Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:14](=[O:15])[CH2:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10]1.CI.[C:22](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:22][CH:13]1[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:14]1=[O:15]
Reactant: O=C([O-])[O-]
Reactant: COc1ccccc1N1Sc2ccccc2CC1=O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccccc1N1Sc2ccccc2C(C)C1=O

Procedure:
5.42 g (20 mmol) of 2,3-dihydro-2-(2-methoxyphenyl)benzothiazin-3-one are dissolved in 100 ml of acetone, and 6.9 ml of methyl iodide and 6.5 g of potassium carbonate are added, and the mixture is heated to reflux for 45 hours. After filtration, the filtrate is concentrated. The product crystallizes on trituration with isopropyl ether.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[S:22][N:21]=[C:20]([CH3:23])[CH:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl.CO.[OH-].[NH4+]>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[S:22][N:21]=[C:20]([CH3:23])[CH:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)sn1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)sn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.4 %

Procedure:
To a solution of N-tert-butyl-2-(3-methylisothiazol-5-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (32 mg, 69.5 mol) in dichloromethane (1.2 mL) was added trifluoroacetic acid (158 mg, 107 μL, 1.39 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained diluted with dichloromethane (1.2 mL), methanol (0.6 mL) and ammonium hydroxide (0.15 mL) and stirred at room temperature for 2 h. The mixture was concentrated and triturated with water. The solid was collected by filtration and washed with water and ether to give N-tert-butyl-2-(3-methylisothiazol-5-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (18 mg, 54.5 mol, 78.4%) as a brown solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.55 (s, 1H), 11.39 (s, 1H), 8.15 (d, J=3.2, 1 H), 8.11 (s, 1H), 7.37 (s, 1H), 6.70 (s, 1H), 2.33 (s, 3H), 1.55 (s, 9H); MS (EI/CI) m/z: 331.1 [M+H].
Reaction SMILES: [N:1]([CH2:4][CH3:5])=[C:2]=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][C:16]3[N:17]([C:19]([CH2:22][C:23]4[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=4)[NH2:26])=[CH:20][N:21]=3)[N:18]=2)=[CH:9][C:8]=1[F:30].C(N(CC)CC)C>C(#N)C>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][C:16]3[N:17]([C:19]([CH2:22][C:23]4[CH:24]=[C:25]([NH:26][C:2]([NH:1][CH2:4][CH3:5])=[O:3])[CH:27]=[CH:28][CH:29]=4)=[CH:20][N:21]=3)[N:18]=2)=[CH:9][C:8]=1[F:30]
Reactant: Nc1cccc(Cc2cnc3ncc(-c4ccc(Br)c(F)c4)nn23)c1
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCNC(=O)Nc1cccc(Cc2cnc3ncc(-c4ccc(Br)c(F)c4)nn23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
Isocyanatoethane (1.3 μL, 0.019 mmol) were added to a mixture of 3-[2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylaniline (5 mg, 0.01 mmol) and triethylamine (7.0 μL, 0.050 mmol) in acetonitrile (0.5 mL). After the reaction mixture was stirred at RT for 30 min, it was purified by RP-HPLC (pH 10) to afford the desired product (2 mg, 30%). LCMS: (M+H)=469.0/470.8.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][N:12]=[C:13]=[O:14].[CH2:15]([C:17]([CH3:19])=O)[CH3:16]>>[CH2:15]([C:17]1([CH3:19])[N:12]([CH3:11])[C:13](=[O:14])[N:6]2[C:2]([N:3]([C:13]([NH:12][CH3:11])=[O:14])[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=32)=[N:1]1)[CH3:16]
Reactant: CCC(C)=O
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CN=C=O
Product: CCC1(C)N=C2N(C(=O)NC)c3ccccc3N2C(=O)N1C

