Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]=[C:11]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[CH2:12][NH:13][C:14](=[O:28])[C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:57][C:58]1[CH:62]=[CH:61][S:60][C:59]=1[C:63](O)=[O:64]>CN(C=O)C.O>[CH3:57][C:58]1[CH:62]=[CH:61][S:60][C:59]=1[C:63]([N:32]1[CH2:31][CH2:30][N:29]([C:11](=[O:10])[CH2:12][NH:13][C:14](=[O:28])[C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:19][CH:20]=2)[CH2:34][CH2:33]1)=[O:64]
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Reactant: Cc1ccsc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccsc1C(=O)N1CCN(C(=O)CNC(=O)c2ccc(Oc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 74.8 %

Procedure:
DIPEA (85.5 mg, 0.114 mL, 0.66 mmol) was added to a stirred solution of N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide (60 mg, 0.176 mmol) in DMF (3 mL). HOBT (21.89 mg, 0.16 mmol) and EDCI.HCl (70.5 mg, 0.36 mmol) were then added at room temperature. After 2 minutes, 3-methyl-thiophene-2-carboxylic acid (20.9 mg, 0.15 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then diluted with cold water, and the resulting precipitate was filtered, washed with water then hexane and dried to afford 52 mg (76.5% yield) of N-{2-[4-(3-methyl-thiophene-2-carbonyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenoxy-benzamide as a pale brown solid. LCMS Purity: 98.86%, HPLC Purity: 98.50%. 1H NMR (CDCl3): δ 7.8 (d, 2H), 7.4 (m, 2H), 7.3 (d, 1H), 7.2 (s, 1H), 7.1 (t, 1H), 7.0 (m, 4H), 6.85 (d, 1H), 4.3 (dd, 2H), 3.7 (m, 6H), 3.5 (t, 2H), 2.2 (s, 3H).
Reaction SMILES: [C:1]12([C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:16][C:15]=3F)=[N:12][OH:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.N#N.[H-].[Na+].O>CN(C=O)C>[C:1]12([C:11]3[C:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:16][C:15]=4[O:13][N:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: ON=C(c1ccc(OCc2ccccc2)cc1F)C12CC3CC(CC(C3)C1)C2
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc3c(C45CC6CC(CC(C6)C4)C5)noc3c2)cc1
Temperature: 25 °C
Yield: 94550.1 %

Procedure:
1-adamantyl-(4-benzyloxy-2-fluorophenyl)methanone oxime (2.3 mg, 6 mM) in DMF (30 ml) was added at 0° C. dropwise under N2, to a stirred suspension of NaH (0.61 g, 18 mM, 60% oil dispersion) in DMF (10 ml). After the complete addition, the reaction mixture was allowed to warm to room temperature and poured into H2O. The precipitate was collected by filtration to give the expected product (2.06 g, 95%). mp 132° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH:46]=O)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][C@@H:51]1[CH2:56][NH:55][CH2:54][CH2:53][N:52]1C(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([CH2:46][N:55]6[CH2:54][CH2:53][NH:52][C@H:51]([CH3:50])[CH2:56]6)[CH:41]=5)[C:36]([F:39])=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(C=O)c3)c2)c1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN[C@H](C)C4)c3)c2)c1
Reaction time: 1.5 h

