Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)=[CH2:2].C(OC([N:23]1[CH:28]=[CH:27][N:26]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C:25](=[O:37])[CH2:24]1)=O)C1C=CC=CC=1>>[C:33]([O:32][C:30]([NH:29][N:26]1[CH2:27][CH2:28][N:23]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=2)(=[O:11])=[O:10])[CH2:24][C:25]1=[O:37])=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NN1C=CN(C(=O)OCc2ccccc2)CC1=O
Product: C=Cc1ccc(S(=O)(=O)N2CCN(NC(=O)OC(C)(C)C)C(=O)C2)cc1

Procedure:
Except for using 4-vinylphenylsulfonyl chloride instead of 6-chloronaphthalene-2-sulfonyl chloride and starting from 4-benzyloxycarbonyl-1-(tert-butoxycarbonylamino)-2-oxo-1,2,3,4-tetrahydropirazine (2.5 g), the process similar to that in Reference Example 5 was employed to obtain the title compound (2.12 g) as a colorless amorphous material.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:14][C:15]([F:38])([F:37])[C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23][C:24]2[CH:36]=[CH:35][CH:34]=[CH:33][C:25]=2[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([NH:6][C:7]([N:22]([C:19]1[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:37])[F:38])=[CH:21][CH:20]=1)[S:23][C:24]1[CH:36]=[CH:35][CH:34]=[CH:33][C:25]=1[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27])=[O:8])=[O:5]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: CCCCOC(=O)c1ccccc1SNc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: CCCCOC(=O)c1ccccc1SN(C(=O)NC(=O)c1c(F)cccc1F)c1ccc(C(F)(F)F)cc1
Reaction time: 18 h
Yield: 88 %

Procedure:
A solution of 2,6-difluorobenzoyl isocyanate (1.1 g) in dry toluene (5.0 ml) was added to a stirred solution of butyl 2-[[[4-(trifluoromethyl)phenyl]amino]thio]benzoate (1.9 g) in the same solvent (7.0 ml) at room temperature. After 18 hours, the reaction mixture was cooled to -5°, and the crystalline precipitate was separated, washing with cold toluene followed by light petroleum. The pure product was obtained as colourless crystals (2.5 g, melting point 79°-81°) after recrystallisation from diethyl ether/light petroleum.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]2[N:10]([CH3:11])[C:9]3[CH:12]=[C:13]([N:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]4=[O:23])[CH:14]=[CH:15][C:8]=3[N:7]=2)[CH2:5][CH2:4]1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[F:32]>C1COCC1>[CH:3]1([C:6]2[N:10]([CH3:11])[C:9]3[CH:12]=[C:13]([N:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[F:32])=[CH:18][C:17]4=[O:23])[CH:14]=[CH:15][C:8]=3[N:7]=2)[CH2:4][CH2:5]1
Reactant: Fc1ccccc1CBr
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccccc4F)cc3=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a stirred suspension of NaH (40% oil dispersion, 50 mg) in THF (9 ml) was added a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg) in THF (1 ml) at 0° C., and then the mixture was stirred at room temperature for 30 min. 1-Bromomethyl-2-fluorobenzene (150 mg) in THF (0.5 ml) was added, and the resulting mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with ice-water and extracted with DCM. The extract was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) followed by crystallization with DCM/hexane (19:1, 2 ml) to give the title compound (56 mg) as a white solid.
Reaction SMILES: [CH2:1]([C@@:8]1([O:41][C@H:40]([CH2:42][OH:43])[C@@H:38]([OH:39])[C@H:11]([O:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]([NH:21][C@@H:22]([C:35](=[O:37])[NH2:36])[CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:20])[CH3:18])=[O:15])[C@H:10]1[NH:44][C:45](=[O:47])[CH3:46])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:48](OC(=O)C)(=[O:50])[CH3:49].CO>N1C=CC=CC=1>[CH2:1]([C@@:8]1([O:41][C@H:40]([CH2:42][O:43][C:48](=[O:50])[CH3:49])[C@@H:38]([OH:39])[C@H:11]([O:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]([NH:21][C@@H:22]([C:35](=[O:37])[NH2:36])[CH2:23][CH2:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])=[O:20])[CH3:18])=[O:15])[C@H:10]1[NH:44][C:45](=[O:47])[CH3:46])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)N[C@@H]1[C@@H](OCC(=O)N[C@@H](C)C(=O)N[C@H](CCC(=O)OCc2ccccc2)C(N)=O)[C@H](O)[C@@H](CO)O[C@@]1(O)Cc1ccccc1
Solvent: CO
Solvent: c1ccncc1
Product: CC(=O)N[C@@H]1[C@@H](OCC(=O)N[C@@H](C)C(=O)N[C@H](CCC(=O)OCc2ccccc2)C(N)=O)[C@H](O)[C@@H](COC(C)=O)O[C@@]1(O)Cc1ccccc1