Procedure:
The title compound was prepared from 2-aminobenzimidazole, methyl ethyl ketone and methyl isocyanate employing the procedure of the first paragraph of Example 1. The product was purified by column chromatography, developing with chloroform/methanol (97%/2.4% by volume), giving a tan solid, mp 113°-119° C. (dec.). The confirmatory elemental analysis is shown in Table III.
Reaction SMILES: [N:1]1([C:7]([C@@H:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][N:10]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.C([O-])(O)=O.[Na+]>O1CCCC1>[N:1]1([CH2:7][C@@H:9]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][N:10]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C([C@@H]1Cc2ccccc2CN1C(=O)OCc1ccccc1)N1CCOCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1Cc2ccccc2C[C@H]1CN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 5.3 g of the product obtained in Step A (13.9 mmol) in 278 mL of tetrahydrofuran there are added 14 mL of BH3Me2S (27.8 mmol) at ambient temperature. The whole is heated for 4 hours at 80° C. It is allowed to return to ambient temperature, and then there are added 7 mL (14 mmol) of BH3Me2S. The reaction mixture is again heated at 80° C. for 2 hours. The tetrahydrofuran is subsequently evaporated off, and there are then added slowly methanol and then 5.6 mL of 5N hydrochloric acid (27.8 mmol). The mixture is stirred at ambient temperature overnight and then at 80° C. for one hour. There is subsequently added a saturated NaHCO3 solution to the reaction mixture at 0° C. until a pH of 8 is reached, and then extraction with ethyl acetate is carried out. The organic phase is subsequently dried over magnesium sulphate and then filtered and evaporated to dryness. The title product is obtained in the form of an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4]Br.C([O-])([O-])=O.[K+].[K+].[CH3:13][C:14]1[N:15]=[C:16]([N+:19]([O-:21])=[O:20])[NH:17][CH:18]=1>CC(C)=O>[CH3:13][C:14]1[N:15]=[C:16]([N+:19]([O-:21])=[O:20])[N:17]([CH2:4][CH:3]=[C:2]([CH3:6])[CH3:1])[CH:18]=1
Reactant: CC(C)=CCBr
Reactant: Cc1c[nH]c([N+](=O)[O-])n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)=CCn1cc(C)nc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3,3-Dimethylallyl bromide (14.08 g, 94.49 mmol) was added to a suspension of anhydrous K2CO3 (13.0 g, 94.20 mmol) and 4-methyl-2-nitroimidazole (10.0 g, 78.74 mmol, D. P. Davies et al, J Heterocyclic Chem., 1982, 19, 253-256) in dry acetone (100 mL). The reaction mixture was stirred at room temperature under nitrcgen atmosphere for 15 hours. The insoluble inorganic material was removed by filtration and the filtrate was evaporated to afford a brown paste which was loaded onto a silica gel column and eluted with hexane-ethyl acetate (8.5:1.5). The fractions containing the compound with Rf 0.51 (silica gel TLC, hexane-ethyl acetate, 7:3) were collected and evaporated to afford a solid which was recrystallized from ethyl acetate-hexane to provide 1-(4-methyl-2-nitro-1H-imidazol-1-yl)-3-methyl-2-butene as a light yellow crystalline solid in 60% (9.21 g) yield; mp. 53°-54° C.; 1H NMR (CDCl3) δ 1.80[s, 6H, C(CH3)2 ], 2.26(s, 3H, imi-CH3), 4.97(d, 2H, J=7.26 Hz, NCH2), 5.36 (t, 1H, J=7.26 Hz, CH2CH) and 6.90(s, 1H, imi-CH). 13C NMR (CDCl3) δ 13.80(imi-CH3), 18.16 & 25.70[C(CH3)2 ], 47.76(NCH2), 117.35(CH2CH), 122.77(imi-CH), 138.09[C(CH3)2 ], 139.97(imi-CCH3) and 143.53(CNO2). MS m/e 196 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.[O:26]1[CH2:31][CH2:30][CH2:29][O:28][CH:27]1[CH2:32][CH2:33][N:34]1[C:42]2[C:37](=[CH:38][C:39]([O:43][CH:44]([F:46])[F:45])=[CH:40][CH:41]=2)[C:36]([Sn](CCCC)(CCCC)CCCC)=[N:35]1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[O:28]1[CH2:29][CH2:30][CH2:31][O:26][CH:27]1[CH2:32][CH2:33][N:34]1[C:42]2[C:37](=[CH:38][C:39]([O:43][CH:44]([F:46])[F:45])=[CH:40][CH:41]=2)[C:36]([C:2]2[N:3]=[C:4]3[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]3=[N:6][CH:7]=2)=[N:35]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(CCC2OCCCO2)c2ccc(OC(F)F)cc12
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCC4OCCCO4)c4ccc(OC(F)F)cc34)nc12
Temperature: 90 °C
Reaction time: 4 h
Yield: 62.5 %

