Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][P:6]([O:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([O:20]C)=[O:19])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.CO.O>[C:9]([O:8][P:6]([O:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([OH:20])=[O:19])([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: COC(=O)c1cccc(COP(=O)(OC(C)(C)C)OC(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OP(=O)(OCc1cccc(C(=O)O)c1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a solution of methyl 3-((di-tert-butoxyphosphoryloxy)methyl)benzoate (0.1 g, 0.3 mmol) in THF (3 mL), methanol (3 mL), water (3 mL) was added lithium hydroxide (0.035 g, 0.81 mmol). The reaction mixture was stirred at rt for 1 h. After this time, the organic solvents were removed under reduced pressure, and EtOAc (30 mL) was added to the residual material followed by acetic acid (30%). The organic layer was washed with water (2×10 mL), dried over Na2SO4 and concentrated under vacuum to afford 3-((di-tert-butoxyphosphoryloxy)methyl)benzoic acid (80 mg, 0.23 mmol). 1H NMR (400 MHz, DMSO-d6): 1.41 (s, 18H), 5.00 (d, J=8, 2H), 7.52 (t, J=7.6, 1H), 7.62 (d, J=7.6, 1H), 7.90 (d, J=8.0, 1H), 7.99 (s, 1H). LCMS-m/z: 343.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.C([Li])CCC.[CH:18](N1CCOCC1)=[O:19]>O1CCCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:5]1[CH:6]=[CH:7][C:2]([CH:18]=[O:19])=[CH:3][CH:4]=1
Reactant: Brc1ccc(C2OCCO2)cc1
Reactant: O=CN1CCOCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(C2OCCO2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
To a tetrahydrofuran (100 mL) solution of 2-(4-bromo-phenyl)-1,3-dioxolane (8 g, 34.9 mmol) was added dropwise n-butyl lithium (19.6 mL, 2.67 M hexane solution, 52.4 mmol) at −78° C. After 1 hour of stirring at −78° C., N-formylmorpholine (4.42 g, 38.4 mmol) was added to the mixture, and stirred for 3 hours at the same temperature. This mixture was partitioned into diethyl ether and water. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (6.3 g). This compound was used in the subsequent reaction without being purified.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[N:19]=[CH:18][C:17]([CH:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH3:21])=[CH:16][CH:15]=1.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C>O1CCCC1>[F:13][C:14]1[C:15]([B:28]([OH:33])[OH:29])=[CH:16][C:17]([CH:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH3:21])=[CH:18][N:19]=1
Reactant: CC(c1ccc(F)nc1)N1CCOCC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(c1cnc(F)c(B(O)O)c1)N1CCOCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A stirred solution of diisopropylamine (2.152 mL, 15.35 mmol) in tetrahydrofuran (20 mL) was treated with n-butyllithium 1.6M in Hexanes (9.60 mL, 15.35 mmol) at −40° C. The yellow solution was stirred at the same temperature for 1 h and then cooled to −78° C. A solution of 4-(1-(6-fluoropyridin-3-yl)ethyl)morpholine (2.69 g, 12.79 mmol) in THF (15 mL) was added via cannula over 20 min. The deep-red mixture was stirred at the same temperature for 1.5 h. Then a solution of triisopropyl borate (4.41 mL, 19.19 mmol) in THF (10 mL) was added slowly into the mixture. The resulting mixture was stirred at the same temperature for 30 min and then the cooling bath was removed. After the reaction mixture had warmed to room temperature, the tan mixture was quenched with 1 N NaOH (aq) (15 mL) and stirred. The separated aqueous layer was removed and the flask was rinsed with 1 N NaOH (aq) (2×20 mL) and the organic layer was extracted with 1 N NaOH (2×10 mL). The aqueous layer was collected and carefully acidified with 5 N HCl until acidic (pH 5 about 6) and the resulting cloudy mixture was extracted with EtOAc (3×30 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The product remained in the aqueous layer. The aqueous layer was frozen and the water removed by lyophilization. The mixture was diluted with 1:1 MeOH/DCM and placed into a sonicator for 5 min. The mixture was filtered through a fine-fritted funnel and the filtrate was concentrated in vacuo to give 2-fluoro-5-(1-morpholinoethyl)pyridin-3-ylboronic acid (3.120 g, 12.28 mmol, 96% yield) as a yellow solid. 1H NMR (400 MHz, d4-MeOH) δ 8.00 (dd, J=8.22, 2.54 Hz, 1H) 7.88 (d, J=2.35 Hz, 1H) 3.68 (t, J=4.69 Hz, 4H) 3.40-3.54 (m, 1H) 2.56 (d, J=10.76 Hz, 2H) 2.35-2.50 (m, 2H) 1.41 (t, J=6.65 Hz, 3H). m/z (ESI, +ve ion) 255.1 (M+H)+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C:14](=[CH:17][C:18]2[S:19][C:20]3[N:21]=[C:22]([N:33]4[C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=5[N:35]=[C:34]4[CH2:42][CH3:43])[N:23]=[C:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[C:25]=3[N:26]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CC(O)=O.[OH-].[OH-].[Pd+2]>[CH2:42]([C:34]1[N:33]([C:22]2[N:23]=[C:24]([N:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[C:25]3[N:26]=[C:18]([CH2:17][CH:14]4[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]4)[S:19][C:20]=3[N:21]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:35]=1)[CH3:43]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=C3CCN(C(=O)OCc4ccccc4)CC3)sc2n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)sc2n1
Reaction time: 2 h
Yield: 41.4 %

