Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:26]([OH:28])=O)[CH2:20][O:21][C:22]([CH3:25])([CH3:24])[CH3:23])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:37]>ClCCl>[C:1]([NH:18][C@H:19]([C:26]([F:37])=[O:28])[CH2:20][O:21][C:22]([CH3:25])([CH3:24])[CH3:23])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2]
Reactant: Fc1nc(F)nc(F)n1
Reactant: CC(C)(C)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N-FMOC-O-t-Butyl-L-serine (10 g, 26.07 mmol) (Bachem) was dissolved in dichloromethane (135 mL). Pyridine (2.11 mL, 26.07 mmol) (Aldrich) and cyanuric fluoride (3.52 g, 26.07 mmol) (Aldrich) were successively added at room temperature and the mixture was stirred overnight. Ice cold water (100 mL) was added and the resulting slurry was filtered. The filtrate was poured into a separatory funnel and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford N-FMOC-O-t-butyl-L-serinyl fluoride as a colorless oil which solidified upon standing. (Yield 9.79 g., 97%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.NC1OC2C=CC=CC=2N=1.C1(C[C@@H:66]([N:75]2[CH2:83]C3C(=CC=CC=3)C2=O)[C:67]([NH:69][C:70]2SC=C[N:74]=2)=O)CCCCC1>>[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36]([NH:74][C:70]2[CH:83]=[N:75][CH:66]=[CH:67][N:69]=2)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Reactant: O=C(Nc1nccs1)[C@@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1nc2ccccc2o1
Product: O=C(Nc1cnccn1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O

Procedure:
BOP coupling of (S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Example 1, Step A; 144 mg; 0.50 mmol) and 2-aminobenzoxazole (67 mg; 0.50 mmol) in a manner similar to that used for the preparation of (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 9, Step B) provided after flash chromatography (Merck Silica gel 60, 230-400 mesh, eluent: 50% ethyl acetate/hexanes) 161 mg (96%)of (S)-N-Benzdoxazol-2-yl-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide as a white foam: EI-HRMS m/e calcd for C24H25N3O3 (M+) 403.1896, found 403.1895.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25]I.O>CN(C)C=O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH:6]([C:7]2[N:11]([CH3:12])[N:10]=[C:9]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:8]=2)[CH3:25])=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1Cc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(c1ccc(Cl)cc1)c1nc(-c2c(F)cccc2Cl)nn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of 1.0 g of 5-(4 chlorobenzyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole in 10 ml of N,N-dimethylformamide at 0° C. was added 0.13 g of 60% sodiumhydride. After stirring at room temperature for 30 minutes, 0.42 g of methyl iodide added dropwise to the solution at 0° C. The reaction mixture was stirred at the same temperature for 1 hour and then at room temperature for 2 hours, poured into iced water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 1.0 g of 5-(4-chloro-α-methylbenzyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:35][O:36]S(C)(=O)=O)=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].[CH2:41](O)[CH2:42][CH3:43]>>[F:1][C:2]1[C:3]([CH2:35][O:36][CH2:41][CH2:42][CH3:43])=[C:4]([F:34])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: CCCO
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)C(C)(C)C)c(F)c(COS(C)(=O)=O)c(F)c3o2)cc1F
Product: CCCOCc1c(F)c(NC(=O)C(C)(C)C)c2c(=O)cc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)oc2c1F
Temperature: 100 °C
Reaction time: 2 h

Procedure:
582 mg (1.00 mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-7-methanesulfonyloxymethyl-5-pivaloylamino-4H-1-benzopyran-4-one obtained in EXAMPLE 120 (1) was dissolved in 100 mL of propanol, and the solution was stirred at 100° C. for 2 hours. The solvent was distilled off under reduced pressure to give the crude product of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-pivaloylamino-7-propyloxymethyl-4H-1-benzopyran-4-one. This compound was used for the next step without further purification.
Reaction SMILES: [C:1]([Cl:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([Cl:6])=[O:5]>CCOCC>[C@@H:2]1([C:1]([Cl:8])=[O:7])[CH2:4][CH:3]=[CH:2][CH2:1][C@H:3]1[C:4]([Cl:6])=[O:5]
Reactant: O=C(Cl)/C=C/C(=O)Cl
Solvent: CCOCC
Product: O=C(Cl)[C@@H]1CC=CC[C@H]1C(=O)Cl
Temperature: -50 °C

