Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][C@@H:20]3[O:46][C@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:21]3[O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH:12]=[CH:11]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:62][CH2:63][CH2:64][Cl:65]>CC(C)=O>[Cl:65][CH2:64][CH2:63][CH2:62][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[O:19][C@@H:20]3[O:46][C@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])[C@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:34])[CH3:35])[C@H:21]3[O:22][C:23](=[O:28])[C:24]([CH3:26])([CH3:27])[CH3:25])[CH:12]=[CH:11]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2cccc3ccn(CCc4ccc(O)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2cccc3ccn(CCc4ccc(OCCCCl)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[2-(4-hydroxyphenyl)ethyl]-7-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indole (0.2 g), cesium carbonate (0.17 g) and 1-bromo-3-chloropropane (0.05 mL) in acetone (4 mL) was stirred at room temperature overnight. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1) to give 1-{2-[4-(3-chloropropoxy)phenyl]ethyl}-7-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indole (0.21 g). This material was dissolved in acetonitrile (6 mL). To the solution was added sodium iodide (46 mg), and the mixture was heated for reflux overnight. To the reaction mixture were added tris(hydroxymethyl)aminomethane (0.31 g) and ethanol (4 mL), and the mixture was stirred at 60° C. for 2 days. The reaction mixture was purified by column chromatography on aminopropylated silica gel (eluent: methylene chloride/methanol=30/1-5/1) to give 1-[2-(4-{3-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl-amino]propoxy}phenyl)ethyl]-7-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-indole (0.13 g). This material was dissolved in methanol (3 mL). To the solution were added water (0.3 mL) and lithium hydroxide monohydrate (24 mg), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by solid phase extraction method on ODS (washing solvent: distilled water, eluent: methanol) to give the title compound (71 mg).
Reaction SMILES: N[C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[C:3]=1N.FC1N=C(F)N=C(SCCCC)N=1>>[CH:7]1[C:6]2[C:5](=[O:17])[C:4]3[C:13](=[CH:14][CH:15]=[CH:2][CH:3]=3)[C:12](=[O:16])[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1ccc2c(c1N)C(=O)c1ccccc1C2=O
Agent: CCCCSc1nc(F)nc(F)n1
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
Instead of using a unitary diaminoanthraquinone of the formula (2) it is also possible to use a mixture of diaminoanthraquinones, for example a mixture of 1,5-, 1,6- and 1,7-diaminoanthraquinone. Mixtures of the diaminoanthraquinones which are formed in the industrial manufacture of diaminoanthraquinones by dinitration of anthraquinone and subsequent reduction are particularly suitable. Such mixtures contain for example small amounts of 2,7- and 2,8-diaminoanthraquinone (β-isomers) and 1-aminoanthraquinone in addition to the 1,8-, 1,5-, 1,7- and 1,6-diaminoanthraquinones principally obtained, or they contain small amounts of 1-aminoanthraquinone, 2-aminoanthraquinone and 1-amino-2-, -4-, -5- and -8-hydroxyanthraquinone in addition to 1,6-, 1,8-, 1,7-, 2,6-, 2,7- and 1,5-diaminoanthraquinone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])O)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.B(F)(F)F.[CH3:26]COCC.[Zn](C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH3:26])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: OC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12
Reactant: CCOCC
Agent: C[Zn]C
Agent: FB(F)F
Solvent: C1CCOC1
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-(2,6-dichloro-3-fluorophenyl)methanol (5.05 g, 12.9 mmol) was dissolved in anhydrous THF (100 mL). To this solution was added BF3.OEt2 (10.66 mL, 6.5 eq.) at −78° C. The resulting solution was stirred for 10 min at the same temp before a solution of ZnMe2 (35.60 mL, 5.5 eq., 2 N in toluene) was added. The resulting mixture was allowed to warm up to rt in 1 h. The solution was then stirred at 65° C. for 3.5 h. Reaction was monitored by LC-MS. After achieving >95% conversion, the reaction was allowed to cool down to rt. Then it was further cooled down to −78° C. and quenched by adding sat. aq. NH4Cl solution (10 mL). The mixture was slowly warmed up to rt. Solvents were removed under reduced pressure. To the residue was added aq. NaHCO3 solution and the mixture was then extracted with CHCl3 (100 mL×4). The organic extracts were combined, dried (Na2SO4), and concentrated in vacuo to give a crude residue which was purified by flash chromatography (eluent: 10% ethyl acetate in hexane). 1H NMR (400 MHz. DMSO-d6): δ=11.85 (br. s., 1H), 8.21 (d, J=2.0 Hz, 1H), 7.49-7.59 (m, 2H), 7.41 (dd, J=8.8, 8.6 Hz, 1H), 7.30 (d, J=2.0 Hz, 1H), 5.11 (q, J=7.3 Hz, 1H), 1.80 (d, J=7.3 Hz, 3H); 13C NMR (100.6 MHz, DMSO-d6): δ 156.74 (JCF=247.4 Hz), 146.91, 142.24, 141.02, 129.37, 127.56, 125.98, 121.73 (JCF=19.8 Hz), 120.18, 115.98 (JCF=23.4 Hz), 113.62, 109.99, 33.53, 15.94. MS (ES+): m/z=386.93, 388.91, 390.89 [MH+]. HPLC: tR=4.17 min (ZQ3, polar—5 min).
Reaction SMILES: [N:1]1([C:7](=[O:24])[CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=CC=C[CH:19]=2)(=[O:16])=[O:15])[C:10]([OH:12])=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+].BrCC(C)C.OOS([O-])=O.[K+]>CCO.O>[CH3:19][CH:18]([CH3:23])[CH2:17][S:14]([CH2:13][CH:9]([CH2:8][C:7]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:24])[C:10]([OH:12])=[O:11])(=[O:15])=[O:16]
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(C)CBr
Product: CC(C)CS(=O)(=O)CC(CC(=O)N1CCOCC1)C(=O)O
Temperature: 25 °C