Procedure:
A mixture of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(6-fluoro-3′-formyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.000152 mol) in 1,2-dichloroethane (4 mL) with 1,1-dimethylethyl (2R)-2-methyl-1-piperazinecarboxylate (48 mg, 0.00024 mol) and sodium triacetoxyborohydride (68 mg, 0.00032 mol) and AcOH (12 μL) was placed on an oscillating shaker overnight at room temperature. The reaction was quenched with sat. aq. NaHCO3, then extracted with 1,2-dichloroethane (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. The crude product was taken up in 1,2-dichloroethane (10 mL) containing 25% TFA and allowed to stand at room temperature for 1.5 h. LC-MS showed the reaction to be complete and the solution stripped to dryness. Purification was carried out on Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP Column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of 1,2-dichloroethane and transferred to a vial and pumped down to afford the title compound as an ivory colored solid [62.1 mg (53%)]. LC-MS m/z 747.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=4)[CH:17]3[C:27]([O:29][CH3:30])=[O:28])(=[O:15])=[O:14])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[N:33]1([CH2:38][CH2:39]O)[CH:37]=[CH:36][N:35]=[CH:34]1.FC1C=CC(OC2C=CC(S(N3CCC4C(=CC=C(OCCCN5CCN(C)CC5)C=4)C3C(OC)=O)(=O)=O)=CC=2)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([S:13]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[C:21]([O:26][CH2:39][CH2:38][N:33]5[CH:37]=[CH:36][N:35]=[CH:34]5)[CH:22]=4)[CH:17]3[C:27]([O:29][CH3:30])=[O:28])(=[O:14])=[O:15])=[CH:11][CH:12]=2)=[CH:31][CH:32]=1
Reactant: OCCn1ccnc1
Reactant: COC(=O)C1c2ccc(O)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Agent: COC(=O)C1c2ccc(OCCCN3CCN(C)CC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Product: COC(=O)C1c2ccc(OCCn3ccnc3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1

Procedure:
Methyl 2-[4-(4-fluorophenoxy)benzenesulfonyl]-6-hydroxy-1,2,3,4-tetrahydro-isoquinoline-1-carboxylate (3B) is reacted with 2-imidazol-1-ylethanol by the method described under 3C.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH3:25]N(C)C=O.CI>O>[CH3:25][N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[C:18](=[O:22])[O:19][CH2:20][CH3:21]
Reactant: CCOC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCOC(=O)N(C)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
A mixture of 1.5 g of [3-(3-methyl-1,2,4-triazolo[4,3-b]-pyridazin-6-yl)phenyl]carbamic acid, ethyl ester, 0.29 g of sodium hydride (50% in oil) and 150 ml of dimethylformamide was stirred under argon for 1 hour and then 0.38 ml methyl iodide was added. This mixture was stirred overnight then poured onto 500 ml of water and extracted with 150 ml portions of dichloromethane. The extracts were combined, dried and concentrated in vacuo. The residue was chromatographed on 300 g of silica gel with dichloromethane-methanol (97:3). The fractions containing product were combined, the solvent evaporated in vacuo and the solid recrystalized from dichloromethane-hexane, to give 1.25 g of an off-white powder, mp 146°-149° C.
Reaction SMILES: CC1(C)[O:6][CH:5]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[N:8]=2)[CH2:4][O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CN=C1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>CO.CN(C)C=O>[NH2:13][C:9]1[N:8]=[C:7]([CH:5]([OH:6])[CH2:4][O:3][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC1(C)OCC(c2ccnc(N)n2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1c[nH]cn1
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC(O)c1ccnc(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.6 %

