Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][OH:11])[CH2:4][CH2:3]1.[H-].[Na+].[Br:14][C:15]1[CH:16]=[C:17]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28](F)=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:18]=[CH:19][CH:20]=1>O1CCCC1>[Br:14][C:15]1[CH:16]=[C:17]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:11][CH2:10][CH2:9][CH2:8][CH:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: CN1CCC(CCCO)CC1
Reactant: O=[N+]([O-])c1cc2c(Nc3cccc(Br)c3)ncnc2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(CCCOc2cc3ncnc(Nc4cccc(Br)c4)c3cc2[N+](=O)[O-])CC1
Temperature: 65 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1.45 g of 3-(1-methylpiperidin-4-yl)propan-1-ol in 40 ml of tetrahydrofuran are added 360 mg of sodium hydride. The white suspension formed is stirred for 15 minutes at 65° C., cooled and mixed with 1.45 g of 4-[(3-bromophenyl)amino]-7-fluoro-6-nitroquinazoline, whereupon the mixture suddenly turns dark red. The reaction mixture is stirred first for 10 minutes at ambient temperature, then for 45 minutes at 65° C. As the reaction is not yet complete, a further 150 mg of sodium hydride are added and the mixture is stirred for a further 45 minutes at 65° C. The solvent is distilled off using a rotary evaporator and the brown residue is stirred with 50 ml of ice water. The aqueous phase is extracted with methylene chloride. The combined extracts are washed with water, dried over sodium sulfate and concentrated by evaporation. The crude product is purified by chromatography over a silica gel column with methylene chloride/methanol/concentrated ammonia solution (90:10:0.05). Yield: 1.30 g of (65% of theory); Rf value: 0.28 (silica gel, methylene chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1); mass spectrum (ESI+): m/z=500, 502 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>>[Br:20][C:21]1[CH:22]=[C:23]([CH2:24][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[CH:26]=[CH:27][CH:28]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cccc(Br)c4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-bromobenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-bromophenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [C:1]1([S:11]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][CH2:26]OS(C4C=CC(C)=CC=4)(=O)=O)[CH:21]=3)[NH:16][N:15]=2)(=[O:13])=[O:12])[C:10]2C(=CC=[CH:8][CH:9]=2)C=[CH:3][CH:2]=1.[CH2:38]([NH:40][CH2:41][CH3:42])[CH3:39].[CH2:43]1[CH2:47]O[CH2:45][CH2:44]1>>[CH2:38]([N:40]([CH2:41][CH3:42])[CH2:26][CH2:25][CH2:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[C:14]2[S:11]([C:1]1[C:10]2[C:9](=[CH:47][CH:43]=[CH:44][CH:45]=2)[CH:8]=[CH:3][CH:2]=1)(=[O:13])=[O:12])[CH3:39]
Reactant: Cc1ccc(S(=O)(=O)OCCCOc2ccc3[nH]nc(S(=O)(=O)c4cccc5ccccc45)c3c2)cc1
Reactant: CCNCC
Reactant: C1CCOC1
Product: CCN(CC)CCCOc1ccc2[nH]nc(S(=O)(=O)c3cccc4ccccc34)c2c1
Temperature: 25 °C

Procedure:
A solution of toluene-4-sulfonic acid 3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl ester (0.080 mg, 0.15 mmol) and diethylamine (0.45-0.75 mmol) in THF (10 mL) was stirred at 90° C. for about 2 hours in a sealed tube. After cooling to ambient temperature the reaction mixture was solvent evaporated. It was dissolved in ethyl acetate and washed twice with aqueous sodium bicarbonate. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was dissolved in methanol and chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacuo at 80° C. for 17 hours. Diethyl-{3-[3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-propyl}-amine hydrochloride was a tan foam (69.9 mg, 98.3%); Mass Spectrum (+EI, [M+H]+) m/z 438. 1HNMR (500 MHz, DMSO-d6): δ14.13-14.11 (br, 1H), 9.59-9.63 (br, 1H), 8.75 (d, 1H, J=8.42 Hz), 8.51 (dd, 1H, J=7.44 Hz and 1.10 Hz), 8.27 (d, 1H, J=8.29 Hz), 8.03-8.05 (m, 1H), 7.70-7.74 (m, 1H), 7.52-7.64 (m, 3H), 7.05-7.11 (m, 2H), 4.10 (t, 2H, J=5.98 Hz), 3.11-3.25 (m, 6H), 2.09-2.24 (m, 2H), 1.18 ppm (t, 6H, J=7.20 Hz).