Procedure:
4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid (10.90 g, 40.15 mmol) was dissolved in 100 mL dry EtOH and set to stir at room temperature. NaOH pellets (4.81 g, 120.45 mmol) were added in one portion, and the reaction mixture was allowed to stir for 10 minutes. 1-Bromo-2-methyl propane (5.0 g, 36.49 mmol) was then added, and the reaction mixture was allowed to stir at ambient temperature for 20 hours. Upon completion (LCMS), the reaction mixture was diluted with water and the pH was lowered to ˜pH2. The reaction mixture was then washed 3× with EtOAc. The organic phase was concentrated in vacuo and then diluted with 200 mL aqueous MeOH. Oxone (10.02 g, 14.57 mmol) was added in one portion and the reaction was stirred at room temperature for 4 hours. Conversion of sulfide to sulfone was monitored via LCMS. Upon completion, reaction was quenched by the addition of sodium thiosulfate. Salts were filtered, and the reaction mixture was washed 3× with ethyl acetate and dried over sodium sulfate. The organics were evaporated by vacuum under reduced pressure. Product was purified via HPLC. Yield: 1.1 g, 23.1%. m/z (LCMS) M+ 322.01, Rf=2.03. δH 12.6 (1H, br s), 3.5 (4H, m), 3.5 (1H, m), 3.4 (4H, m), 3.25 (2H, d), 3.0 (2H, m), 2.9 (2H, d), 2.4 (1H, m), 1.3 (6H, d d).
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([Cl:12])[N:9]=[C:10](Cl)[C:5]=2[S:4][CH:3]=1.C(O)(C)C.[NH3:17]>>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([Cl:12])[N:9]=[C:10]([NH2:17])[C:5]=2[S:4][CH:3]=1
Reactant: Clc1nc(Cl)c2scc(Br)c2n1
Reactant: N
Solvent: CC(C)O
Product: Nc1nc(Cl)nc2c(Br)csc12
Temperature: 80 °C
Reaction time: 5 h
Yield: 74.6 %

Procedure:
7-Bromo-2,4-dichlorothieno[3,2-d]pyrimidine (3.0 g, 10.64 mmol) was added to a sealed reactor and 2.0 N ammonia isopropanol (26.6 mL, 53.2 mmol) was added thereto. The reaction mixture was stirred at 80° C. for 5 hours and then cooled to room temperature. The reaction mixture was added to ice water (100 mL). Thus prepared solid was filtered and dried by blowing nitrogen gas. The resultant target compound (2.1 g, 75% yield) was used in the following reaction without purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[O:16][CH2:15][CH2:14]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:33]([O:37][C:38]([N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[C:41]1[CH2:49]Cl)=[O:39])([CH3:36])([CH3:35])[CH3:34].[I-].[K+]>CC#N>[C:33]([O:37][C:38]([N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[C:41]1[CH2:49][N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:23])[CH:13]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[O:16][CH2:15][CH2:14]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NCCCCNC1CCOc2cccnc21
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCCN(Cc1nc2ccccc2n1C(=O)OC(C)(C)C)C1CCOc2cccnc21
Temperature: 25 °C
Yield: 67.5 %