Procedure:
To a solution of 4-[5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethylene]piperidine-1-carboxylic acid benzyl ester (300 mg, 0.50 mmol) in AcOH (20 mL) was added 10% Pd(OH)2/C (200 mg) and the resulting mixture stirred under an atmosphere of H2 for 2 h. The reaction mixture was filtered through Celite®, washing with EtOAc. The filtrate was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, 2M NH3/MeOH:DCM, 0-10%) affording 5-(2-Ethylbenzoimidazol-1-yl)-7-morpholin-4-yl-2-piperidin-4-ylmethylthiazolo[5,4-d]pyrimidine (96 mg, 41%). 1H NMR (CDCl3, 400 MHz): δ 7.99-7.98 (1 H, m), 7.74-7.73 (1 H, m), 7.30-7.26 (2 H, m), 4.43 (4 H, s), 3.88 (4 H, t, J=4.74 Hz), 3.33 (2 H, q, J=7.48 Hz), 3.12-3.08 (2 H, m), 2.99 (2 H, d, J=7.14 Hz), 2.63 (2 H, td, J=12.12, 2.54 Hz), 2.03-1.91 (1 H, m), 1.79 (2 H, brd d, J=13.18 Hz), 1.42 (3 H, t, J=7.48 Hz), 1.30-1.29 (2 H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[C:5]([O:9]COC)=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+]>C1COCC1.Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([OH:9])=[C:6]([I:8])[CH:7]=1
Reactant: COCOc1cnc(Cl)cc1I
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Oc1cnc(Cl)cc1I
Temperature: 60 °C
Reaction time: 12 h
Yield: 91.3 %

Procedure:
2-Chloro-4-iodo-5-methoxymethoxy-pyridine (0.8 g, 2.7 mmol) was dissolved in THF (4 mL) and 3N HCl (6 mL). The mixture was heated to 60° C. with magnetic stirring. Heating was maintained for 3 hours. The mixture was cooled to room temperature and the pH was adjusted to 7 with the slow addition of saturated aqueous sodium bicarbonate. The result was extracted with EtOAc (3×50 mL) dried over Na2SO4, filtered and concentrated. The solid was suspended in EtOAc and stirred for 12 hours at room temperature. The mixture was filtered and the filtrate was concentrated to yield an off white solid (0.63 g, 93%). 1H NMR (400 MHz, DMSO-d6): δ 11.10 (br s, 1H), 7.89 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C@@H:4]([CH:5]=O)[C@H:3]1[C:7]([O-:9])=[O:8].[Na+].[Cl-].[CH3:13][O:14][CH2:15][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.P(O)(O)([O-])=O.[Na+]>CN(C)C=O>[CH3:1][C:2]1([CH3:10])[CH:4]([CH:5]=[CH:13][O:14][CH3:15])[CH:3]1[C:7]([OH:9])=[O:8]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C)[C@H](C(=O)[O-])[C@@H]1C=O
Agent: O=P([O-])(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC=CC1C(C(=O)O)C1(C)C
Reaction time: 1.5 h