Procedure:
2-Bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (244 mg, 571 μmol) and 1-(2-(1,3-dioxan-2-yl)ethyl)-5-(difluoromethoxy)-3-(tributylstannyl)-1H-indazole (335 mg, 571 μmol) were dissolved in DMF (3.00 mL) under argon, tetrakis(triphenylphosphine)palladium (0) (33.0 mg, 28.6 μmol) and CuI (21.7 mg, 114 mmol, Eq: 0.20) were added and the mixture sonicated for 5 min with bubbling argon. The reaction mixture was stirred at 90° C. (oil bath temperature) for 4 h. The reaction mixture was concentrated under high vacuum and the residue (dark solid) was purified by chromatography (80 g column, 50 μm from Analogix, 0-50% EtOAc in hexanes over 30 min) to give 2-(1-(2-(1,3-dioxan-2-yl)ethyl)-5-(difluoromethoxy)-1H-indazol-3-yl)-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (230 mg, 357 μmol, 62.5%) as an off-white solid. MS (M+Na)+=667.1; 1H NMR (CDCl3) δ: 9.25 (s, 1H), 8.37 (s, 1H), 8.32 (d, J=2.0 Hz, 1H), 8.06 (s, 1H), 7.56 (dd, J=9.1, 0.5 Hz, 1H), 7.35 (dd, J=9.1, 2.3 Hz, 1H), 6.55 (t, J=74.3 Hz, 1H), 5.75 (s, 2H), 4.65 (t, J=6.9 Hz, 2H), 4.55 (t, J=4.9 Hz, 1H), 4.12-4.21 (m, 2H), 3.74 (td, J=12.3, 2.5 Hz, 2H), 3.56-3.65 (m, 2H), 2.34 (td, J=6.8, 5.3 Hz, 2H), 2.05-2.23 (m, 1H), 1.65 (s, 9H), 1.39 (dt, J=13.4, 1.3 Hz, 1H), 0.94-1.04 (m, 2H), −0.06-0.05 (m, 9H).
Reaction SMILES: [CH2:1]=[CH:2]C(NCCO)=O.O1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[O:15][CH2:16][CH2:17][OH:18]>C(O)COCCO>[CH2:10]([O:15][CH2:16][CH2:17][OH:18])[C:11]1[CH:2]=[CH:1][CH:14]=[CH:13][CH:12]=1
Reactant: OCCOC1CCCCO1
Reactant: C=CC(=O)NCCO
Solvent: OCCOCCO
Product: OCCOCc1ccccc1

Procedure:
A synthetic pathway to compounds of the invention is depicted in scheme 1. Protected HEAA derivatives 3 and 10 were prepared respectively starting from 2-(tetrahydro-2H-pyran-2-yloxy)ethanol 1 (commercially available or obtained from THP selective monoprotection of diethylene glycol) and commercially available 2-(benzyloxy)ethanol 8. Fully protected 3 was obtained by a two steps procedure including formation of acid 2 by reaction of alcohol 1 with bromoacetic acid, followed by DIC/DMAP promoted coupling with benzyl alcohol. Further removal of THP protecting group afforded alcohol 4 which was coupled with acid 2 to give dimer 5 with 82% yield. Final deprotection by acidic treatment led to the obtention of desired alcohol 6, first building block for key trimer compound 11 obtention. This conversion also led to the formation of small amounts of alcohol 7, thus reflecting the instability of this latter in these conditions (probable intramolecular transesterification of the dimer alcohol 6). Attempts to obtain pure dimer 6 by flash chromatography gave only poor yields and crude residue was finally used for next step without further purification.
Reaction SMILES: [CH:1]1([C:4]2[C:5]3[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=3[N:7]([CH2:11][CH3:12])[CH:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+].C(C1C=C(C(C)C)C=C(C(C)C)C=1S([N:41]=[N+:42]=[N-:43])(=O)=O)(C)C.C(O)(=O)C>C1COCC1>[N:41]([C:9]1[N:10]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]2[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=2[N:7]([CH2:11][CH3:12])[CH:8]=1)=[N+:42]=[N-:43]
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Reactant: CCN1C=CN=C(C2CC2)c2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCN1C=C(N=[N+]=[N-])N=C(C2CC2)c2ccccc21
Temperature: 30 °C
Reaction time: 0.17 h
Yield: 82.2 %