Procedure:
To a solution of 4-(2,2-dimethyl-1,3-dioxolan-4-yl)pyrimidin-2-amine (2f) (7.18 g) in methanol (300 mL) was added p-toluenesulfonic acid monohydrate (10.49 g) and the solution was stirred at room temperature overnight. The mixture was filtered through sodium carbonate and concentrated under vacuum to give a brown solid that was dissolved in N,N-dimethylformamide (400 mL) to which was added imidazole (5.2 g) and tert-butyldimethylsilyl chloride (7.7 g) and the solution was stirred at room temperature overnight. The mixture was concentrated on silica under vacuum and purified by silica flash chromatography eluting with 50% to 75% ethyl acetate in heptane to give the title compound (850 mg).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([CH2:8][CH2:9][CH2:10][CH2:11][B:12]([OH:14])[OH:13])[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[Cl:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>CN(C=O)C.O>[ClH:28].[NH2:3][C:4]([CH:15]1[CH2:16][CH2:17][N:18]([C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=2)[CH2:19][CH2:20]1)([CH2:8][CH2:9][CH2:10][CH2:11][B:12]([OH:14])[OH:13])[C:5]([OH:7])=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NC(CCCCB(O)O)(C(=O)O)C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: NC(CCCCB(O)O)(C(=O)O)C1CCN(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
To a stirring solution of crude 2-amino-6-borono-2-(piperidin-4-yl)hexanoic acid dihydrochloride (150 mg, 0.371 mmol) in dry DMF (7.4 mL) under nitrogen was added triethylamine (0.31 mL, 2.23 mmol) to give a white slurry. 4-Chlorobenzoyl chloride (0.106 mL, 0.835 mmol) was added dropwise to the slurry, and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (15 mL) and extracted with ethyl acetate (2×20 mL), and the organic phase was back-extracted with 1 N HCl (15 mL). The organic layer was discarded, and all aqueous layers were combined and washed with ethyl acetate (2×15 mL). The aqueous layer was concentrated under reduced pressure to give the crude product which was purified by reverse phase HPLC [Phenomenex Luna 250×30.00 mm, 10 micron column. 40 mL/min flow rate. Gradient: solvent A is 0.07% TFA in acetonitrile; solvent B is 0.10% TFA in water; 5% to 50% A over 24 min, then 50% to 100% A over 1 min]. Product fractions were pooled and concentrated, and the residue was taken up in 0.5N HCl (3 mL)/acetonitrile (6 mL) and concentrated. The residue was once again treated with 0.5N HCl (3 mL)/acetonitrile (6 mL) and concentrated and dried under high vacuum overnight to give 2-amino-6-borono-2-[1-(4-chlorobenzoyl)piperidin-4-yl]hexanoic acid hydrochloride (75 mg, 47%) as a faint yellow solid. 1H NMR (MeOH-d6, 400 MHz) δ 7.51 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 4.77 (m, 1H), 3.82 (m, 1H), 3.19 (m, 1H), 2.85 (m, 1H), 2.25 (m, 1H), 2.10-1.40 (m, 8H), 1.28 (m, 2H), 0.85 (bt, J=7.2 Hz, 2H). ESI+ MS found for C18H26BClN2O5 m/z 379.3 (M−18+H); ESI+ MS m/z 395.4 (M−H), 377.4 (M−18−H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([NH2:28])[CH3:27].O>C(O)C>[CH2:26]([NH:28][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])[CH3:27]
Reactant: CCN
Reactant: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCNc1ccc(-c2nc3ccccc3o2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 94.3 %

Procedure:
To a suspension of 2-(4-fluoro-3-nitrophenyl)benzoxazole (see Working Example 15-2) (300 mg, 1.16 mmol) in ethanol (5 mL) was added potassium carbonate (321 mg, 2.32 mmol) and aqueous ethylamine solution (ca. 70%, 149 mg, 2.32 mmol), and this was heated to reflux for 4 hours. After the reaction was complete, this was cooled to room temperature, water was added, and after the precipitated crystals were filtered and washed with water, they were dried to yield the title compound (310 mg, 94.3% yield).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:39])[CH2:41][OH:42])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f22) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: N1(CCOC2C=CC(NC3SC(C4C=CC(O)=CC=4)=CN=3)=CC=2)CCCC1.C[O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]2[S:38][C:39]([C:42]3[CH:46]=[CH:45][S:44][CH:43]=3)=[CH:40][N:41]=2)=[C:32]([CH3:47])[CH:31]=1.B(Br)(Br)Br>C(Cl)Cl.CO>[CH3:47][C:32]1[CH:31]=[C:30]([OH:29])[CH:35]=[CH:34][C:33]=1[NH:36][C:37]1[S:38][C:39]([C:42]2[CH:46]=[CH:45][S:44][CH:43]=2)=[CH:40][N:41]=1
Reactant: COc1ccc(Nc2ncc(-c3ccsc3)s2)c(C)c1
Agent: BrB(Br)Br
Agent: Oc1ccc(-c2cnc(Nc3ccc(OCCN4CCCC4)cc3)s2)cc1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(O)ccc1Nc1ncc(-c2ccsc2)s1