Procedure:
A solution of 9 g of 96.5% potassium tert.-butylate in 90 ml of dimethylformamide was added at -60° C. to a solution of 12.58 g of sodium (1R,cis) 2,2-dimethyl-3-formyl-cyclopropane-carboxylate, 350 ml of dimethylformamide and 26.27 g of methoxymethyl triphenylphosphonium chloride and the temperature was allowed to rise to 20° C. with stirring over 90 minutes. The mixture was poured into aqueous monosodium phosphate solution and was extracted with diisopropyl oxide. The combined organic phases were extracted with 100 ml of aqueous N sodium hydroxide and the aqueous extract was stirred at 5° C. with a mixture of diisopropyl oxide and monosodium phosphate. The mixture was diluted with water and the decanted aqueous phase was extracted with diisopropyl oxide. The organic phase was evaporated to dryness under reduced pressure to obtain 5.22 g of (1R,cis)(E+Z) 2,2-dimethyl-3-(2-methoxy-1-ethenyl)-cyclopropane-carboxylic acid.
Reaction SMILES: [CH3:1][S:2][CH:3]([CH3:16])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)=[O:5].[H-].[Na+].[CH3:19]I.O>O1CCCC1>[CH3:1][S:2][C:3]([CH3:19])([CH3:16])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=1)=[O:5]
Reactant: CSC(C)C(=O)c1ccc(C(F)(F)F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CSC(C)(C)C(=O)c1ccc(C(F)(F)F)cc1
Yield: 59.5 %

Procedure:
To 2.02 g of 2-methylthio-4'-(trifluoromethyl)propiophenone dissolved in 20 ml of tetrahydrofuran was added under ice-cooling 0.33 g of a 60% aqueous solution of sodium hydride, and the mixture was reacted at room temperature with stirring until no bubbles were produced. After an addition of 1.27 g of methyl iodide, the mixture was stirred at room temperature for a further 2 hours. The resultant reaction mixture was poured into ice-cooled water and extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography using n-hexane to obtain 1.27 g of an oily product of 2-methylthio-4'-(trifluoromethyl)isobutyrophenone (yield: 59.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.C[Si](C[C:14]#[N:15])(C)C.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[C:3]([C:14]#[N:15])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1cccc(Cl)c1
Reactant: C[Si](C)(C)CC#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1ncccc1Cl
Yield: 84.1 %

Procedure:
A mixture of 3-chloropyridine-N-oxide (2.12 g, 16.30 mmol), trimethylsilyl(acetonitrile) (3.25 g, 32.80 mmol), triethylamine (3.30 g, 32.60 mmol) and acetonitrile (10 mL) was heated at reflux for 6 h. After concentration under reduced pressure, the resulting residue was basified with aqueous sodium carbonate (3N) and extracted with methylene chloride. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-chloropicolinonitrile (1.90 g). The crude product was carried forward without further purification. MW=139 confirmed by LC-MS, tr=2.33 min (Method E) MH+=140.
Reaction SMILES: O[CH:2]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>C(#N)C>[Br:32][CH:2]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)C(O)c1ccsc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COC(=O)C(Br)c1ccsc1
Reaction time: 2 h

