Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Mg]Cl)CCC.[C:14]([O:18][C:19]([NH:21][C@@H:22]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:23]([O:25]C)=O)=[O:20])([CH3:17])([CH3:16])[CH3:15].[Br:34][CH2:35][Cl:36].Cl>C(OCC)(=O)C.O.C1COCC1>[CH2:27]([C@H:22]([NH:21][C:19](=[O:20])[O:18][C:14]([CH3:15])([CH3:16])[CH3:17])[C:23](=[O:25])[CH:35]([Br:34])[Cl:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ClCBr
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: CCCC[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)C(Cl)Br
Reaction time: 2 h
Yield: 0 %

Procedure:
Under nitrogen gas, diisopropylamine (19.92 g, 196.9 mmol) was added to n-butylmagnesium chloride (1.8 mol/kg, 99.4 g, 179 mmol) over 30 minutes at 40° C. and the mixture was further stirred for 2 hours at the same temperature to prepare a white slurry (liquor A). Separately, under nitrogen gas in another vessel, a solution was prepared from methyl (S)-2-tert-butyloxycarbonylamino-3-phenylpropanoate (10.0 g, 35.8 mmol), bromochloromethane (9.27 g, 71.6 mmol) and THF (20 g) (liquor B). To this liquor B was added said liquor A over 1.5 hours at an internal temperature of about 5° C., and the reaction was conducted at 5° C. for 1 hour and at 20° C. for 16 hours. This reaction mixture was poured in a mixture of concentrated hydrochloric acid (43.12 g), water (100 g) and ethyl acetate (50 mL) over 10 minutes for hydrolysis. After phase separation, the organic layer was washed serially with water (100 mL) and saturated NaCl/H2O, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to recover 20.08 g of a reddish brown solid. This solid was recrystallized from ethyl acetate/hexane to provide yellow crystals of tert-butyl (S)-(1-benzyl-3-bromo-3-chloro-2-oxopropyl)carbamate (4.409 mg, 90.7 area %, yield 30%, diastereomer ratio=42/58) as a mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]2[CH2:14][S:13][CH:12]3[N:9]([C:10](=[O:23])[CH:11]3[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:8]=2[C:24]([O:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[CH:5][N:6]=1.CO[CH:42](OC)[N:43]([CH3:45])[CH3:44]>O1CCCC1.C(OCC)(=O)C>[CH:27]([O:26][C:24]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[C:4]1[S:3][C:2]([N:1]=[CH:42][N:43]([CH3:45])[CH3:44])=[N:6][CH:5]=1)[CH:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:10]2=[O:23])=[O:25])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(N)s3)CSC12
Reactant: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)C=Nc1ncc(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)OC(C)(C)C)C3SC2)s1
Temperature: 20 °C
Reaction time: 0.42 h
Yield: 51.3 %

Procedure:
A solution of 3-(2-amino-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (4 g) in tetrahydrofuran (50 cc) is treated with dimethoxy(dimethylamino)methane (1.13 g). The reaction mixture is stirred for 25 minutes at 20° C., then diluted with ethyl acetate (150 cc), washed with distilled water (4×150 cc) and with a saturated sodium chloride solution (150 cc) and dried ove magnesium sulphate. The residue obtained after evaporation of the solvent under reduced pressure (30 mm Hg; 4 kPa) at 30° C. is chromatographed on a column (height: 28 cm; diameter: 5 cm) of silica gel (0.04-0.06 mm), elution being carried out under a pressure of 0.6 bar (60 kPa) with ethyl acetate, and 100 cc fractions being collected. Fractions 9 to 23, containing the pure product, are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. 2-Benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(2-dimethylaminomethyleneamino-thiazol-5-yl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (E-form) (2.25 g) is obtained in the form of an orange froth whose characteristics are identical to those of the product obtained in A.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH2:28][C:29](O)=[O:30])[CH2:24][CH2:23]5)=[N:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:32]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:33][N:34](C)C=O.C(N(CC)C(C)C)(C)C.CN.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>O1CCCC1>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([N:22]5[CH2:23][CH2:24][N:25]([CH2:28][C:29]([NH:34][CH3:33])=[O:30])[CH2:26][CH2:27]5)=[N:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:32]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCN(CC(=O)O)CC3)nc1OCC2
Reactant: CN(C)C=O
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)CN1CCN(c2ccc3c(n2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)CC1
Temperature: 25 °C