Procedure:
To a solution of [4-(3,4-Dihydro-2H-pyrano[3,2-b]pyridin-4-ylamino)-butyl]-carbamic acid tert-butyl ester (329 mg, 1.02 mmol) in CH3CN (5 mL) was added N,N-diisopropylethylamine (0.28 mL, 1.63 mmol) followed by 2-chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (328 mg, 1.23 mmol) and potassium iodide (20 mg, 0.1 mmol). The resultant mixture was heated to 60° C. for 16 hours then cooled to room temperature. The mixture was concentrated and the residue was partitioned between CH2Cl2 (25 mL) and saturated aqueous NaHCO3 (20 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (2×15 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by flash column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 95:4:1) provided 2-{[(4-tert-Butoxycarbonylamino-butyl)-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-amino]-methyl}-benzimidazole-1-carboxylic acid tert-butyl ester (380 mg, 67%) as a white foam.
Reaction SMILES: [CH3:1][C:2]1([CH2:9][CH2:10][CH3:11])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[O:8].[Br:12]C1CC(C(C)C)CCC1=O>>[Br:12][CH:4]1[C:3](=[O:8])[C:2]([CH3:1])([CH2:9][CH2:10][CH3:11])[CH2:7][CH2:6][CH2:5]1
Reactant: CC(C)C1CCC(=O)C(Br)C1
Reactant: CCCC1(C)CCCCC1=O
Product: CCCC1(C)CCCC(Br)C1=O

Procedure:
The bromination of 2-methyl-2-propyl-cyclohexanone takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][C@H:7]([C:9]([N:11]2[CH:16]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH:14]([N:19]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])[CH2:15]3)=[O:10])[NH2:8])=[CH:4][CH:3]=1.[O:35]1[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@H:7]([C:9]([N:11]2[CH:16]3[CH2:17][CH2:18][CH:12]2[CH2:13][CH:14]([N:19]([CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[C:20]([N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])=[O:21])[CH2:15]3)=[O:10])[NH:8][CH:38]2[CH2:39][CH2:40][O:35][CH2:36][CH2:37]2)=[CH:33][CH:34]=1
Reactant: O=C1CCOCC1
Reactant: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@H](N)Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN(CC)C(=O)N(C1CCCCC1)C1CC2CCC(C1)N2C(=O)[C@@H](Cc1ccc(Cl)cc1)NC1CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.9 %