Procedure:
A mixture of (RS) methyl 2-hydroxy-2-(thien-3-yl)acetate (see Preparation 24) (4.49 g), triphenylphosphine (8.21 g) and carbon tetrabromide (10.4 g) in acetonitrile (100 ml) was refluxed for 2 hours, cooled, further triphenylphosphine (2.5 g) and carbon tetrabromide (3 g) were added, and refluxing was continued for a further 2 hours. After cooling, the mixture was used directly, without further purification, in Preparation 17.
Reaction SMILES: [C:1]([OH:9])(=O)[CH2:2][O:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N(CC)CC)C.C(Cl)CCl.[NH2:21][C@@H:22]([CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)[C@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[OH:24]>C(Cl)Cl>[C:1]([NH:21][C@@H:22]([CH2:31][N:32]1[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1)[C@H:23]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[OH:24])(=[O:9])[CH2:2][O:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCOCC(=O)O
Reactant: N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOCC(=O)N[C@@H](CN1CCOCC1)[C@@H](O)c1ccccc1
Reaction time: 8 h
Yield: 58.9 %

Procedure:
Methylene chloride (20 ml), 3-oxaheptanoic acid (529.0 mg, 4.0 mmol), triethylamine (1.40 ml, 10.0 mmol) and EDC (1.15 g, 6.0 mmol) were added to (1S,2S)-2-amino-3-morpholino-1-phenyl-1-propanol (944.0 mg, 4.0 mmol), followed by stirring overnight. Methylene chloride (100 ml) was added to the reaction solution. After washed with a saturated sodium hydrogen carbonate solution (50 ml), water (50 ml) and saturated brine (50 ml) successively, the organic layer was dried over sodium sulfate and filtered, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform:ethanol=30:1) to obtain the title compound (825 mg, yield 59%) as colorless oil.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH3:33])[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[N:19][C:20]=2I)=[O:15])[CH2:10][CH2:9]1.[N:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[N:36][CH:35]=1>>[OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]([CH3:33])[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[N:19][C:20]=2[C:38]2[CH:39]=[N:34][CH:35]=[N:36][CH:37]=2)=[O:15])[CH2:10][CH2:9]1
Reactant: OB(O)c1cncnc1
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1
Product: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(-c2cncnc2)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 7, [4-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-piperidin-1-yl]-[5-iodo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazole-4-yl]-methanone (example 53) was reacted with pyrimidine-5-yl-boronic acid to give the title compound light brown oil. MS: 531.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17]C)=[O:9])=[C:6]([NH:19][C@H:20]([C:22]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:26](=[O:34])[C:25]3=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]3[N:23]=2)[CH3:21])[N:5]=[CH:4][N:3]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])=[O:9])=[C:6]([NH:19][C@H:20]([C:22]2[N:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:26](=[O:34])[C:25]3=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]3[N:23]=2)[CH3:21])[N:5]=[CH:4][N:3]=1
Reactant: COc1ccccc1NC(=O)c1c(N)ncnc1N[C@@H](C)c1nn2ccc(C)c2c(=O)n1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3C(=O)Nc3ccccc3O)n(-c3ccccc3)c(=O)c12
Yield: 34.5 %

Procedure:
(S)-4-Amino-N-(2-methoxyphenyl)-6-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)pyrimidine-5-carboxamide (72 mg, 0.14 mmol) was treated with boron tribromide (1M in dichloromethane, 0.43 ml, 0.43 mmol) in dichloromethane (8 ml) according to the method described in Example 23. The crude was purified using SP1® Purification (40% to 100%, hexane-ethyl acetate) to give 24 mg (34% yield) of the title compound as a solid. Purity 99%.
Reaction SMILES: CS([CH2-])=O.[Na+].[H-].[Na+].C([O:10][C:11]([C:13]1[CH:14]=[N:15][N:16]([CH3:26])[C:17]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25])=O)C>CS(C)=O>[CH3:26][N:16]1[C:17]2[NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[NH:25][C:11](=[O:10])[C:13]=2[CH:14]=[N:15]1
Reactant: CCOC(=O)c1cnn(C)c1Nc1ccccc1N
Agent: [CH2-]S(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1ncc2c1Nc1ccccc1NC2=O
Temperature: 65 °C
Reaction time: 2.5 h
Yield: 40 %