Procedure:
2-(4-(2-(1-Isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,2-f][1,4]oxazepin-9-yl)piperazin-1-yl)acetic acid (0.050 g, 0.00011 mol) was dissolved in N,N-Dimethylformamide (1.79 mL, 0.0231 mol) and treated sequentially with N,N-Diisopropylethylamine (0.119 mL, 0.000686 mol) 2.00 M of Methylamine in Tetrahydrofuran (0.228 mL) then N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.0521 g, 0.000137 mol). Stir at r.t. 2 h. Add sat. sodium bicarbonate, extract with ethyl acetate. Dry organics over sodium sulfate and concentrate to give 334, analyzed by rHPLC. MS: (ESI+)=452.2
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>CN1C(=O)CCC1>[F:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[S:3][C:4]=2[CH:10]=1
Reactant: Nc1ccc(O)cc1
Reactant: Fc1ccc2nc(Cl)sc2c1
Solvent: CN1CCCC1=O
Product: Oc1ccc(Nc2nc3ccc(F)cc3s2)cc1

Procedure:
2-Chloro-6-fluorobenzo[d]thiazole (7.0 g, 0.037 mol) and 4-aminophenol (4.0 g, 0.037 mol) in NMP (50 mL) was heated at 160° C. for 7 h. The reaction was quenched with 2N NaOH (100 mL) and then extracted with EtOAc (2×100 mL). The organic layer was washed with 2 N NaOH (50 mL) and to the combined aqueous layer was added 5 N HCl until pH 6 and then extracted with EtOAc (3×200 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The crude was purified by column chromatography (silica gel 100-200 mesh; 80% ethyl acetate in hexanes) to afford 4-(6-fluorobenzo[d]thiazol-2-ylamino)phenol as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:21](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH3:21])[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(NCC2CCOCC2)c1C
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(Cl)cc(N(C)CC2CCOCC2)c1C
Temperature: 80 °C
Yield: 82.8 %

Procedure:
To a stirred solution of methyl 5-chloro-2-methyl-3-(((tetrahydro-2H-pyran-4-yl)methyl)amino)benzoate (0.80 g, 2.71 mmol) in acetonitrile (20 mL), cesium carbonate (1.75 g, 5.42 mmol) and methyl iodide (1.93 g, 13.6 mmol) were added. The resulting reaction mass was heated at 80° C. for 8 h. On completion, the mixture was cooled to room temperature and filtered. The residue was washed with ethyl acetate and the filtrate was concentrated to give crude material which was purified by column chromatography to give the title compound (0.70 g, 84%).
Reaction SMILES: [OH:1][C@@:2]([CH3:11])([CH2:9][OH:10])[C:3](N(OC)C)=[O:4].[OH2:12].[OH-].[Li+:14]>CO>[OH:1][C@@:2]([CH3:11])([CH2:9][OH:10])[C:3]([O-:4])=[O:12].[Li+:14]
Reactant: O
Reactant: CON(C)C(=O)[C@@](C)(O)CO
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: C[C@](O)(CO)C(=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.2 %

Procedure:
To a solution of the compound prepared in Example 130(a) (565 mg) in methanol (7.0 mL) was added lithium hydroxide monohydrate (146 mg) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to give the title compound (446 mg) having the following physical data.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:10][C@H:11]([CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:37][CH2:38][F:39].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:10][C@H:11]([CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:37][CH2:38][F:39])=[CH:24][CH:23]=1)[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: FCCBr
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](CCCc1ccc(O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](CCCc1ccc(OCCF)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Di-tert-butyl (4S)—N-(tert-butoxycarbonyl)-4-[3-(4-hydroxyphenyl)propyl]-L-glutamate (80 mg, 0.16 mmol), 1-bromo-2-fluoroethane (103 mg, 0.81 mmol), and caesium carbonate (158 mg, 0.49 mmol) were dissolved in 8 ml N,N-dimethylformamide and the solution was stirred at 60° C. for 4 h. The reaction was then poured into 1 N aqueous hydrochloric acid (50 ml) and extracted with dichloromethane (3×75 ml). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by pHPLC on a reversed phase (RP-18) column with an acetonitrile/water gradient. The appropriate fractions were collected, the acetonitrile evaporated under reduced pressure and the remaining aqueous solution was lyophilized.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:52])[NH:19][CH2:20][C:21]([N:23]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])[CH:26]([S:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[F:44])(=[O:37])=[O:36])[CH2:25][CH:24]2[C:45](=[O:51])[NH:46][CH2:47][CH:48]([CH3:50])[CH3:49])=[O:22])[CH:14]=[CH:15][CH:16]=1)=[O:10])C1C=CC=CC=1>[Pd].C(O)C>[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH:27]1[N:23]([C:21](=[O:22])[CH2:20][NH:19][C:18](=[O:52])[NH:17][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[C:9]([OH:10])=[O:8])[CH:24]([C:45](=[O:51])[NH:46][CH2:47][CH:48]([CH3:50])[CH3:49])[CH2:25][CH:26]1[S:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[F:44])(=[O:37])=[O:36]
Reactant: CC(C)CNC(=O)C1CC(S(=O)(=O)c2ccccc2F)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)CNC(=O)C1CC(S(=O)(=O)c2ccccc2F)C(c2ccccc2F)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Yield: 82 %