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]/[C:11](=[CH2:15])[CH2:12][CH2:13][OH:14])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C(N(CC)CC)C.[S:23](Cl)([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24].CN(C1C=CC=CN=1)C>ClCCl>[CH2:6]([O:5][P:4](/[CH:9]=[CH:10]/[C:11](=[CH2:15])[CH2:12][CH2:13][O:14][S:23]([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: C=C(/C=C/P(=O)(OCC)OCC)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(/C=C/P(=O)(OCC)OCC)CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
A mixture of E-5-hydroxy-3-methylidene-1-pentenyl-phosphonic acid diethyl ester (1.07 g, 4.6 mmol), triethylamine (0.7 ml, 5 mmol), tosylchloride (0.96 g, 5 mmol) and dimethylaminopyridine (0.005 g, 0.04 mmol) in anhydrous and dichloromethane is stirred 4 hours at 20° C., concentrated in vacuo and the title product is obtained by flash chromatography on silica gel (1.55 g, 87%).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:20]([OH:21])[C@@H:19]([CH3:22])[C:17](=[O:18])[C:16]([CH3:24])([CH3:23])[C@@H:15]([OH:25])[CH2:14][C:12](=[O:13])[O:11][C@H:10](/[C:26](/[CH3:35])=[CH:27]/[C:28]2[N:32]=[C:31]([CH2:33]O)[S:30][CH:29]=2)[CH2:9][C@@H:7]2[O:8][C@:6]2([CH3:36])[CH2:5][CH2:4][CH2:3]1.C1(P([N:51]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.C([O-])(=O)C.[NH4+].CP(C)C.O1CCCC1>O1CCCC1.O>[NH2:51][CH2:33][C:31]1[S:30][CH:29]=[C:28]([CH:27]=[C:26]([CH:10]2[O:11][C:12](=[O:13])[CH2:14][CH:15]([OH:25])[C:16]([CH3:24])([CH3:23])[C:17](=[O:18])[CH:19]([CH3:22])[CH:20]([OH:21])[CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]3([CH3:36])[CH:7]([O:8]3)[CH2:9]2)[CH3:35])[N:32]=1
Reactant: C/C(=C\c1csc(CO)n1)[C@@H]1C[C@@H]2O[C@]2(C)CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: CP(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=Cc1csc(CN)n1)C1CC2OC2(C)CCCC(C)C(O)C(C)C(=O)C(C)(C)C(O)CC(=O)O1
Temperature: 32.5 °C
Reaction time: 5 h

Procedure:
To a suspension of epothilone F (5.0 g, 9.55 mmol, 86.2% potency) and diphenylphosphoryl azide (2.27 ml, 10.5 mmol, 1.1 eq) in tetrahydrofuran (40 ml) was added gradually 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.71 ml, 11.46 mmol, 1.2 eq) and the reaction subsequently stirred at 25-40° C. for 4-6 hrs. To the reaction mixture was then added a 6.0 M solution of ammonium acetate (7.96 ml, 47.7 mmol, 5 eq) followed by 1.0 M trimethylphosphine/tetrahydrofuran solution (1.5 eq). The reaction mixture was diluted with water and the aqueous phase extracted with three portions of ethyl acetate (40 ml each). The organic phase was then washed with three portions of diluted ammonium hydroxide (40 ml each). The combined aqueous washes are then extracted with two portions of ethyl acetate (40 ml each). The combined ethyl acetate phases are washed with two portions of water (20 ml each) then concentrated and azeotropically dried under reduced pressure to a final volume of 60 ml. The resulting solution was heated at 65-75° C. and 70 ml n-heptane was added slowly. The mixture was allowed to cool slowly and stirred at a final temperature of 15-20° C. The resulting solid (3.34 g, 78% corrected for input potency) was isolated by filtration followed by vacuum drying to afford crystalline product.
Reaction SMILES: [O:1]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=2)[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[O:1]([CH2:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH2:32])=[O:27])=[CH:24][CH:23]=2)[N:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(-c2noc([C@H]3CCCCN3C(=O)COc3ccccc3)n2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc(-c2noc([C@H]3CCCCN3C(=O)COc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
34 mg of (R)-4-{5-[1-(2-Phenoxy-acetyl)-piperidin-2-yl]-[1,2,4]oxadiazol-3-yl}-benzoic acid were treated with 1 eq HATU/DIPEA in DMF and added to 1 eq of Rink-Resin. The reaction was shaken overnight at room temperature. The resin was washed with DMF, MeOH, DCM (3 times each) and then treated with TFA/DCM (1:1) for 2 h. The resulting yellow oil was purified via preparative HPLC.