Procedure:
Sodium (methylsulphinyl)methanide (29.7 mmol) was pre-pared from sodium hydride (60% dispersion in oil, 1.19 g, 29.7 mmol) and anhydrous dimethyl sulphoxide (7 ml) by heating at 65° C. until a solution was observed. To this was added a solution of 5-(2-amino-phenylamino)-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester from Example E11.2 (3.63 g, 16.9 mmol) in anhydrous dimethyl sulphoxide (10 ml), and stirring continued at 65° C. for 2.5 h. The mixture was poured into ice (100 ml), and the resulting solid collected and purified by recrystallisation from methanol/EtOAc/60-80 pet ether to yield the title compound (1.46 g, 40%).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]=[N:12][C:13]2[CH:77]=[CH:76][C:16]([O:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([C:51]4[CH:56]=[CH:55][C:54]([O:57][C:58]5[CH:63]=[CH:62][C:61]([N:64]=[N:65][C:66]6[CH:71]=[CH:70][C:69]([NH:72]C(=O)C)=[CH:68][CH:67]=6)=[CH:60][CH:59]=5)=[CH:53][CH:52]=4)([C:26]4[CH:31]=[CH:30][C:29]([O:32][C:33]5[CH:38]=[CH:37][C:36]([N:39]=[N:40][C:41]6[CH:46]=[CH:45][C:44]([NH:47]C(=O)C)=[CH:43][CH:42]=6)=[CH:35][CH:34]=5)=[CH:28][CH:27]=4)[CH3:25])=[CH:20][CH:19]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)(=O)C.Cl.C(O)C>O>[NH2:47][C:44]1[CH:43]=[CH:42][C:41]([N:40]=[N:39][C:36]2[CH:37]=[CH:38][C:33]([O:32][C:29]3[CH:30]=[CH:31][C:26]([C:24]([C:21]4[CH:22]=[CH:23][C:18]([O:17][C:16]5[CH:76]=[CH:77][C:13]([N:12]=[N:11][C:8]6[CH:9]=[CH:10][C:5]([NH2:4])=[CH:6][CH:7]=6)=[CH:14][CH:15]=5)=[CH:19][CH:20]=4)([C:51]4[CH:52]=[CH:53][C:54]([O:57][C:58]5[CH:63]=[CH:62][C:61]([N:64]=[N:65][C:66]6[CH:71]=[CH:70][C:69]([NH2:72])=[CH:68][CH:67]=6)=[CH:60][CH:59]=5)=[CH:55][CH:56]=4)[CH3:25])=[CH:27][CH:28]=3)=[CH:34][CH:35]=2)=[CH:46][CH:45]=1
Reactant: CC(=O)Nc1ccc(N=Nc2ccc(Oc3ccc(C(C)(c4ccc(Oc5ccc(N=Nc6ccc(NC(C)=O)cc6)cc5)cc4)c4ccc(Oc5ccc(N=Nc6ccc(NC(C)=O)cc6)cc5)cc4)cc3)cc2)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(c1ccc(Oc2ccc(N=Nc3ccc(N)cc3)cc2)cc1)(c1ccc(Oc2ccc(N=Nc3ccc(N)cc3)cc2)cc1)c1ccc(Oc2ccc(N=Nc3ccc(N)cc3)cc2)cc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 52.6 %