Procedure:
A solution of 0.33 g of benzyl (benzyl 2-acetamido-2-deoxy-α-D-glucopyranosid-3-O-yl)acetyl-L-alanyl-D-isoglutaminate (12A, n = 2, X1 = L-alanyl, R2 = CH3) in 5 ml of pyridine is stirred at 0° whilst a solution of 0.095 ml of acetic anhydride in 1 ml of pyridine is added dropwise over 30 minutes. The resultant solution is stored at 0° C for 16 hours at which time 1 ml of methanol is added and the mixture is evaporated to dryness. The residue thus obtained is partitioned between 100 ml of chloroform and 100 ml of water, the chloroform phase is dried over magnesium sulfate and concentrated in vacuo, giving 0.36 g of crude product which is purified by preparative thick-layer chromatography giving benzyl (benzyl 2-acetamido-6-O-acetyl-2-deoxy-α-D-glucopyranosid-3-O-yl)acetyl-L-alanyl-D-isoglutamine (12F, n = 2, X1 =L-alanyl, R2 = CH3, R3 = --COCH3).
Reaction SMILES: C([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=O)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Br:24])[CH:17]=1)C1C=CC=CC=1.[CH3:26]CN(C(C)C)C(C)C.CC(C)=O>Cl[Ti](Cl)(Cl)Cl.C(Cl)Cl>[Br:24][C:18]1[CH:17]=[C:16]([C@@H:15]2[C:12]([CH3:8])([CH3:26])[O:11][C:10](=[O:13])[NH:9][CH2:14]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1Br
Reactant: CCN(C(C)C)C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(C)=O
Solvent: ClCCl
Product: COc1ccc([C@H]2CNC(=O)OC2(C)C)cc1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 141.8 %

Procedure:
To a round bottom flask were added 10 mL DCM and (S)-4-benzyl-3-(2-(3-bromo-4-methoxyphenyl)acetyl)oxazolidin-2-one (1.0 g, 2.47 mmol). TiCl4 (2.6 mL, 2.60 mmol, 1M DCM solution) was added at 0° C. After stirring at 0° C. for 5 mins, DIEA (0.45 mL, 2.6 mmol) was added via syringe. The reaction mixture was stirred at 0° C. for 30 mins. Acetone (0.27 mL, 3.71 mmol) was added followed by more of TiCl4 (2.6 mL, 2.6 mmol, 1 M DCM solution). The reaction mixture was stirred at 0° C. for 2 hrs. It was quenched by addition of 80 mL sat. NH4Cl aqueous solution. The resulting reaction mixture was extracted with 120 mL EtOAc/hexane (1:1). Organics were dried over sodium sulfate, filtered and concentrated. Crude product was purified on Combiflash prepacked silica gel column, eluted with 5% to 40% EtOAc in hexane to give 1.1 g desired product as viscous material. 1H NMR (500 MHz, CDCl3): δ 7.70 (s, 1H), 7.1-7.4 (m, 6H), 6.88 (d, J=8.5 Hz, 1H), 4.68 (m, 1H), 4.1 (m, 2H), 3.93 (s, 3H), 3.83 (s, 1H), 3.43 (dd, J=3.4, 13.3 Hz, 1H), 2.82 (dd, J=9.9, 13.3 Hz, 1H), 1.46 (s, 3H), 1.09 (s, 3H).
Reaction SMILES: [H-].[Na+].CS(O[CH2:8][CH2:9][C:10]1[N:11]=[C:12]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=2[CH3:26])(=[O:18])=[O:17])[S:13][CH:14]=1)(=O)=[O:5].[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1.Cl>C1COCC1.O>[OH2:5].[OH2:5].[Cl:25][C:21]1[C:20]([CH3:26])=[C:19]([S:16]([NH:15][C:12]2[S:13][CH:14]=[C:10]([CH2:9][CH2:8][N:27]3[CH:31]=[CH:30][N:29]=[CH:28]3)[N:11]=2)(=[O:17])=[O:18])[CH:24]=[CH:23][CH:22]=1
Reactant: c1c[nH]cn1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCOS(C)(=O)=O)cs1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(CCn2ccnc2)cs1
Reaction time: 1.5 h