Reaction SMILES: Br[CH2:2][C:3]([CH:5]1[CH2:7][CH2:6]1)=O.[NH2:8][C:9]([NH2:11])=[S:10]>CO>[CH:5]1([C:3]2[N:8]=[C:9]([NH2:11])[S:10][CH:2]=2)[CH2:7][CH2:6]1
Reactant: O=C(CBr)C1CC1
Reactant: NC(N)=S
Solvent: CO
Product: Nc1nc(C2CC2)cs1

Procedure:
A solution of 2-Bromo-1-cyclopropyl-ethanone (CAS [69267-75-0], Indian J. Chem. Sect. B, 22(9), 841(1983) (1 g, 6.1 mmol) and thiourea (0.481 g, 6.1 mmol) in 15 ml of methanol was refluxed overnight. The solvent was evaporated off and the title compound was obtained as an off-white solid (1.38 g, 100%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15]C(C3C4N=CC=NC=4C(C4C(Cl)=C(OC)C=C(OC)C=4Cl)=CC=3)=O)=[N:13][CH:14]=2)[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:62][C:63]1[C:64]([C:68]2[C:77]3[N:76]=[CH:75][CH:74]=[N:73][C:72]=3[C:71]([C:78]([OH:80])=O)=[CH:70][CH:69]=2)=[CH:65][S:66][CH:67]=1.CC1C(B(O)O)=CSC=1>C(Cl)Cl.CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:78]([C:71]3[C:72]4[N:73]=[CH:74][CH:75]=[N:76][C:77]=4[C:68]([C:64]4[C:63]([CH3:62])=[CH:67][S:66][CH:65]=4)=[CH:69][CH:70]=3)=[O:80])=[N:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1cscc1-c1ccc(C(=O)O)c2nccnc12
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1cscc1B(O)O
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cc1cscc1-c1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)cn2)c2nccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture at rt overnight, using 2 equiv of 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine hydrochloride (Example 31), TBTU (2 equiv) and 8-(4-methyl-thiophen-3-yl)-quinoxaline-5-carboxylic acid. The carboxylic acid was synthesized as described in Steps 1.2-1.7 but using 4-methyl-3-thiopheneboronic acid in Step 1.4. Title compound: ESI-MS: 459.1 [M+H]+; tR=3.41 min (System 1); TLC: Rf=0.25 (DCM/MeOH, 9:1).
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:52][C:53]1[S:54][CH:55]=[C:56]([C:58]2[CH:66]=[CH:65][C:61]([C:62]([OH:64])=[O:63])=[CH:60][CH:59]=2)[N:57]=1>CN(C=O)C>[CH2:12]([O:11][C:9]([N:1]1[CH2:8][CH2:7][CH2:6][CH:2]1[C:3](=[O:5])[NH:52][C:53]1[S:54][CH:55]=[C:56]([C:58]2[CH:59]=[CH:60][C:61]([C:62]([OH:64])=[O:63])=[CH:65][CH:66]=2)[N:57]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: Nc1nc(-c2ccc(C(=O)O)cc2)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1ccc(-c2csc(NC(=O)C3CCCN3C(=O)OCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Z-ProOH (0.56 g, 2.2 mmol) and HATU (2.2 mmol, 0.83 g) were combined in 35 mL of DMF. To this solution was added DIEA (2.4 mmol, 0.42 mL). This solution was stirred at room temperature for 1 hr. 4-(2-Amino-thiazol-4-yl)-benzoic acid (2.2 mmol, 0.5 g) was then added to the solution. The reaction mixture was stirred at 70° C. overnight. It was brought to room temperature and then evaporated to dryness. The crude was purified using reverse phase HPLC. MS: 452.1 (M+H+)
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH:11]([C@@H:14]1[N:19]([C:20]([O:22][CH2:23][CH:24]=[CH2:25])=[O:21])[CH2:18][CH2:17][C:16]([C:26]2[N:27]=[C:28]([SH:31])[S:29][CH:30]=2)=[CH:15]1)([CH3:13])[CH3:12].O(P(OC1C=CC=CC=1)O[C:41]1[C@H:47]([CH3:48])[C@H:46]2[N:43]([C:44](=[O:56])[C@@H:45]2[C@H:49]([O:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[CH3:50])[C:42]=1[C:57]([O:59][CH2:60][CH:61]=[CH2:62])=[O:58])C1C=CC=CC=1.C(#N)C>C1COCC1>[CH2:23]([O:22][C:20]([N:19]1[C@@H:14]([CH:11]([CH3:13])[CH3:12])[CH:15]=[C:16]([C:26]2[N:27]=[C:28]([S:31][C:41]3[C@H:47]([CH3:48])[C@H:46]4[N:43]([C:44](=[O:56])[C@@H:45]4[C@H:49]([O:51][Si:52]([CH3:53])([CH3:54])[CH3:55])[CH3:50])[C:42]=3[C:57]([O:59][CH2:60][CH:61]=[CH2:62])=[O:58])[S:29][CH:30]=2)[CH2:17][CH2:18]1)=[O:21])[CH:24]=[CH2:25]
Reactant: C=CCOC(=O)C1=C(OP(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Reactant: C=CCOC(=O)N1CCC(c2csc(S)n2)=C[C@@H]1C(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(Sc2nc(C3=C[C@H](C(C)C)N(C(=O)OCC=C)CC3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