Procedure:
To a 100 mL round-bottomed flask with a stir-bar and a condenser, 1,1,1-tris[4-(4-(4-acetamidophenyldiazenyl)phenoxy)phenyl]ethane (Example 4; 0.50 g, 0.49 mmol), 6 M HCl (20 mL) and 95% ethanol (20 mL) were charged and heated to 80° C. The mixture was stirred at 80° C. for 3 days. After the mixture was allowed to cool to room temperature, water (60 mL) added. The resulting red solid was collected by filtration and washed with dilute sodium bicarbonate solution, followed by deionized water (300 mL). After being air dried, the crude product was purified by column chromatography (silica gel, ethyl acetate as eluent). The solvent was removed by a rotary evaporator to afford 0.23 g (52.5%) of orange red solid, mp >300° C. MS (m/e): 892 (M+). Anal. Calcd. for C56H45N9O3: C, 75.40%; H, 5.08%; N, 14.13%. Found: C, 75.44%; H, 5.08%; N, 13.98%. 1H-NMR (d6-DMSO, δ in ppm): 2.12 (s, 3H, CCH3), 6.03 (s, 6H, NH2), 6.67-6.70 (d, 6H, J=8.7 Hz), 6.99-7.02 (d, 6H, J=8.7 Hz), 7.09-7.13 (m, 12H), 7.62-7.66 (d, 6H, J=8.7 Hz), 7.75-7.78 (d, 6H, J=8.7 Hz). 13C-NMR (d6-DMSO, δ in ppm): 30.34, 51.91, 113.41, 118.44, 118.69, 123.52, 124.96, 129.93, 142.92, 144.25, 148.41, 152.56, 154.21, 157.75.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C(N(CC)CC)C.[NH2:19][CH:20]([NH2:38])[C@@H:21]([OH:37])[C@@H:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>ClCCl>[C:30]([C@@H:22]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C@H:21]([OH:37])[C:20]([NH2:38])([NH2:19])[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31]
Reactant: CC(C)(C)OC(=O)[C@@H](CC1CCCCC1)[C@H](O)C(N)N
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H](CC1CCCCC1)[C@H](O)C(N)(N)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.18 ml of benzyl chloroformate are added at a temperature of 2° to 5° to a solution of 5.28 ml of triethylamine and 6.3 g of (2S,3S)-1-amino-3-BOC-amino-4-cyclohexyl-2-butanol in 120 ml of dichloromethane, and the solution obtained is stirred for 30 minutes at room temperature. The solution is then diluted with dichloromethane and washed with 0.25N hydrochloric acid, saturated aqueous sodium bicarbonate solution and water. The organic phase is dried over sodium sulphate and evaporated under vacuum. Chromatography of the residue on silica gel using toluene/ethyl acetate (3:1) as the eluant yields (2S,3S)-3-BOC-amino-1-Cbz-amino-4-cyclohexyl-2-butanol as a slightly yellowish oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]3[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:26](Cl)=[O:27]>>[F:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[C:26]([NH:21][C:20]1[C:15]([NH:14][CH2:13][CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:27]
Reactant: COc1ccc(C(=O)Cl)cc1F
Reactant: Nc1cccnc1NCC1CCN(c2ccncc2)CC1
Product: COc1ccc(C(=O)Nc2cccnc2NCC2CCN(c3ccncc3)CC2)cc1F
Yield: 25.6 %

Procedure:
Using a similar procedure to that described in Example 2, Part D, N2-[1-(4-pyridyl)piperidin-4-ylmethyl]-2,3-pyridinediamine (300 mg, 1.06 mmol) and 3-fluoro-4-methoxybenzoyl chloride (200 mg, 1.17 mmol) yielded 118 mg (15%) of the title compound as a hydrochloride salt.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[OH:13])[C:7]([OH:9])=[O:8].CN(C=O)C.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[OH:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[OH:13])[C:7]([O:9][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:8]
Reactant: O=C(O)c1ccc(O)c(O)c1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(O)c(O)c1
Temperature: 50 °C
Reaction time: 0.33 h

Procedure:
A solution of sodium hydroxide (6.4 g) in water (40 ml) was added to a mixture of 3,4-dihydroxybenzoic acid (24.8 g) and DMF (200 ml) which had been cooled in an ice-bath. The mixture was stirred for 20 minutes and then benzyl bromide (19.1 ml) was added dropwise. After the addition was complete, the mixture was allowed to reach ambient temperature and was stirred for 20 hours. The mixture was then warmed to 50° C. for 2 hours. The solvent was removed by evaporation and the residue was partitioned between water (300 ml) and ethyl acetate (100 ml). The ethyl acetate layer was separated and the aqueous layer extracted with ethyl acetate (100 ml). The combined ethyl acetate extracts were washed with water (100 ml), saturated sodium hydrogen carbonate solution (100 ml), water (100 ml) and with saturated sodium chloride solution (100 ml) and dried (MgSO4). The solvent was removed by evaporation to give a brown solid which was crystallised from toluene to give benzyl 3,4-dihydroxybenzoate (19 g) as a solid; m.p. 147°-149° C.