Procedure:
0.30 g of the N-[8-(4-chloro-D-phenylalanyl)-8-azabicyclo[3.2.1]oct-3-yl]-N-cyclohexyl-N′,N′-diethylurea endo compound, obtained in step 1.5, is dissolved in 3 ml of dichloromethane under N2 in the presence of 0.061 g of tetrahydro-4H-pyran-4-one and of 0.17 g of sodium triacetoxyborohydride. The reaction medium is stirred at ambient temperature for 3 days. After evaporation and hydrolysis with a saturated aqueous sodium hydrogen carbonate solution, extraction is carried out with ethyl acetate until the aqueous phase is completely depleted. The organic phase is washed with H2O and then with a saturated aqueous sodium chloride solution. Drying over MgSO4 and concentration to dryness are carried out. The crude is chromatographed on silica gel, elution being carried out with a 99/1 and then 98/2 mixture of dichloromethane and methanol. 0.23 g of N-{8-[4-chloro-N-(tetrahydro-2H-pyran-4-yl)-D-phenylalanyl]-8-azabicyclo[3.2.1]oct-3-yl}-N-cyclohexyl-N′,N′-diethylurea is then obtained.
Reaction SMILES: C1CCN2C(=[N:5]CCC2)CC1.[C:12]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]3[N:24]=[C:25](S(C)(=O)=O)[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:21]3=[CH:20][C:19]=2[Cl:39])=[CH:14][CH:13]=1.C([O-])(=O)C.[NH4+].O>CN(C=O)C>[C:12]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]3[N:24]=[C:25]([NH2:5])[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:21]3=[CH:20][C:19]=2[Cl:39])=[CH:14][CH:13]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1c(N)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DBU (0.204 ml, 1.354 mmol) was added to a stirred mixture of 5-([1,1′-biphenyl]-4-yl)-6-chloro-2-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (232 mg, 0.451 mmol) and ammonium acetate (348 mg, 4.51 mmol) in DMF (2 ml), and the mixture was stirred at room temperature overnight. Water (30 mL) was added and the mixture was extracted with ethyl acetate (2×30 mL). The combined organic fractions were washed with brine (saturated, 20 mL), dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative HPLC Reverse phase (C-18), eluting with acetonitrile/water+0.1% TFA. The combined fractions was concentrated, dissolved in MeOH, neutralized with NH4OH, concentrated, redissolved in MeOH, filtered through silica gel pad, washed with DCM:MeOH:NH4OH(10:1:0.1) and dried to give title compound. LC-MS: calculated for C24H27ClN4OSi 450.16 observed m/e: 451.13 (M+H)+ (Rt 1.25/2 min).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15]>>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:20]2[CH2:21][CH2:22][N:17]([S:14]([CH3:13])(=[O:16])=[O:15])[CH2:18][CH2:19]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Product: COc1cc(N2CCN(S(C)(=O)=O)CC2)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared according to the method described for Preparation 78 using 4-fluoro-2-methoxy-1-nitrobenzene and 1-(methylsulfonyl)piperazine for 96 hours. The residue was purified by silica gel column chromatography eluting with 50-100% DCM in cyclohexanes.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:19](=[O:20])[C:18]2[C:9](=[C:10]3[C:15](=[C:16]([F:21])[CH:17]=2)[N:14]([CH2:22][CH3:23])[CH:13]=[C:12]([C:24]([O:26]CC)=[O:25])[C:11]3=[O:29])[N:8]([CH2:30][CH3:31])[CH:7]=1)=[O:5])C>Cl>[CH2:30]([N:8]1[C:9]2[C:18](=[CH:17][C:16]([F:21])=[C:15]3[C:10]=2[C:11](=[O:29])[C:12]([C:24]([OH:26])=[O:25])=[CH:13][N:14]3[CH2:22][CH3:23])[C:19](=[O:20])[C:6]([C:4]([OH:5])=[O:3])=[CH:7]1)[CH3:31]
Reactant: CCOC(=O)c1cn(CC)c2c(cc(F)c3c2c(=O)c(C(=O)OCC)cn3CC)c1=O
Agent: Cl
Product: CCn1cc(C(=O)O)c(=O)c2c1c(F)cc1c(=O)c(C(=O)O)cn(CC)c12
Temperature: 90 °C
Reaction time: 4 h
Yield: 41.1 %

Procedure:
A mixture of 0.935 g (2.17 mmol) of the compound of Example 2 and 20 ml of 6N HCl is stirred at 90° C. for 4 hours. After cooling, the mixture is concentrated under reduced pressure. The residue is triturated with cold ethanol to furnish 0.334 g (41.1%) of title compound as a tan solid:
Reaction SMILES: C([NH:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][Br:16])(OC(C)(C)C)=O.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20].[Br:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][O:9][NH2:8]
Reactant: CC(C)(C)OC(=O)NOCCCCCCBr
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NOCCCCCCBr
Reaction time: 1 h