Procedure:
A The process is performed as described in Example 2A, but starting with 3.2 g of (2RS,4SR,5RS)-1-{2-[3-(3-benzyloxycarbonylphenyl)ureido]acetyl}-5-(2-fluorophenyl)-4-(2-fluorophenyl)sulphonyl-2-isobutylcarbamoylpyrrolidine, 0.35 g of 10% palladium-on-charcoal and 100 cm3 of ethanol under a hydrogen atmosphere (130 kPa). After treatment, 2.3 g of (2RS,4SR,5RS)-3-(3-{2-[5-(2-fluorophenyl)-4-(2-fluorophenyl)sulphonyl-2-isobutylcarbamoyl-1-pyrrolidinyl]-2-oxoethyl}ureido)benzoic acid are obtained [Rf=0.3; eluent: methylene chloride/methanol (90/10); 1H NMR spectrum (200 MHz, (CD3)2SO with addition of a few drops of CD3COOD, at a temperature of 83 K, δ in ppm): 0.96 (d, J=6.5 Hz, 6H: C(CH3)2); 1.88 (mt, 1H: CH); from 2.45 to 2.65 and 2.90 (2 mts, 1H each: CH2 at 3); 3.09 (mt, 2H: NCH2); 3.70 and 3.90 (broad d and d respectively, J=17 Hz, 1H each: COCH2N); 4.14 (mt, 1H: H4); 4.86 (t, J=8 Hz, 1H: H2); 5.70 (d, J=3 Hz, 1H: H5); from 6.90 to 8.00 (mt, 10H: aromatic H); 8.00 (mt, 1H: aromatic H (H2: ortho to the COOH)); 8.20 (broad t, J=8 Hz, 1H: H of the aromatic at 5 (H6))].
Reaction SMILES: [Cl-].[Cl-].[Cl-].[In+3].[CH3:5][Mg]Cl.[CH3:8][O:9][C:10]([C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([C:22]([F:25])([F:24])[F:23])=[N:19]2)=[C:14](OS(C(F)(F)F)(=O)=O)[C:13]=1[N+:34]([O-:36])=[O:35])=[O:11]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:8][O:9][C:10]([C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([C:22]([F:25])([F:24])[F:23])=[N:19]2)=[C:14]([CH3:5])[C:13]=1[N+:34]([O-:36])=[O:35])=[O:11]
Reactant: COC(=O)c1cc2nc(C(F)(F)F)ccc2c(OS(=O)(=O)C(F)(F)F)c1[N+](=O)[O-]
Reactant: C[Mg]Cl
Agent: Cl[Pd]Cl
Agent: [Cl-]
Agent: [In+3]
Solvent: C1CCOC1
Product: COC(=O)c1cc2nc(C(F)(F)F)ccc2c(C)c1[N+](=O)[O-]
Temperature: -78 °C