Procedure:
NaH (95% dry, 32 mg, 1.28 mmol) was added to a stirred solution of EXAMPLE 191A (250 mg, 0.61 mmol) and imidazole (46 mg, 0.67 mmol) in THF (10 mL) at room temperature. The mixture was stirred for 2 h at 40° C. when additional imidazole (41 mg, 0.61 mmol) and NaH (95% dry, 15 mg, 0.61 mmol) was added. The reaction was allowed to proceed for 1.5 h and was then neutralized by adding aqueous HCl (2 M). The solvent was evaporated and the resulting crude material was dissolved in TFA and purified by reversed phase flash chromatography on LiChroprep RP-18. The product was gradient eluting with (CH3CN in H2O/0.4% conc. HCl) to yield (80 mg, 0.21 mmol, 34%): MS (Ionspray, [M+H]+) m/z 382. Anal. Calcd. (found) for C15H15ClN4O2S2.2 H2O: C, 43.0 (42.9)%; H, 4.6 (4.3)%; N, 13.4 (13.7)%.
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[CH2:10]([N:17]1[C:29]2[CH2:28][CH2:27][CH2:26][C:25](=[O:30])[C:24]=2[C:23]2[C:18]1=[C:19]([CH3:31])[CH:20]=[CH:21][CH:22]=2)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+]>C1COCC1.CN(C=O)C>[CH2:10]([N:17]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:30])[C:24]=2[C:23]2[C:18]1=[C:19]([CH3:31])[CH:20]=[CH:21][CH:22]=2)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cccc2c3c(n(Cc4ccccc4)c12)CCCC3=O
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1cccc2c3c(O)cccc3n(Cc3ccccc3)c12
Temperature: 75 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
Pyridinium bromide perbromide (0.2032 g, 0.64 mmol) is added to a mixture of 9-benzyl-8-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one in THF (0.7 mL) and DMF (0.5 mL) and the mixture is heated to 75° C. After stirring for 8 h, THF is removed under reduced pressure and the residue is partitioned between dichloromethane and brine. The combined organic layers are washed with dilute sodium thiosulfate/brine and the aqueous layer is backwashed with dichloromethane. The combined organic layers are dried over magnesium sulfate and concentrated under reduced pressure to give a residue. A mixture of the resulting residue, lithium bromide (0.1005 g, 0.0012 mol), lithium carbonate (0.0768 g, 0.0010 mol) and DMF (2 mL) is heated at 120° C. for two hours. The DMF is removed under high vacuum and the residue is partitioned between dichloromethane and water. The combined organic layers are dried over sodium sulfate and concentrated to an oil. The oil is chromatographed on silica gel (75 mL) using ethyl acetate/heptane (10/90) to give 0.0888 g (59%) of the title compound. The product is then recrystallized from ethyl acetate/hexane; MS (ESI+) for C20H17NO m/z 288.1 (M+H)+; IR (drift) 3537, 1587, 1492, 1451, 1351, 1338, 1315, 1271, 1236, 1205, 963, 792, 745, 729, 720 cm−1; 1H NMR (CDCl3) δ2.64, 5.32, 5.76, 6.58, 6.88, 7.02, 7.15-7.26, 8.24. Anal. Calcd for C20H17NO: C, 83.59; H, 5.96; N, 4.87. Found: C, 80.86; H, 5.73; N, 4.72.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH2:20][CH:21](OCC)[O:22]CC)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][CH:7]=1.C(O)=O.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH2:20][CH:21]=[O:22])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CN1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCC1=O)OCC
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=CO
Product: O=CCN1CCN(C(=O)/C=C/c2cccc(Cl)c2)CCC1=O
Reaction time: 1.5 h
Yield: 45.6 %