Procedure:
The title compound is prepared as described in Example 7 for 4-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-thiazol-5-yl}-phenol but starting from (4-methoxy-2-methyl-phenyl)-(5-thiophen-3-yl-thiazol-2-yl)-amine and using 4 equivalents of BBr3. Title compound: ES-MS: 289.0 [M+H]+; single peak at tR=3.33 min (System 2); Rf=0.15 (CH2Cl2/MeOH, 95/5).
Reaction SMILES: [Cl:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[NH:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].CCN(C(C)C)C(C)C>C(O)(C)C>[Cl:1][CH:2]1[CH2:7][CH2:6][N:5]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[CH2:4][CH:3]1[NH:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]
Reactant: CCOP(=O)(NC1CNCCC1Cl)OCC
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOP(=O)(NC1CN(c2ccncc2[N+](=O)[O-])CCC1Cl)OCC
Temperature: 70 °C
Yield: 69 %

Procedure:
To a solution of diethyl 4-chloropiperidin-3-ylphosphoramidate (1.0 equiv.) in isopropyl alcohol (0.1M) was added 4-chloro-3-nitropyridine (2.0 equiv.) and DIEA (1.1 equiv.). The reaction was heated to 70° C. for 18 h, then quenched with water and extracted with ethyl acetate. The organics were dried and concentrated under vacuo. The crude was purified via ISCO (ethyl acetate and hexanes then 10% methanol in DCM) to yield diethyl 4-chloro-1-(3-nitropyridin-4-yl)piperidin-3-ylphosphoramidate in 69% yield. LCMS (m/z): 393.1 (MH+), Rt=2.01 min.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.P(Cl)(Cl)(Cl)=O.C(N(CC)CC)C.[CH:18]1([C:24]2[N:32]3[C:27](C(=O)NC=N3)=[C:26]([I:34])[N:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(#N)C>[CH:18]1([C:24]2[N:32]3[C:27]([C:5]([NH2:1])=[N:4][CH:3]=[N:2]3)=[C:26]([I:34])[N:25]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: c1nc[nH]n1
Reactant: O=c1[nH]cnn2c(C3CCCCC3)nc(I)c12
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: Nc1ncnn2c(C3CCCCC3)nc(I)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1H-1,2,4-triazole (1 g, 0.02 mol) in acetonitrile (23 mL) was added dropwise phosphoryl chloride (0.6 mL, 0.007 mol) and triethylamine (3 mL, 0.02 mol) at 0° C. To this mixture was added 7-cyclohexyl-5-iodoimidazo[5,1-f][1,2,4]triazin-4(3H)-one (77 mg, 0.224 mmol) and the resulting mixture refluxed overnight. The cooled mixture was then quenched with excess NH3 in iPrOH (pH 8) stirred at rt for 30 min. then filtered and the isolated solid washed with DCM. The filtrate was concentrated in vacuo and purified by chromatography over silica gel eluting with 2% MeOH in DCM to afford the 7-cyclohexyl-5-iodoimidazo[5,1-f][1,2,4]triazin-4-amine. 1H NMR (400 MHz—DMSO-d6) δ 1.14-1.91 (m, 10H), 3.11-3.18 (m, 1H), 6.75 (br.s, 1H), 7.84 (s, 1H) 8.42 (bs, 1H); MS (ES+): m/z: 344.01 (100) [MH+]. HPLC: tR=3.10 min (OpenLynx: polar—5 min).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][CH:14]=2)[N:10]=1.[CH2:35](P(=O)(OCC)OCC)[P:36](=[O:43])([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39].CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:35]/[P:36](=[O:43])([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:32][CH:33]=2)[N:10]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1)OCC
Reaction time: 15 h
Yield: 64.7 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.37 g), tetraethyl methylenediphosphonate (0.26 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.04 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.31 g, yield 65%) from a fraction eluted with ethyl acetate-hexane (3:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 131-132° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][C:16]1[N:24]=[C:23]2[C:19]([NH:20][CH:21]=[N:22]2)=[C:18]([NH2:25])[N:17]=1>CN(C=O)C.O>[CH2:7]([N:22]1[CH:21]=[N:20][C:19]2[C:23]1=[N:24][C:16]([CH3:15])=[N:17][C:18]=2[NH2:25])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1nc(N)c2[nH]cnc2n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(N)c2ncn(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
K2CO3 (0.26 g, 1.88 mmol) and benzyl bromide (0.5 ml, ca. 2 mmol) were added to a solution of 70 mg (0.47 mmol) of 2-methyladenine in a mixture of DMF (15 ml) and water (5 ml), and stirred at room temperature for 16 h. The solvent was evaporated under vacuum, and the residue was extracted by chloroform. The resulting organic layer was dried over MgSO4, and evaporated under vacuum. 9-Benzyl-2-methyladenine was obtained by the purification of the residue using column chromatography (CH2Cl2 :MeOH=50:1-30:1).
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH2:10]([O-:12])[CH3:11].[Na+].Cl[CH2:15][CH2:16][N:17](CC)[CH2:18][CH3:19]>C(O)C>[CH2:16]([N:17]([CH2:11][CH2:10][O:12][C:7]1[CH:8]=[CH:9][CH:2]=[CH:3][C:4]=1[CH:5]=[O:6])[CH2:18][CH3:19])[CH3:15]
Reactant: CC[O-]
Reactant: O=Cc1cccc(O)c1
Reactant: CCN(CC)CCCl
Agent: [Na+]
Solvent: CCO
Product: CCN(CC)CCOc1ccccc1C=O
Reaction time: 0.25 h
Yield: 68.7 %