Procedure:
To a stirring solution of 5-cyclopropyl-1-ethyl-1H-benzo[e][1,4]diazepine (6.4 g, 0.028 mol) in THF (125 ml) cooled to −78° C. was added potassium tert-butoxide (2.05 eq, 0.057 mol, 57.2 ml of a 1 M solution in THF) dropwise over 15 min. A solution of 2,4,6-triisopropylphenyl-sulfonylazide (9.5 g, 0.031 mol) in THF (100 ml) was added over 5 min. The solution was stirred for 10 min, acetic acid (7.7 ml,0.123 mol) was added and the reaction warmed to 30° C. for 2 hour. The reaction was concentrated the residue dissolved in dichloromethane (200 mL) and washed with satd. NaHCO3 (200 ml). The aqueous layer was back extracted with dichloromethane (100 ml). The organic layers were combined, dried with Na2SO4 and evaporated to a foam. The foam was chromatographed over silica eluting with 30% ethyl acetate:hexane. The appropriate fractions were collected and evaporated under reduced pressure to give 5.83 g of a powder. MP=158-160° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][N:7]=1)=[O:5])C.[N+](C1C(C(O)=O)=NNC=1)([O-])=O.S(Cl)(Cl)=O.CO>CCO>[CH3:1][O:3][C:4]([C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][NH:8][N:7]=1)=[O:5]
Reactant: CCOC(=O)c1n[nH]cc1[N+](=O)[O-]
Agent: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Solvent: CCO
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1n[nH]cc1[N+](=O)[O-]

Procedure:
The compound was prepared in a manner analogous to 4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester (Example 16A) using 4-nitro-1H-pyrazole-3-carboxylic acid (100 g, 636 mmol), thionyl chloride (55.5 ml, 764 ml) and MeOH (750 ml), instead of EtOH. 4-Nitro-1H-pyrazole-3-carboxylic acid methyl ester was obtained as an off-white solid (109 g, 100%). (LC/MS (acidic method): Rt 1.82 min, [M+H]+ 172).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.Cl.[CH3:15][C:16]1[S:17][C:18]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20][C:19]=2[N:25]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:23][CH2:24][C:18]4[SH:17]=[C:16]([CH3:15])[NH:25][C:19]=4[CH2:20][CH2:21]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: Cc1nc2c(s1)CCNCC2
Agent: Cl
Product: CC1=[SH]C2=C(CCN(C(=O)c3cc4ncc(Br)cn4n3)CC2)N1

Procedure:
The title compound was prepared in accordance with the general method of example 1 from 6-bromo-pyrazolo[1,5-A]pyrimidine-2-carboxylic acid and 2-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine hydrochloride. The reaction mixture was purified by HPLC chromatography and lyophilized. Yield: 13 mg (16% of theory). ESI-MS: m/z=392 (M+H)+;
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]([OH:14])=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(O[N:23]1[N:31]=[N:30]C2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N-]=[N+]=[N-].[Na+].CCN(C(C)C)C(C)C>CN(C=O)C.C1COCC1>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]([N:30]=[N+:31]=[N-:23])=[O:14])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cc(-c2ccccc2)no1
Agent: F[P-](F)(F)(F)(F)F
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: [N-]=[N+]=NC(=O)c1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.7 %