Procedure:
A suspension of indium trichloride (2.0 g) in dry THF (5 mL) under an argon atmosphere is cooled to −78° C. and then treated drop wise with methyl magnesium chloride (9.1 mL, 3 M in THF). The milky suspension is allowed to warm to room temperature and then added drop wise to a refluxing solution of bis(triphenylphosphine)palladium(II)chloride (0.19 g) and 6-nitro-5-trifluoromethanesulfonyloxy-2-trifluoromethyl-quinoline-7-carboxylic acid methyl ester (4.05 g) in dry THF (35 mL). The mixture is refluxed under an argon atmosphere, monitoring by TLC. After reaction completion, the reaction mixture is concentrated in vacuum. The residue is taken up in diethyl ether and washed successively with diluted hydrochloric acid and brine. The diethyl ether phase is dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue is purified by column chromatography (hexane/ethyl acetate=4:1) to give 2.0 g of the title compound of the formula
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[CH:32]1([NH2:36])[CH2:35][CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH:32]1([NH:36][C:3](=[O:5])[CH:2]([OH:1])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:16]=[C:15]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:18]=4[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=3)=[CH:10][CH:11]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: NC1CCC1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NC1CCC1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 23.9 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), cyclobutanamine (4.95 mg, 0.070 mmol), HATU (22.92 mg, 0.060 mmol), and 4-methylmorpholine (18.76 mg, 0.185 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention=14.17 min) to provide (R/S)-N-cyclobutyl-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (7 mg, 0.011 mmol, 23.93% yield): LCMS=485.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.12-8.23 (2 H, m), 7.53-7.73 (7 H, m), 5.09 (1 H, s), 4.15-4.42 (1 H, m), 2.28 (2 H, dddd, J=10.07, 4.90, 4.62, 2.86 Hz), 1.98-2.13 (2 H, m), 1.70-1.79 (2 H, m); HPLC peak RT=10.4 min (Method A).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH3:8])[N:7]=1.[Br:9]N1C(=O)CCC1=O.C(OC(C)C)(C)C>C(O)(=O)C>[ClH:1].[NH2:2][C:3]1[S:4][C:5]([Br:9])=[C:6]([CH3:8])[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1csc(N)n1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CC(=O)O
Product: Cc1nc(N)sc1Br
Yield: 89.7 %

Procedure:
To a solution of 2-amino-4-methylthiazole hydrochloride (3.0 g) in acetic acid (20 ml) was added once N-bromosuccinimide (4.0 g) at room temperature with stirring. The mixture was stirred at room temperature for 1.5 hours and the reaction mixture was poured into isopropyl ether under ice cooling. The precipitates were collected by filtration, washed with ethyl ether and dried in vacuo to give 2-amino-5-bromo-4-methylthiazole hydrochloride (4.1 g, yield: 89.1%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:22][C@@H:17]2[C@H:18]([O:19][CH2:20][CH3:21])[C@H:12]1[CH:13]([O:16]2)[O:14]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[CH2:1]([O:8][C:9]([N:11]1[CH2:22][C@@H:17]([OH:16])[C@H:18]([O:19][CH2:20][CH3:21])[C@H:12]1[CH:13]=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCO[C@@H]1[C@H]2C(OC)O[C@@H]1CN2C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCO[C@H]1[C@H](O)CN(C(=O)OCc2ccccc2)[C@@H]1C=O
Reaction time: 3 h
Yield: 77 %

Procedure:
To an aqueous solution (1 mL) of methyl N-benzyloxycarbonyl-2,5-dideoxy-3-O-ethyl-2,5-imino-D-lyxofuranoside, trifluoroacetic acid (1 mL) was added, and the mixture was stirred for three hours. The reaction liquor was concentrated under reduced pressure, and the obtained residue was extracted with methylene chloride. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was purified by thin layer chromatography (ethyl acetate:n-hexane=1:1, v/v), to obtain the title compound (92 mg, 77%) as an oily matter.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9].ClCCl.CO>C(OCC)(=O)C>[Br:1][C:2]1[CH:15]=[C:14]([NH2:16])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9]
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1Br
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCN(CC)CCOc1ccc(N)cc1Br

Procedure:
Prepared analogously to Example 3.1.b. from 1.10 g (3.47 mmol) of [2-(2-bromo-4-nitrophenoxy)ethyl]diethylamine in ethyl acetate. Yield: 0.58 g (58% of theory); C12H19BrN2O (M=287.202); calc.: molecular ion peak (M+H)+: 287/289; found: molecular ion peak (M+H)+: 287/289; Rf value: 0.30 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].Cl.Cl[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[CH2:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1ccncc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 126.6 %

