4-benzyloxy-3-chloro-5-methoxybenzoyl chloride (578 mg) were added to the solution, and then the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=6:1) to obtain the title compound (498 mg) as a pale yellow oily substance.
Reaction SMILES: CO[C:3]([CH:5]1[CH2:7][N:6]1[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)(=[O:10])=[O:9])=[O:4].[I-].[Na+].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30].[OH-].[Na+].[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:35]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH:5]([C:3]([N:44]2[CH2:45][CH2:46][N:41]([C:35]3[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:34]=3[CH3:33])[CH2:42][CH2:43]2)=[O:4])[CH2:7][N:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)(=[O:9])=[O:10])[C:29]1=[O:30]
Reactant: O=C=Nc1ccccc1Cl
Reactant: Cc1ccc(C)c(N2CCNCC2)c1
Reactant: COC(=O)C1CN1S(=O)(=O)c1cccc(OC)c1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc(S(=O)(=O)N2CC(C(=O)N3CCN(c4cc(C)ccc4C)CC3)N(c3ccccc3Cl)C2=O)c1

Procedure:
In analogy to example 1, (RS)-1-(3-methoxy-benzenesulfonyl)-aziridine-2-carboxylic acid methyl ester (step 2 of example 1) was first reacted with sodium iodide and 2-chlorophenylisocyanate; subsequent ester hydrolysis using sodium hydroxide and coupling with 1-(2,5-dimethylphenyl)-piperazine gave the title compound as a colorless solid. MS: 583.3 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Cl:11][S:12](O)(=[O:14])=[O:13]>>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([O:9][CH3:10])[CH:4]=[CH:5][C:6]=1[S:12]([Cl:11])(=[O:14])=[O:13]
Reactant: COc1cccc(Cl)c1Cl
Reactant: O=S(=O)(O)Cl
Product: COc1ccc(S(=O)(=O)Cl)c(Cl)c1Cl
Temperature: 25 °C

Procedure:
To 5.31 g of 2,3-dichloroanisole is slowly added 10 ml of chlorosulfonic acid over a period of 30 minutes. The reaction is mildly exothermic and at the end of the addition, a clear solution is formed. The yellowish solution is stirred at room temperature for 1 additional hour and quenched with 200 g of crushed ice. The solid is filtered, air-dried and recrystallized from ether-pentane to give 6.9 g of 2,3-dichloro-4-methoxybenzenesulfonyl chloride as off-white prisms, mp 93°-95°.
Reaction SMILES: CC(C1C(S(C)=O)=C(N)N([C:13]2[C:18](Cl)=[CH:17][C:16]([C:20](F)(F)F)=[CH:15][C:14]=2Cl)N=1)=O.CC[S+]([O-])[C:28]1[C:29](C#N)=[N:30][N:31](C2C(Cl)=CC(C(F)(F)F)=CC=2Cl)C=1N.C1C(C(F)(F)F)=CC(Cl)=C(N2N=C(C#N)C([S+]([O-])C(F)(F)F)=C2N)C=1Cl.COC1C(=O)C=C/C(=C\NC2N(C3C(Cl)=CC(C(F)(F)F)=CC=3Cl)N=C(C#N)C=2SC(F)(F)F)/C=1.C1N=CC(CNC2N(C3C(Cl)=CC(C(F)(F)F)=CC=3Cl)N=C(C#N)C=2SCF)=NC=1>>[C:16]1([C:20]2[CH:28]=[CH:29][NH:30][N:31]=2)[CH:15]=[CH:14][CH:13]=[CH:18][CH:17]=1
Reactant: CC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Reactant: CC[S+]([O-])c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: COC1=C/C(=C/Nc2c(SC(F)(F)F)c(C#N)nn2-c2c(Cl)cc(C(F)(F)F)cc2Cl)C=CC1=O
Agent: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1[S+]([O-])C(F)(F)F
Agent: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(NCc2cnccn2)c1SCF
Product: c1ccc(-c2cc[nH]n2)cc1

Procedure:
acetoprole, ethiprole, fipronil, vaniliprole, pyripiole, and pyrafluprole.
Reaction SMILES: C[NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[N:6]=1.[C:12]([N:15]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)[CH3:16])(=[O:14])[CH3:13].C([O-])(=O)C.[Na+].O>C(O)C>[CH3:11][C:7]1[N:6]=[C:5]([CH2:4][CH2:3][NH:2][S:23]([C:20]2[CH:19]=[CH:18][C:17]([N:15]([C:12](=[O:14])[CH3:13])[CH3:16])=[CH:22][CH:21]=2)(=[O:25])=[O:24])[CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)N(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNCCc1cccc(C)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)N(C)c1ccc(S(=O)(=O)NCCc2cccc(C)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-Methyl-N-[2-(6-methyl-2-pyridyl)ethyl]amine (14.66 g, 97.7 mmol) was added to a suspension of the 4-(N-acetyl-N-methylamino) benzenesulfonyl chloride (24.2 g, 97.3 mmol) prepared in Preparative Example 12 and sodium acetate (24.0 g) in ethanol (140 ml). The obtained mixture was stirred at room temperature overnight, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give N-[2-(6-methyl-2-pyridyl)ethyl]-4-(N-acetyl-N-methylamino)benzenesulfonamide as a colorless oil. This oil was dissolved in 4N aqueous hydrochloric acid. The solution was heated under reflux for 2 hours. The pH of the mixture was adjusted to about 8 by the addition of an aqueous solution of sodium hydrogencarbonate. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give an oily residue. This residue was purified by flash column chromatography (chloroform/methanol/aqueous ammonia=97:3:0.3) to give the title compound as a light brown oil (25.8 g, overall yield of two steps: 83%).