Procedure:
To a solution of 3-phenylisoxazole-5-carboxylic acid (1.0 g, 5 mmol, 1.0 equiv.) in DMF (20 mL) and THF (20 mL), was added HBTU (2.28 g, 6 mmol, 1.2 equiv.), followed by sodium azide (0.65 g, 10 mmol, 2.0 equiv.) and DIEA (2.6 mL, 15 mmol, 3.0 equiv.). The mixture was stirred at RT for 30 min, concentrated, followed by adding of H2O (40 mL). The precipitate was filtered, washed with H2O, and dried in vacuo to give 3-phenylisoxazole-5-carbonyl azide (0.65 g, 60%). LRMS (M-18+H+) m/z 187.1.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:9]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[C:20]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=1)(=[O:27])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(Cl)Cl>CN(C=O)C.CO>[CH2:1]([C:5]1[N:6]([CH2:40][C:37]2[CH:38]=[CH:39][C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[S:25](=[O:27])(=[O:26])[NH:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[CH:35][CH:36]=2)[C:7](=[O:17])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCc1nn(-c2ccccc2Cl)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCc1nn(-c2ccccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
To a solution of 78 mg (0.310 mmole) of 5-n-butyl-2-(2-chlorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 5, Step A) in 620 μL of dry DMF was added 14.9 mg (0.372 mmole) of sodium hydride (60% in oil), and the mixture was stirred under N2 at 50° C. for 1 hour, until gas evolution was complete. The resulting solution was cooled to room temperature and treated dropwise with a solution of 178 mg (0.465 mmole) of [2'-(N-t-butylsulfamoyl)biphenyl-4-yl]methyl bromide (from Example 12, Step D) in DMF. The mixture was stirred at 50° C. for 1.5 hours, by which time TLC (98:2 CH2Cl2 --MeOH) indicated complete reaction. The mixture was quenched by addition of approximately 6 ml of H2O followed by extraction with 3×10 ml of EtOAc. The combined EtOAc extracts were washed with 2×15ml of H2O followed by 15 ml of brine. The organic phase was dried over Na2SO4, filtered, and concentrated. Column chromatography of the residue on silica gel (elution with 0.5% MeOH in CH2Cl2) yielded 130 mg (76%) of the title compound as a white, stiff foam, homogeneous by TLC in 98:2 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 553 (M+1)+.
Reaction SMILES: C=O.N[CH2:4][CH:5]([OH:37])[CH2:6][NH:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:25]=3)=[O:23])[CH:18]=[CH:17][C:16]=2[CH3:36])[CH:11]=[CH:10][N:9]=1.[C:38]([BH3-])#[N:39].[Na+].[CH2:42](O)C>C(O)(=O)C.O>[CH3:42][N:39]([CH3:38])[CH2:4][CH:5]([OH:37])[CH2:6][NH:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:20]=[C:19]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH:25]=3)=[O:23])[CH:18]=[CH:17][C:16]=2[CH3:36])[CH:11]=[CH:10][N:9]=1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1Nc1ccnc(NCC(O)CN)n1
Reactant: [BH3-]C#N
Reactant: CCO
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1Nc1ccnc(NCC(O)CN(C)C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Formaldehyde (40% solution in water, 0.2 ml) was added to a suspension of 2-(3-amino-2-hydroxypropylamino)-4-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)anilino]pyrimidine (0.1 g) and sodium cyanoborohydride (0.04 g) in a 3:1 mixture of ethanol and water (16 ml). Acetic acid (0.5 ml) was added to take the pH to approximately 4. The mixture was stirred at ambient temperature for 3 hours. The ethanol was evaporated and a saturated aqueous sodium bicarbonate solution was added to the residue to bring the pH to 8. The mixture was partitioned between methylene chloride and water. The organic phase was washed with brine, dried over sodium sulphate and evaporated to give the title compound as a solid (0.073 g); NMR Spectrum: (DMSOd6) 2.11 (s, 3H), 2.16 (s, 3H), 3.11 (m, 2H), 3.52 (m, 4H), 3.7 (m, 4H), 5.86 (m, 1H), 6.24 (m, 1H), 7.08 (m, 1H), 7.18 (m, 1H), 7.22 (m, 1H), 7.47 (m, 1H), 7.78 (m, 1H), 7.88 (m, 1H), 8.26 (m, 1H), 8.21 (s, 1H), 10.19 (s, 1H); Mass Spectrum: M+H+ 507.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([CH3:11])[CH:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]([N:22]2[CH2:23][CH2:24][N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:26][CH2:27]2)=[O:21])[N:8]=[C:9]([CH3:11])[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: CCOC(=O)c1cc(C)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 5-methyl-2H-pyrazole-3-carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 6.94–7.0 (m, 2H), 6.84–6.88 (dd, 2H), 6.58 (s, 1H), 5.04 (s, 2H), 4.3–4.38 (q, 2H), 3.62–3.80 (m, 4H), 3.02–3.14 (m, 4H), 2.3 (s, 3H), 1.32–1.38 (t, 3H). 13C NMR (400 MHz, CDCl3): 180, 165, 119, 116.2, 116, 109, 61.8, 52, 51.5, 50.8, 45.8, 42.6, 14.4, 10.2.
Reaction SMILES: [CH2:1]([S:9][C:10]1[CH:11]=[C:12]([C:15]([OH:17])=O)[NH:13][CH:14]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:18][C:19]1[CH:30]=[CH:29][C:22]([O:23][CH2:24][C:25]([CH3:28])([OH:27])[CH3:26])=[C:21]([O:31][CH3:32])[CH:20]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>ClC(Cl)C.CCOC(C)=O>[OH:27][C:25]([CH3:28])([CH3:26])[CH2:24][O:23][C:22]1[CH:29]=[CH:30][C:19]([NH:18][C:15]([C:12]2[NH:13][CH:14]=[C:10]([S:9][CH2:1][CH2:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:11]=2)=[O:17])=[CH:20][C:21]=1[O:31][CH3:32]
Reactant: O=C(O)c1cc(SCCc2ccccc2)c[nH]1
Reactant: COc1cc(N)ccc1OCC(C)(C)O
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: COc1cc(NC(=O)c2cc(SCCc3ccccc3)c[nH]2)ccc1OCC(C)(C)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.9 %