Procedure:
A solution of 1.00 g (2.53 mmol) of 1-[(E)-3-(3-chloro-phenyl)-acryloyl]-4-(2,2-diethoxy-ethyl)-[1,4]diazepan-5-one in 10 ml of toluene was treated at RT with 5.22 ml formic acid and 1.5 ml water. The reaction was stirred for 1.5 h, evaporated and neutralized with aqueous saturated NaHCO3 and extracted with Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (EtOAc) to yield 0.37 g (45%) of the title compound as off-white foam. MS: 321.3 (MH+, Cl).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)=[CH:5][C:4]([C:16]2[C:21]([CH:22]=[O:23])=[C:20]([N:24]3[CH2:35][CH2:34][C:33]4[C:32]5[CH2:31][C:30]([CH3:37])([CH3:36])[CH2:29][C:28]=5[S:27][C:26]=4[C:25]3=[O:38])[N:19]=[CH:18][CH:17]=2)=[CH:3]1.[BH4-].[Na+]>CO>[OH:23][CH2:22][C:21]1[C:20]([N:24]2[CH2:35][CH2:34][C:33]3[C:32]4[CH2:31][C:30]([CH3:36])([CH3:37])[CH2:29][C:28]=4[S:27][C:26]=3[C:25]2=[O:38])=[N:19][CH:18]=[CH:17][C:16]=1[C:4]1[CH:5]=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1
Reactant: Cn1cc(-c2ccnc(N3CCc4c(sc5c4CC(C)(C)C5)C3=O)c2C=O)cc(Nc2ccncn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2ccnc(N3CCc4c(sc5c4CC(C)(C)C5)C3=O)c2CO)cc(Nc2ccncn2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
A mixture of 143b (110 mg, 0.2 mmol), NaBH4 (30 mg, 0.8 mmol), and MeOH (5 mL) was stirred at 25° C. for 30 mins. The mixture was evaporated in vacuo and the residue was extracted with EtOAc (10 mL×2). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 143 (48 mg, 44%). LCMS: [M+H]+ 529. 1H NMR (500 MHz, DMSO) δ 9.23 (s, 1H), 8.76 (d, J=2.5, 1H), 8.65 (s, 1H), 8.51-8.49 (m, 1H), 8.31 (m, 1H), 7.67 (d, J=3.0, 1H), 7.38-7.37 (m, 1H), 7.33-7.31 (m, 1H), 5.02-5.01 (m, 1H), 4.43 (d, J=2.5, 2H), 4.18-4.15 (m, 1H), 3.83-3.81 (m, 1H), 3.61-3.59 (m, 3H), 3.03-2.99 (m, 1H), 2.91-2.89 (m, 1H), 2.76 (s, 2H), 2.60-2.53 (m, 2H), 1.23-1.22 (m, 6H)
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[SH:13].[CH3:14][S:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=O.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[CH3:14][S:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]1[S:13][C:4]2[CH:5]=[CH:6][C:7]([C:9]([F:10])([F:11])[F:12])=[CH:8][C:3]=2[N:2]=1
Reactant: CSc1ccccc1C=O
Reactant: Nc1cc(C(F)(F)F)ccc1S
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CSc1ccccc1-c1nc2cc(C(F)(F)F)ccc2s1
Temperature: 175 °C
Yield: 59.5 %

Procedure:
A mixture of 2-amino-4-trifluoromethylbenzenethiol hydrochloride (0.50 g), 2-methylsulfanylbenzaldehyde (0.33 g), diisopropylethylamine (0.28 g), and DMSO (4 ml) was heated to 170-180° C., and stirred with heating for 3 hours. Into the reaction mixture cooled to room temperature, water was poured, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 0.42 g of 2-(2-methylsulfanylphenyl)-5-trifluoromethylbenzothiazole (hereinafter referred to as Present Compound 84).
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[CH2:7][C:8]1[N:12]2[N:13]=[CH:14][CH:15]=[CH:16][C:11]2=[C:10]([C:17]2[N:22]=[C:21]([NH2:23])[C:20]([NH2:24])=[C:19]([NH2:25])[N:18]=2)[N:9]=1.Cl[C:31]([O:33][CH2:34][CH2:35][Cl:36])=[O:32]>N1C=CC=CC=1.ClCCl>[NH2:25][C:19]1[C:20]([NH:24][C:31](=[O:32])[O:33][CH2:34][CH2:35][Cl:36])=[C:21]([NH2:23])[N:22]=[C:17]([C:10]2[N:9]=[C:8]([CH2:7][C:6]3[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=3[F:4])[N:12]3[C:11]=2[CH:16]=[CH:15][CH:14]=[N:13]3)[N:18]=1
Reactant: O=C(Cl)OCCCl
Reactant: Nc1nc(-c2nc(Cc3ccccc3F)n3ncccc23)nc(N)c1N
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Nc1nc(-c2nc(Cc3ccccc3F)n3ncccc23)nc(N)c1NC(=O)OCCCl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
247 mg (0.623 mmol) of the compound prepared in Example 9A were initially charged in pyridine (2.5 ml) and dichloromethane (2.5 ml), 64 μl (0.623 mmol) of 2-chloroethyl chloroformate were added at 0° C. and the mixture was stirred at 0° C. for 10 min. After 16 hours of stirring at 20° C., another 64 μl (0.623 mmol) of 2-chloroethyl chloroformate were added, and the mixture was stirred at 20° C. for 16 hours. The reaction mixture was then poured onto ice-water and extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue (314 mg) was used for the next step without further purification.
Reaction SMILES: [CH3:1][Li].[O:3]1[C@H:5]2[CH2:6][C@H:7]3[C@:22]([CH3:24])([CH2:23][C@@H:4]12)[C@@H:21]1[C@H:10]([C@H:11]2[C@:18]([CH3:26])([CH2:19][C:20]1=[O:25])[C@@H:14]([C:15](=[O:17])[CH3:16])[CH2:13][CH2:12]2)[CH2:9][CH2:8]3.[Cl-].[NH4+]>CCOCC>[OH:3][C@@H:5]1[C@@H:4]([CH3:1])[CH2:23][C@@:22]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:25])[CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1
Reactant: [Li]C
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](C)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 4 h