Procedure:
Freshly distilled fumaryl dichloride (3.7 g; 24 mmol) is dissolved in 10 ml of dry Et2O in an oven dried 20-neck 50 ml round bottom flask, fitted with a gas inlet and dry ice Dewar condenser. The stirred solution is cooled to approximately -50° C. (dry ice/CH3CN). Butadiene (ca. 3 ml) is condensed into the flask and the cooling bath removed. Within 25-30 min the exothermic reaction ceases. After an additional 10 min the excess butadiene and solvent are removed in vacuo to furnish 4.7 g (approx 95%) of the Diels-Alder adduct as a colorless liquid which is used immediately without further purification. IR (neat) 3140 and 1785 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]\[C:10]2[CH:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[N:30]=[C:29](Cl)[C:28]([Cl:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:25]1[N:30]=[C:29]([NH:1][C:2]2[CH:3]=[C:4](/[CH:8]=[CH:9]\[C:10]3[CH:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH:13]=[CH:12][N:11]=3)[CH:5]=[CH:6][CH:7]=2)[C:28]([Cl:32])=[CH:27][N:26]=1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(/C=C\c2cccc(N)c2)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccnc(/C=C\c2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Yield: 90 %

Procedure:
To a solution of tert-butyl {2-[(Z)-2-(3-aminophenyl)vinyl]pyridin-4-yl}carbamate (50.0 mg, 0.16 mmol) and 2,4,5-trichloropyrimidine (0.019 mL, 0.17 mmol) in N,N-dimethylformamide (0.50 mL) was added potassium carbonate (66.6 mg, 0.48 mmol). The resultant mixture was stirred for 16 hours at room temperature. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and brine then dried (Na2SO4), filtered and concentrated to give the desired product as a light brown gum (66 mg, 90%). LCMS for C22H22Cl2N5O2 (M+H)+: m/z=458.0, 460.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.[H-].[Na+].[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34]Cl)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][N:16]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]2=[O:17])=[CH:32][CH:33]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(OCc2ccccc2)cc1
Temperature: 60 °C

Procedure:
A mixture of 6-(2,6-dimethoxyphenyl)piperidin-2-one (110 mg; 0.46 mmol) in anh. DMF (2 ml) was treated at rt with NaH (60% dispersion in mineral oil; 118 mg; 2.95 mmol), and with commercially available 1-(benzyloxy)-4-(chloromethyl)benzene (130 mg; 0.56 mmol). The resulting mixture was then heated to 60° C., under nitrogen, for 1 h. After cooling to rt, aq. sat. NaHCO3 was added, and this mixture was extracted with AcOEt (2×). The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (AcOEt) afforded 1-(4-(benzyloxy)benzyl)-6-(2,6-dimethoxyphenyl)piperidin-2-one as a yellow oil. LC-MS (conditions E): tR=0.82 min.; [M+H]+: 432.24 g/mol.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([OH:29])[CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([O:20][CH2:21]C)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([O:29][S:45]([C:42]1[CH:43]=[CH:44][C:39]([CH3:49])=[CH:40][CH:41]=1)(=[O:47])=[O:46])[CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([O:20][CH3:21])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C(c1ccccc1)C(O)CCCCNC(=O)OCc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: COC(=O)C(c1ccccc1)C(CCCCNC(=O)OCc1ccccc1)OS(=O)(=O)c1ccc(C)cc1
Yield: 61.8 %

Procedure:
The same procedures as in Example 30 were performed except that 27.2 g (70.4 mmol) of methyl 7-(N-benzyloxycarbonylamino)-3-hydroxy-2-phenylheptanoate obtained in Example 9 was dissolved in 136 ml of pyridine; 1.27 g (10.39 mmol) of dimethylaminopyridine was added; and 20.1 g (105.6 mmol) of p-toluenesulfonyl chloride was added; to prepare the target compound as a pale yellow oil in an amount 23.5 g at a yield of 61.8%. The analytical results on the target compound are given below.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Na+].[I-].Cl[CH2:18][C:19]1([CH3:22])[CH2:21][O:20]1>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][C:19]2([CH3:22])[CH2:21][O:20]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: CC1(CCl)CO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(COc2ccc(I)cc2)CO1
Temperature: 70 °C
Reaction time: 15 h
Yield: 68.6 %