Procedure:
To a solution of N-methyl-4-nitroaniline (5 g, 32.9 mmol) in DMF (75 ml) was slowly added NaH (60% in mineral oil, 4.21 g, 105 mmol) at RT (Warning: important gaz evolution occurred!). The suspension was vigorously stirred at RT for 15 min then cooled to 0° C. (ice bath). 4-(Chloromethyl)pyridine hydrochloride (8.09 g, 49.3 mmol) was added carefully then the slurry was allowed to warm to RT and further stirred for 45 min. The reaction mixture was poured into water and extracted with Et2O (3×). The combined organic phases were dried over Na2SO4, filtered and evaporated to dryness to yield the crude title compound (10.13 g) as an orange solid, which was used in the next step without further purification. HPLC: AtRet=1.01 min; LC-MS: m/z 244.5 [M+H]+; 1H NMR (400 MHz, DMSO-d6): 3.23 (s, 3H), 4.82 (s, 2H), 6.77-6.83 (m, 2H), 7.17-7.22 (m, 2H), 8.02-8.08 (m, 2H), 8.49-8.54 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[CH:23]=[CH:22][C:12]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[O:14])=[C:11]([Cl:24])[CH:10]=1.[C:25](=O)([O:36]C1C=CC([N+]([O-])=O)=CC=1)[O:26][CH2:27][O:28][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[Cl:24][C:11]1[CH:10]=[C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:25](=[O:36])[O:26][CH2:27][O:28][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:23]=[CH:22][C:12]=1[C:13](=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: CCCCCC(=O)OCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2N)cc1Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCCC(=O)OCOC(=O)Nc1ccccc1Nc1ccc(C(=O)c2ccccc2C)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-(2-aminophenylamino)-2-chloro-2′-methylbenzophenone (305 mg, 1.0 mmol) and hexanoyloxymethyl 4-nitrophenyl carbonate (Compound 207) (3.3 g, 10 mmol) in DMF (50 ml) was added 1-hydroxybenzotriazole (270 mg, 2.0 mmol) followed by N-ethyl di-iso-propylamine (0.18 ml, 1.05 mmol). The reaction mixture was stirred at room temperature. After 72 hours, the reaction mixture was poured into ice/water and extracted with diethylether. The etheral extracts were washed with a saturated sodium carbonate solution, water, and brine and dried over anhydrous sodium sulphate. Filtration and concentration in vacuo afforded the crude product. This was further purified by chromatography using Et2O/hexane 2:1 as eluent.
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([C:17]1[C:22]([Cl:23])=[CH:21][N:20]=[CH:19][N:18]=1)([OH:16])[CH2:12]2)=O)(C)(C)C>Cl.O1CCOCC1>[ClH:23].[Cl:23][C:22]1[C:17]([C:11]2([OH:16])[CH2:12][CH:13]3[NH:8][CH:9]([CH2:15][CH2:14]3)[CH2:10]2)=[N:18][CH:19]=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1ncncc1Cl)C2
Agent: Cl
Solvent: C1COCCO1
Product: OC1(c2ncncc2Cl)CC2CCC(C1)N2
Reaction time: 1 h

Procedure:
3-(5-Chloro-pyrimidin-4-yl)-3-hydroxy-8-aza-bicyclo{3.2.1]octane-8-carboxylic acid tert-butyl ester (0.14 g, 0.41 mmol) was dissolved in a solution of hydrogen chloride in dioxane (4 N, 2 mL). The mixture was stirred for 1 hour and the solvent removed by evaporation under vacuum to afford the title compound. LCMS m/z 240.3 [M+H]+. R.T.=0.36 min (Analytical Method 3).
Reaction SMILES: CC1C=CC(S(O)(=O)=O)=CC=1.O.C(OC([NH:20][CH2:21][CH:22]([N:31]([CH3:41])[C:32]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=[O:33])[CH2:23][C:24]1([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=O)(C)(C)C>C(O)C.CCOCC>[NH2:20][CH2:21][CH:22]([N:31]([CH3:41])[C:32]([O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:40])[CH3:39])=[O:33])[CH2:23][C:24]1([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CN(C(=O)OCC[Si](C)(C)C)C(CNC(=O)OC(C)(C)C)CC1(O)CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CN(C(=O)OCC[Si](C)(C)C)C(CN)CC1(O)CCCCC1
Temperature: 62.5 °C
Yield: 108.4 %

Procedure:
A solution of p-TsOH.H2O (25 mg) in ethanol (0.5 mL) was added to 1-(3-(t-butoxy-carbonylamino)-2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)amino)propyl)cyclohexanol (50 mg, 0.12 mmol) dissolved in ether (12 mL). The transfer was completed with additional ether (2 mL). The resulting solution was evaporated under reduced pressure at rt to remove Et2O and heated at 60-65° C. for 20 min under reduced pressure to remove ethanol. The residue was dissolved in MeOH and aqueous K2CO3 was added. The mixture was evaporated and extracted with EtOAc (3×). The combined organic phases were dried over Na2SO4, filtered and evaporated to give 1-(3-amino-2-(N-methyl-N-(2-(trimethylsilyl)ethoxycarbonyl)-amino)propyl)cyclohexanol (43 mg, 89%). MS m/z 453 (M+Na+).