Procedure:
To a stirring solution of N-Boc-O-(6-bromohexyl)hydroxylamine (954 mg, 3.22 mmol) in dichloromethane (16 mL) at 0° C. was added trifluoroacetic acid (8.0 mL). Stirring continued for 1 h at 0° C. (Gilmore, J. M.; Scheck, R. A.; Esser-Kahn, A. P.; Joshi, N. S.; Francis, M. B. Angew. Chem. Int. Ed. 2006, 45, 5307.) The volatile compounds were removed under reduced pressure and the excess acid was removed by azeotroping with toluene (3×20 mL). O-(6-bromohexyl)hydroxylamine trifluoroacetate salt (1b) was obtained as a clear oil (998 mg, quant.), which was carried on without further purification. 1H-NMR (CDCl3, 300 MHz): δ 10.41 (broad s, 3H), 4.05 (broad t, J=6.2 Hz, 2H), 3.4 (t, J=7.0 Hz, 2H), 1.85 (pent, J=6.7 Hz, 2H), 1.68 (broad pent, J=6.3 Hz, 2H), 1.51-1.33 (m, 4H). 13C-NMR (CDCl3, 75 MHz): δ 33.7, 32.6, 27.8, 27.6, 24.2. HRESI-MS calcd for C6H15BrON [M+H]+ 196.0332. found 196.0332.
Reaction SMILES: [NH2:1][N:2]1[C:6]2[N:7]=[C:8]([CH:14]3[CH2:16][CH2:15]3)[CH:9]=[C:10]([C:11]([OH:13])=O)[C:5]=2[CH:4]=[N:3]1.[NH2:17][CH2:18][C:19]1[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=1[CH3:25].ON1C2N=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CS(C)=O>[NH2:1][N:2]1[C:6]2[N:7]=[C:8]([CH:14]3[CH2:16][CH2:15]3)[CH:9]=[C:10]([C:11]([NH:17][CH2:18][C:19]3[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])=[O:13])[C:5]=2[CH:4]=[N:3]1
Reactant: Nn1ncc2c(C(=O)O)cc(C3CC3)nc21
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CC3)nc3c2cnn3N)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described for intermediate 56 using 1-amino-6-cyclopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (73 mg, 0.335 mmol), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (76 mg, 0.502 mmol), 1-hydroxy-7-azabenzotriazole (91 mg, 0.669 mmol), DMSO (10 mL), EDC (128 mg, 0.669 mmol), and N-methylmorpholine (0.147 mL, 1.338 mmol). The aq. phase was extracted with EtOAc (5×30 mL). The combined EtOAc extracts were dried over MgSO4, filtered, and concentrated in vacuo. The final product was collected as 0.068 g (58%). LCMS E-S (M+H)=353.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99-1.14 (m, 4H), 2.13 (s, 3H), 2.22 (s, 4H), 4.35 (d, J=4.80 Hz, 2H), 5.90 (s, 1H), 6.31 (s, 2H), 7.41 (s, 1H), 8.04 (s, 1H), 8.74 (s, 1H), 11.58 (br. s., 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@H:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][C@H:9]1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([O:30]C)=[O:29])=[N:26][CH:27]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@H:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][C@H:9]1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[N:26][CH:27]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O)c3ccccc3)N2C(=O)OC(C)(C)C)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)nc2)CC[C@@H]1[C@H](O)c1ccccc1
Temperature: 60 °C

Procedure:
To a solution of methyl 5-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)pyridine-2-carboxylate (330 mg, 0.77 mmol) in THF (4 mL) and methanol (4 mL) was added 1N NaOH solution (4 mL, 4.0 mmol) and the resulting solution heated at 60° C. for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure to remove the organic solvents. The aqueous layer was adjusted to pH of 6.5 (using 2.0M aqueous HCl) and extracted with ethyl acetate (2×10 mL) and dichloromethane (10 mL). The organics were combined, dried over sodium sulfate, filtered, and concentrated to dryness under vacuum. The product (304 mg, 96%) did not require any further purification and was of reagent grade quality for analog syntheses. LC-MS: C23H28N2O5 calculated 412.20 found m/z (ES) 413.1 (MH)+ and 313.2 (M-Boc)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH3:22])[CH2:18][CH2:19][CH2:20][NH2:21])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:25]([NH:27][C:28](=[N:36][CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[CH:42]=1)OC1C=CC=CC=1)#[N:26]>>[C:25]([NH:27][C:28]([NH:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:16][CH2:15][N:8]([CH2:7][C:6]1[CH:23]=[CH:24][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:22])=[N:36][CH2:37][CH2:38][CH2:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:48]2[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]2)[CH:42]=1)#[N:26]
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Reactant: COc1ccc(CN(CCN(C)CCCN)c2ccccn2)cc1
Product: COc1ccc(CN(CCN(C)CCCNC(=NCCCOc2cccc(CN3CCCCC3)c2)NC#N)c2ccccn2)cc1

Procedure:
Preparation is effected analogously to Example 1, using 0.52 g (1.6 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,3-propanediamine and the equimolar amount of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a viscous oil which crystallises from absolute ether at -20° C.; MS (+FAB method): m/z (rel. int. [%])=627 ([M+H]+, 6), 241 (11), 121 (100); IR (KBr): 2165 cm-1 (C≡N); m.p.: 62°-65° C. (ether).