A solution of lithium hexamethyldisilazide in THF (1M, 0.62 ml, 0.62 mmol) was added at 0–5° C. to a solution of allyl (6S)-6-isopropyl-4-(2-mercapto-1,3-thiazol-4-yl)-3,6-dihydro-1(2 H)-pyridinecarboxylate (202 mg, 0.62 mmol) in THF (11.0 ml) and the mixture was stirred for 15 minutes. To the reaction solution was added at 0° C. a solution of allyl (4R,5R,6S)-3-[(diphenoxyphosphino)oxy]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in acetonitrile (30%, 2.37 g, 1.2 mmol) and the solution was allowed to stand in a refrigerator for 16 hours. To the reaction solution was added ice water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was purified with silica gel chromatography (hexane/ethyl acetate: 1/5→1/3) to give allyl (4R,5S,6S)-3-[(4-{(6S)-1-[(allyloxy)carbonyl]-6-isopropyl-1,2,3,6-tetrahydro-4-pyridinyl}-1,3-thiazol-2-yl)sulfanyl]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.24 g, 61%).
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.Cl.Cl.[F:28][C:29]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:30]=1[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:28][C:29]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:30]=1[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:6][CH2:7][N:8]2[C:16]3[N:15]=[C:14]([NH2:17])[N:13]4[N:18]=[C:19]([C:21]5[O:22][CH:23]=[CH:24][CH:25]=5)[N:20]=[C:12]4[C:11]=3[CH:10]=[CH:9]2)[CH2:35][CH2:34]1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Reactant: Fc1ccc(CCN2CCNCC2)c(F)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2c(ccn2CCN2CCN(CCc3ccc(F)cc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title A compound, 1-(2,4-difluorophenethyl)piperazine dihydrochloride (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give 7-(2-(4-(2,4-difluorophenethyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=493.2). 1H NMR (CDCl3, 400 MHz) δ 2.55 (m, 10H), 2.78 (t, 4H, J=6.8 Hz), 4.28 (t, 2H, J=6.8 Hz), 5.67 (s, 2H), 6.58 (d, 1H, J=3.6 Hz), 6.73-6.80 (m, 3H), 6.97 (m, 1H), 7.15 (m, 1H), 7.24 (m, 1H), 7.61 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=2[C:16]2[C:17]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([CH3:33])=[C:22]([C:34]([OH:36])=O)[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:3][CH2:2]1.[NH2:37][CH:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:13])[F:14])=[CH:8][C:7]=2[C:16]2[C:17]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:30])[CH3:31])[C:23]([CH3:33])=[C:22]([C:34]([NH:37][CH:38]4[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43]4)=[O:36])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(C(F)(F)F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Product: Cc1c(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c2ncnc(-c3cc(C(F)(F)F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c8) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as colorless foam.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[I:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=1O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH2:8][O:9][C:16]2[CH:15]=[C:14]([Cl:17])[CH:13]=[CH:12][C:11]=2[I:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cc(Cl)ccc1I
Reactant: OCc1ncccc1Br
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: Clc1ccc(I)c(OCc2ncccc2Br)c1
Temperature: 0 °C
Yield: 49.3 %

Procedure:
(3-Bromo-pyridin-2-yl)-methanol (3.4 g, 18 mmol), and 2-iodo-5-chlorophenol 4.5 g, 18 mmol), are dissolved in benzene (60 mL) and cooled to 0° C. To the solution is added tributylphosphine (15 mL, 90 mmol), and 1,1′-(azodicarbonyl) dipiperidine (ADDP) (6.6 g, 18 mmol) and the mixture is heated at 40° C. for 3 h. The reaction mixture is diluted with ethyl acetate, washed with saturated aqueous NH4Cl and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (Biotage® Si65M, 15% ethyl acetate/hexane) to yield 3.77 g (51%) of the title compound as a white solid. GCMS m/e 296, 298 [M-I]−.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:18][CH:19]([C:25](=[O:36])[NH:26][C@H:27]([C:32](=[O:35])[NH:33][CH3:34])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:20][C:21](C)([CH3:23])[CH3:22])([CH2:6][N:7]1C(=O)C2=CC=CC=C2C1=O)=[O:5])[CH3:2].[OH2:37].NN>C(O)C>[C:32]([OH:35])(=[O:37])[CH3:27].[CH2:1]([O:3][P:4]([CH2:6][NH2:7])([CH2:18][CH:19]([C:25](=[O:36])[NH:26][C@H:27]([C:32](=[O:35])[NH:33][CH3:34])[CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:5])[CH3:2]