Procedure:
A 1.6 molar solution of methyl lithium in ether (30 ml.) was added to a stirred suspension of cuprous iodide (4.56 g.) in dry ether (100 ml.) under nitrogen at -20°. A cold solution of 2α,3α-epoxy-5α-pregnane-11,20-dione (1.33 g.) in dry ether (20 ml.) was then added and the mixture was maintained at 0° for 40 hours and then at room temperature for 4 hours. The mixture was then poured into aqueous ammonium chloride solution and extracted into ethyl acetate. The organic extract was washed with water, dried (MgSO4) and evaporated in vacuo. The residue (2.9 g.) was purified by preparative TLC and crystallisation from methyl acetate/petroleum ether to give the title compound (0.5 g.) m.p. 142°-146° [α]D + 121+ (c 0.8).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][CH2:14][P:15]([C:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])[CH3:21])(=[O:19])[O:16][CH2:17][CH3:18].C[O:29][C:30](=O)[CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(O)(=O)C.[Cl-].[Na+]>C1COCC1>[C:36]([O:35][C:33]([NH:32][CH2:31][C:30](=[O:29])[CH:14]([P:15]([C:20]([O:25][CH2:26][CH3:27])([O:22][CH2:23][CH3:24])[CH3:21])(=[O:19])[O:16][CH2:17][CH3:18])[F:13])=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CCOC(C)(OCC)P(=O)(CF)OCC
Reactant: COC(=O)CNC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(C)(OCC)P(=O)(OCC)C(F)C(=O)CNC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 44.6 %

Procedure:
To a solution of diisopropylamine (2.5 mL, 14.5 mmol, 3.5 eq) in THF (30 mL) at −10° C. was added dropwise (about 10 minutes) n-BuLi (1.4 M in hexanes, 9.0 mL, 14.5 mmol). After 10 minutes, the reaction was cooled to −78° C., and a solution of ethyl (fluoromethyl)(1,1-diethoxyethyl)phosphinate (2.0 g, 8.26 mmol, 2 eq) in THF (10 mL) was added dropwise over 10 minutes. After the addition the reaction mixture was stirred at −78° C. for 1 h. A solution of N-Boc-glycine methyl ester (0.8 g, 4.1 mmol) in THF (10 mL) was added dropwise over 10 minutes such that the internal temperature was maintained below −70° C. After the addition was complete the reaction was stirred at −78° C. for 1 h. The reaction was quenched with acetic acid (1 mL, 14.5 mmol) and then warmed to room temperature. Saturated aqueous sodium chloride (75 mL) was added to the reaction and the organic phase separated. The aqueous phase was then extracted with ethyl acetate (2×75 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure affording the crude product as a pale yellow oil (2.69 g). The crude product was purified by column chromatography (2×35 cm column), eluting with 40% ethyl acetate in hexane. This method afforded ethyl (3-(N-(tert-butoxycarbonyl)amino)-1-fluoro-2-oxopropyl)(1,1-diethoxyethyl)phosphinate as a clear colorless oil (0.73 g, 44%). 1H NMR (300 MHz, CDCl3) δ 5.78-5.24 (m, 2H), 4.52-4.08 (m, 4H), 3.94-3.50 (m, 4H), 1.62-1.51 (m, 3H), 1.50-1.32 (m, 3H), 1.42 (s, 9H), 1.30-1.12 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:26])([F:25])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([NH:36][CH2:37][C:38](O)=[O:39])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].[N:41]1[CH:46]=[CH:45][C:44]([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)=[CH:43][CH:42]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[O:22][C:23]([F:25])([F:26])[F:24])(=[O:13])=[O:12])[C:6](=[O:27])[C:5]2([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35])[NH:36][CH2:37][C:38](=[O:39])[N:50]1[CH2:51][CH2:52][N:47]([C:44]2[CH:45]=[CH:46][N:41]=[CH:42][CH:43]=2)[CH2:48][CH2:49]1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: COc1ccc(S(=O)(=O)N2C(=O)C(NCC(=O)O)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(NCC(=O)N3CCN(c4ccncc4)CC3)(c3ccccc3OC)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 75.2 %