Procedure:
A mixture of 4-iodophenol (2.00 g, 9.09 mmol), powdered K2CO3 (2.54 g, 18.4 mmol), NaI (364 mg, 2.43 mmol) and 2-(chloromethyl)-2-methyloxirane (97) (0.90 mL, 9.31 mmol) in anhydrous DMF (5 mL) was stirred in a sealed vial at 70° C. for 15 h. Further 2-(chloromethyl)-2-methyloxirane (97) (0.18 mL, 1.86 mmol) was added and the mixture was then stirred at 73° C. for 17 h. The cooled mixture was added to ice/aqueous NaHCO3 (100 mL) and extracted with Et2O (5×100 mL). The extracts were washed with water (100 mL) and then evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-15% CH2Cl2/petroleum ether firstly gave foreruns, and then further elution with 15-20% CH2Cl2/petroleum ether gave 2-[(4-iodophenoxy)methyl]-2-methyloxirane (96) (1.81 g, 69%) as a white solid: mp (CH2Cl2/pentane) 40-41° C.; 1H NMR (CDCl3) δ 7.55 (dt, J=9.0, 2.7 Hz, 2H), 6.70 (dt, J=9.0, 2.7 Hz, 2H), 4.01 (d, J=10.5 Hz, 1H), 3.90 (d, J=10.5 Hz, 1H), 2.85 (d, J=4.7 Hz, 1H), 2.72 (d, J=4.7 Hz, 1H), 1.47 (s, 3H). Anal. (C10H11IO2) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.Br[CH2:36][C:37]1[CH:50]=[CH:49][C:40]([O:41][CH2:42][C:43]([O:45][CH2:46][CH:47]=[CH2:48])=[O:44])=[CH:39][CH:38]=1>CN(C=O)C>[CH2:46]([O:45][C:43](=[O:44])[CH2:42][O:41][C:40]1[CH:39]=[CH:38][C:37]([CH2:36][O:12][C:9]2[CH:8]=[CH:7][C:6]([C:4](=[O:5])[C:3]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:2]=3[NH2:1])=[CH:11][CH:10]=2)=[CH:50][CH:49]=1)[CH:47]=[CH2:48]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccc(O)cc1
Reactant: C=CCOC(=O)COc1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C=CCOC(=O)COc1ccc(COc2ccc(C(=O)c3cc(Cl)ccc3N)cc2)cc1

Procedure:
A solution was formed by dissolving 2-amino-5-chloro-4'-hydroxybenzophenone (1.72 g, 8.07 mmol) in 40 mL of DMF. Potassium bis(trimethylsilyl)amide that was 0.5M in toluene (16.1 mL, 8.07 mmol, 1.0 equivalents) was added dropwise with stirring. Allyl 2-(4-bromomethylphenoxy)acetate (2.30 g, 8.07 mmol, 1.0 equivalents) was then added and the resulting orange slurry was stirred at ambient temperature for 45 minutes. The slurry was concentrated in vacuo, then diluted with CH2Cl2 (150 mL) and was extracted with 1N aqueous sodium bicarbonate (100 mL) and with 1N aqueous sodium chloride (100 mL), then dried over sodium sulfate and concentrated in vacuo to give the product as a yellow solid which was approximately 95% pure and was taken to the next step without purification. The product had Rf of 0.55 in 50:50:2 ethyl acetate/hexane/triethylamine. The structure was confirmed by proton NMR, carbon-13 NMR, and electron impact mass spectroscopy.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.[N:39]([C:42]1[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=1)=[C:40]=[O:41]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][C:40]([NH:39][C:42]1[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=1)=[O:41])[CH:29]=3
Reactant: N#Cc1ccc(N=C=O)cc1
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(NC(=O)Nc2cc3cc(c2)Nc2nc(ncc2Cl)Nc2cccc(c2)CC3)cc1
Yield: 52 %

Procedure:
The desired compound was prepared according to the procedure of Example B83, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and 4-isocyanatobenzonitrile as the starting materials in 52% yield. LCMS for C26H21ClN7O (M+H)+: m/z=482.2. 1H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 9.49 (s, 1H), 9.35 (s, 1H), 8.97 (s, 1H), 8.12 (s, 1H), 7.86 (m, 1H), 7.67 (m, 2H), 7.59 (m, 2H), 7.33 (m, 1H), 7.23 (m, 1H), 7.05 (m, 2H), 6.83 (m, 2H), 2.82 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([F:15])[CH:14]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[SH:11].[OH-].[K+].[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][Cl:22].Cl.CN(CC[Cl:30])C.[OH-].[Na+]>CN(C)C=O.C1(C)C=CC=CC=1.O>[ClH:22].[ClH:30].[CH3:18][N:19]([CH3:23])[CH2:20][CH2:21][S:11][C:7]1[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([F:1])[CH:14]=[C:13]([F:15])[CH:12]=2)[CH:10]=[CH:9][N:8]=1
Reactant: Fc1cc(F)cc(Cn2ccnc2S)c1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCSc1nccn1Cc1cc(F)cc(F)c1
Temperature: 25 °C