Reactant: CCOP(=O)(CC(CC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC)CN1C(=O)c2ccccc2C1=O
Reactant: O
Agent: NN
Solvent: CCO
Product: CC(=O)O
Product: CCOP(=O)(CN)CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC

Procedure:
3.2 g of [(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]-4-methylpentyl](phthalimidomethyl)phosphinic acid ethyl ester were treated in a manner analogous to that described in Example 2(A)(i), with the exception that a 0.33 M solution of hydrazine hydrate in ethanol was used, to give 2.06 g of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester acetate in the form of a white foam.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.CO.O1CCOC[CH2:25]1>>[CH3:25][O:20][C:19](=[O:21])[CH2:18][C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:17][CH:16]=1
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: C1COCCO1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CO
Product: COC(=O)Cc1ccc(Nc2ccncc2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A mixture of 0.500 g of 4-chloro-3-nitro-pyridine (LANCASTER) and 0.467 g of (4-amino-phenyl)-acetic acid (Aldrich) in 10 ml of MeOH/dioxane (1/1 v/v) is stirred and refluxed for 6 hours. The mixture obtained is allowed to cool to rt and is concentrated in vacuo. Crude [4-(3-nitro-pyridin-4-ylamino)-phenyl]-acetic acid methyl ester is obtained.
Reaction SMILES: BrBr.[NH2:3][C:4]([NH2:6])=[S:5].CC[N:9](C(C)C)[CH:10]([CH3:12])[CH3:11].CCOC(C)=O.[CH2:22]1[CH2:26][O:25][CH2:24][CH2:23]1>O>[NH2:3][C:4]1[S:5][C:23]2[C:24](=[O:25])[NH:9][C:10]([CH3:12])([CH3:11])[CH2:26][C:22]=2[N:6]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: C1CCOC1
Reactant: NC(N)=S
Agent: BrBr
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)Cc2nc(N)sc2C(=O)N1
Temperature: 25 °C
Yield: 53 %

Procedure:
To a stirred suspension of Intermediate 3 (0.50 g, 3.55 mmol) in THF (10 mL) was added Br2 (0.59 g, 0.19 mL, 3.72 mmol) dropwise at 0° C. The reaction mixture was then allowed to warm to r.t. and thiourea (0.27 g, 3.55 mmol), DIPEA (1.37 g, 1.85 mL, 10.65 mmol) and THF (5 mL) were added. The reaction mixture was heated to 85° C. for 1 h, cooled to r.t., and then EtOAc (10 mL) and water (10 mL) were added. The aqueous layer was extracted with EtOAc (2×15 mL) and the combined organic layers were washed with aqueous sat. NaHCO3 solution (15 mL) and brine (3×15 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (0.37 g, 53%) as a yellow solid that was used without further purification. δH (DMSO-d6) 7.63 (2H, s), 7.17 (1H, s), 2.62 (2H, s), 1.23 (6H, s). LCMS (ES+) 198.0 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[C:9]([O:13][C:14](=[O:36])[CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][C:23]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:24][C:19]=2[N:18]=[C:17]1[CH2:33][CH2:34][CH3:35])([CH3:12])([CH3:11])[CH3:10].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:9]([O:13][C:14](=[O:36])[CH2:15][N:16]1[C:20]2[CH:21]=[CH:22][C:23]([N:25]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])=[CH:24][C:19]=2[N:18]=[C:17]1[CH2:33][CH2:34][CH3:35])([CH3:12])([CH3:11])[CH3:10]
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1cccs1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3cccs3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Thiophene-2-carbonyl chloride (38 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C28H31N3O3S+H: 490, observed: 490.