Procedure:
With 300 mg of the compound obtained in Step 58-2 and 89 mg of 1-pyridin-4-yl piperazine as starting material, 280 mg of the title compound (colorless amorphous) was obtained by a similar method to Step 51-2.
Reaction SMILES: [O:1]=[CH:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6]>C(O)C.[Pd]>[O:1]=[CH:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6]
Reactant: CC(C)COC(=O)/C=C/C=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)COC(=O)CCC=O
Yield: 99.5 %

Procedure:
To a solution of isobutyl (E)-4-oxo-2-butenoate (97 g, 0.62 mol) in 96% ethanol (800 ml), 5% palladium on charcoal (9.7 g) was added and hydrogen was bubbled at 5°-10° C. and at atmospheric pressure for 20 hours. Removal of the catalyst and evaporation of the solvent gave 97.6 g (99%) of the title compound; Rf=0.41 (silica gel plates, eluent: cyclohexane-ethvl- acetate 6:4). NMR (CDCl3): deltaH =12.5 (d, J=1 Hz, 1H, CHO); 3.85 (d, J=6 Hz, 2H, COOCH2); 2.80-2.40 (c.a., 4H, CH2CH2CO); 2.10-1.70 (c.a., 1H, CH2CHMe2); 0.90 (d, J=6 Hz, 6H, CH3). MS (E.I., 70 eV, 1.5 mA) m/z=103 (M--C3H3O)+, 85 (M--C3H5O2)+, 57 (M--C4H5O3)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].N1C=CN=C1.Cl[Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20]>O1CCCC1>[N+:8]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:11][Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[C:2]=1[NH2:1])([O-:10])=[O:9]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1cccc([N+](=O)[O-])c1N)(C(C)C)C(C)C
Yield: 105.4 %

Procedure:
A solution of 2-amino-3-nitro-phenol (42.9 g, 278 mmol) and imidazole (28.4 g, 417 mmol) in tetrahydrofuran (750 ml) was treated with chloro-triisopropyl-silane (62.3 g, 323 mmol). After 18 hours the mixture was filtered, diluted with ethyl acetate, washed with water, dried and evaporated to give an oil (91 g).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([O:15][C:16]1[CH:30]=[CH:29][C:19]([CH2:20][S:21][CH2:22][CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[N:25]2)=[CH:18][CH:17]=1)[CH:13]=[CH2:14]>C(OCC)(=O)C.ClCCl>[CH2:12]([O:15][C:16]1[CH:30]=[CH:29][C:19]([CH2:20][S:21]([CH2:22][CH2:23][N:24]2[CH:28]=[CH:27][N:26]=[N:25]2)=[O:9])=[CH:18][CH:17]=1)[CH:13]=[CH2:14]
Reactant: C=CCOc1ccc(CSCCn2ccnn2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(CS(=O)CCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
A solution of 1.86 g (8.29 mmol) 77% 3-chloroperbenzoic acid in 40 ml ethyl acetate was added at -30° C. within 20 min. to a solution of 1.90 g (6.90 mmol) 1-[2-(4-allyloxy-benzylsulfanyl)-ethyl]-1H-[1,2,3]triazole in 160 ml dichloromethane and stirred for 1 h. The mixture was allowed to warm to r.t. washed with sat. NaHCO3-solution, water and evaporated. The residue was purified by chromatography on silica gel (ethyl acetate/methanol 5:1) to give 1.25 g of the title compound as white powder.