Procedure:
1-(3,5-Difluorobenzyl)-2-mercaptoimidazole (2.26 g, 0.010) and potassium hydroxide (0.056 g, 0.010 mole) are dissolved in dimethylformamide (10 ml) containing water (0.5 ml) with stirring under argon at ambient temperature. To this solution is added dropwise 2-dimethylaminoethyl chloride (1.08 g, 0.010 mole) in toluene (10 ml). [This solution is prepared by stirring 1.44 g of dimethylaminoethyl chloride hydrochloride with an excess of sodium hydroxide pellets in the presence of toluene (10 ml) and a few drops of water, followed by filtering the solution of neutralized base.] The reaction mixture is warmed to 95° C., stirred at this temperature for one hour, cooled and then diluted with water. The layers are shaken together and separated and then the aqueous phase is extracted twice with ether. The toluene and ether extracts are combined and the solvents are removed in vacuo. The residual oil is dissolved in ether and hydrogen chloride in ether is added slowly with stirring until a slight excess is present. The precipitated white crystalline solid is filtered and recrystallized from ethanol ether to give 2-(2-dimethylaminoethylthio)-1-(3,5-difluorobenzyl)imidazole dihydrochloride.
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][C@@H:8]([F:10])[CH2:7][N:6]1[C:11]([NH:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]([NH2:25])=[O:24])[CH:15]=1)=[O:12])=[N+]=[N-]>C1COCC1>[NH2:1][CH2:4][C@@H:5]1[CH2:9][C@@H:8]([F:10])[CH2:7][N:6]1[C:11]([NH:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([C:23]([NH2:25])=[O:24])[CH:15]=1)=[O:12]
Reactant: [N-]=[N+]=NC[C@@H]1C[C@@H](F)CN1C(=O)Nc1cn(C(N)=O)c2ccccc12
Solvent: C1CCOC1
Product: NC[C@@H]1C[C@@H](F)CN1C(=O)Nc1cn(C(N)=O)c2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-[((2S,4R)-2-Azidomethyl-4-fluoro-pyrrolidine-1-carbonyl)-amino]-indole-1-carboxylic acid amide (500 mg, 2.84 mmol) was suspended in THF (5 mL). Air was removed from the flask and replaced with nitrogen three times. Pd/C 10% (100 mg) was added to the solution which was again degassed, placed under a hydrogen atmosphere, and stirred at RT for 1.5 h. The catalyst was removed through a pad of Celite and washed with THF and MeOH to give the desired material which was used in the next step without further purification. MS (LC-MS): 320.2 [M+H]+, 639.2 [2M+H]+, 661.3 [2M+Na]+, 318.1 [M−H]−; tR (HPLC conditions f): 0+1.02+1.61 min.
Reaction SMILES: [C:1]1([P:7](Cl)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][C:17]1[CH:22]=[C:21]([C:23]([Cl:26])([Cl:25])[Cl:24])[CH:20]=[CH:19][N:18]=1.Cl>>[C:1]1([P:7]([NH:16][C:17]2[CH:22]=[C:21]([C:23]([Cl:25])([Cl:24])[Cl:26])[CH:20]=[CH:19][N:18]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1cc(C(Cl)(Cl)Cl)ccn1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Product: O=P(Nc1cc(C(Cl)(Cl)Cl)ccn1)(c1ccccc1)c1ccccc1
Reaction time: 12 h
Yield: 56.7 %