Procedure:
To a solution of 4-(phenethylthio)-1H-pyrrole-2-carboxylic acid (25.0 mg, 0.101 mmol) and 1-(4-amino-2-methoxyphenoxy)-2-methylpropan-2-ol (21.4 mg, 0.101 mmol) in dichloroethane (0.880 mL) was added EDC (38.8 mg, 0.202 mmol) and HOBT (30.9 mg, 0.202 mmol) and the reaction was allowed to stir at rt for 16 h. The reaction mixture was diluted with EtOAc (15 mL), washed with sat. NaHCO3 (3×20 mL), water, brine, dried over anhydrous Na2SO4, concentrated and purified by preparative HPLC: PHENOMENEX® Luna AXIA 5μ C18 21.2×100 mm, 15 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 5 min hold; 20 mL/min, UV detection at 220 nm, 10.739 min retention time to afford 21.3 mg of the title compound as brown solid: 1H NMR (500 MHz, CDCl3) δ 1.34 (s, 6 H), 2.85-2.97 (m, 4 H), 3.81 (s, 2 H), 3.85 (s, 3 H), 6.67 (br. s, 1 H), 6.88 (d, J=8.8 Hz, 1 H), 6.95 (dd, J=8.8, 2.2 Hz, 1 H), 7.02 (s, 1 H), 7.15-7.23 (m, 3 H), 7.24-7.32 (m, 2 H), 7.37 (s, 1 H), 7.55 (d, J=3.8 Hz, 1 H), 9.83 (br. s, 1 H); HPLC a) column: PHENOMENEX® Luna 5μ 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% H3PO4 to 90% MeOH/10% H2O/0.1% H3PO4; 1 min hold, 4 mL/min UV detection at 220 nm, 3.650 min retention time, (>98%); HPLC b) column: PHENOMENEX® Luna C18 4.6×50 mm, 4 min gradient, 10% MeOH/90% H2O/0.1% TFA to 90% MeOH/10% H2O/0.1% TFA, 1 min hold; 4 mL/min, UV detection at 220 nm, 3.660 min retention time; MS (ES) 441 [M+H]+.
Reaction SMILES: C([C:3]1[C:4]([Br:14])=[C:5]([CH:10]=[CH:11][C:12]=1[F:13])[O:6]C([O-])=O)C.FC1C=C(F)C([N+:23]([O-:25])=[O:24])=CC=1O>>[Br:14][C:4]1[C:3]([N+:23]([O-:25])=[O:24])=[C:12]([F:13])[CH:11]=[CH:10][C:5]=1[OH:6]
Reactant: CCc1c(F)ccc(OC(=O)[O-])c1Br
Reactant: O=[N+]([O-])c1cc(O)c(F)cc1F
Product: O=[N+]([O-])c1c(F)ccc(O)c1Br
Yield: 87.5 %

Procedure:
This compound was prepared from ethyl-2-bromo-4-fluorophenoxycarboxlate (4.0 g, 15.2 mmol) in the manner described for 2,4-difluoro-5-nitrophenol, affording 3.14 g (87.5%) of 2-bromo-4-fluoro-3-nitrophenol as a yellow solid. 1H-NMR (DMSO-d6) δ 11.19 (s, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.57 (d, J=5.1 Hz, 1H).