Procedure:
6.2 ml (0.03 mol) of diphenylphosphoryl chloride were added to 6.3 g (0.03 mol) of 2-amino -4trichloromethylpyridine and 60 ml of pryidine at 0° C. After 12 hours at 25° C., the reaction mixture was added to 200 ml of 5% strength hydrochloric acid. The colorless precipitate formed was isolated. 7.0 g (53%) of the desired product were obtained. Mp.: 134°-136° C.; Active Ingredient Example 1.016
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH2:17][C@H:18]1[CH2:21][C@H:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:25][CH:24]=2)[CH2:19]1)C(=O)OC(C)(C)C>ClCCl>[CH3:8][NH:9][CH2:17][C@H:18]1[CH2:21][C@H:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:25][CH:24]=2)[CH2:19]1
Reactant: CN(C[C@H]1C[C@H](Oc2ccc(CN3CCCC3)cc2)C1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC[C@H]1C[C@H](Oc2ccc(CN3CCCC3)cc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Trifluoroacetic acid (8.6 mL, 111 mmol) was added to a solution of compound 9 (5.56 g, 15 mmol) in dichloromethane (50 mL). The reaction mass was stirred at room temperature for 24 h and evaporated in vacuo. The residue was diluted with water (50 mL), and the obtained solution was extracted with CH2Cl2. The organic layer was discarded. The aqueous one was alkalized with 10 N NaOH to pH 12 and extracted with CHCl3 (3×100 mL). The combined extracts were dried and evaporated to afford the title compound (3 g, 74%) as a yellow oil. LCMS-data: M+H 275.2, 276.2 (calc. 274.4). 1H NMR-data (DMSO-d6): 7.16 (d, 2H, Ph, J=8.6); 6.72 (d, 2H, Ph, J=8.6); 4.65-4.78 (m, 1H); 3.46 (s, 2H, CH2); 2.56 (d, 2H, CH2, J=7.6); 2.34-2.41 (m, 4H); 2.28 (s, 3H, NCH3); 2.00-2.30 (m, 5H); 1.60-1.71 (m, 4H).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[C:4]([Cl:12])[CH:3]=1.C([Li])CCC.[B:18](OC)([O:21]C)[O:19]C.[NH4+].[Cl-]>CCOCC.CCCCCC>[Cl:12][C:4]1[CH:3]=[C:2]([B:18]([OH:21])[OH:19])[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=1
Reactant: Clc1cc(Br)c2c(c1)OCCO2
Reactant: COB(OC)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1cc(Cl)cc2c1OCCO2
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a stirred solution of 5-bromo-7-chloro-2,3-dihydro-benzo[1,4]dioxine (Preparation 28, 1.5 g, 6 mmol) in dry Et2O (45 ml) under nitrogen at −70° C. was added n-butyl lithium (2.63 ml of a 2.5M solution in hexane, 6.6 mmol) and the resultant mixture stirred for 1 hour. Trimethyl borate (0.92 ml, 8 mmol) was then added and the mixture stirred at room temperature overnight. Saturated aqueous NH4Cl was added (60 ml) and the aqueous layer extracted with diethyl ether (3×100 ml). The combined organic extracts were concentrated in vacuo. The residue was taken up in 1M aqueous NaOH and washed with diethyl ether (100 ml). The aqueous layer was then acidified with 2N aqueous HCl (pH 2) and extracted with diethyl ether (3×100 ml). The organic extracts were combined, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound as a white solid (1.12 g, 87% yield).
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(C(C)C)CC)(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>>[S:20]([O:9][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])([CH3:19])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCCC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCC(C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 100.3 %

Procedure:
To 130 g (0.995 mol) of 2-octanol and 207 ml (1.19 mol, 1.2 equiv) of diisopropylethylamine in 1.5 L dichloromehane at 0° C. under a CaSO4 drying tube was added dropwise 84.4 ml (1.09 mol, 1.1 equiv.) of methanesulfonyl chloride over 1 hour while keeping the internal temperature at less than 5° C. The faintly yellow solution was stirred at 0° C. for an additional 1.5 h. The cold reaction solution was then washed with 2×1 L ice-cold 1M HCl and 1 L of ice-cold H2O and brine and dried over MgSO4. The residue was filtered through Celite and concentrated in vacuo below 35° C. to afford 208 g of a yellow oil. The yellow oil was placed under high-vacuum for 2 h at 25° C. to give 205 g of yellow oil. NMR spectra confirmed the desired title-product having only trace amounts of solvents present.
Reaction SMILES: [C:1]1(=[O:9])[C:8]2[N:4]([CH:5]=[CH:6][CH:7]=2)[CH2:3][CH2:2]1.[Br:10]N1C(=O)CCC1=O>C1COCC1>[Br:10][C:6]1[CH:7]=[C:8]2[N:4]([CH2:3][CH2:2][C:1]2=[O:9])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CCn2cccc21
Solvent: C1CCOC1
Product: O=C1CCn2cc(Br)cc21
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A mixture of 2,3-dihydro-1H-pyrrolizin-1-one (300 mg, 2.48 mmol) in THF (20 mL) was cooled to −10° C. in a brine bath. N-Bromosuccinimide (441 mg, 2.48 mmol) in THF (5 mL) was added dropwise, and the reaction mixture was stirred at −10° C. for 1 hour. The reaction was subsequently quenched with water (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layers were combined and dried and to give the title compound, which was used without further purification (520 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.02-3.05 (m, 2H), 4.17-4.20 (m, 2H), 6.58 (d, J=4.40 Hz, 1H), 6.67 (d, J=3.90 Hz, 1H). ESI-MS m/z [M+H]+ calc'd for C7H6BrNO, 200. found, 200.