Procedure:
6.1 g (50 mmol) of 3-hydroxybenzaldehyde were dissolved in 100 ml of ethanol and 3.5 g (50 mmol) of sodium ethanolate were added. The mixture was stirred for 15 minutes. Then 7.5 g (55 mmol) of N-(2-chloroethyl)-N,N-diethylamine were added, and the mixture was refluxed for 12 hours. The reaction mixture was then concentrated in vacuo. The residue was then partitioned between ether and 1M sodium hydroxide solution, and the ether phase was separated off, dried and concentrated in vacuo. 7.6 g of the intermediate were obtained.
Reaction SMILES: [OH2:1].[Se](=O)=O.[CH3:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:14]=2)[N:9]=[CH:8][CH:7]=1>O1CCOCC1>[C:16]1([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][CH:7]=[C:6]3[CH:5]=[O:1])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccnc2ccc(-c3ccccc3)cc12
Reactant: O
Agent: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1ccnc2ccc(-c3ccccc3)cc12
Reaction time: 1 h

Procedure:
1.4 ml of water and 17 g of selenium dioxide are added to 8.5 g (38.8 mmol) of 4-methyl-6-phenyl-quinoline in 85 ml of dioxane and the mixture is boiled for 1 hour. The selenium is filtered off with suction and washed with methanol and the filtrate is concentrated. The resulting mixture is separated by flash chromatography, the clean fractions are concentrated and the residue is stirred with ether, filtered off with suction and washed with ether. 3.2 g of colourless crystals of melting point 115° C. are obtained.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].IC.[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[S:20])[N:14]([CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][O:23]1)[C:13]2=[O:27]>CN(C)C=O>[Br:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([S:20][CH3:1])[N:14]([CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][O:23]1)[C:13]2=[O:27]
Reactant: O=c1c2cc(Br)ccc2[nH]c(=S)n1CC1CCCO1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CSc1nc2ccc(Br)cc2c(=O)n1CC1CCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium carbonate (6.0 g, 44 mmol), iodomethane (2.5 g, 1.1 mL, 17.6 mmol), and the title compound of Step A (3.0 g, 8.8 mmol) were combined in dimethylformamide (90 mL) and stirred for 2 h at room temperature. The reaction mixture was then concentrated to dryness under reduced pressure, and the ensuing residue was partitioned between 200 mL each of ethyl acetate and water. The phases were separated and the organic phase was subsequently washed with saturated aqueous NaCl and dried over Na2SO4 (anhydrous). Following solvent removal under reduced pressure and trituration of the resulting material with cold hexanes, 2.8 g of the title compound of Step B, a compound of the invention, was obtained as a solid melting at 68-72° C. 1H NMR (300 MHz, CDCl3): δ 1.64-1.83 (m,1H), 1.80-2.18 (m,3H), 2.62 (s,3H), 3.78 (dd,1H), 3.96 (dd,1H), 4.17 (dd,1H), 4.21 (dd,1H), 4.38-4.50 (m,1H), 7.41 (d,1H), 7.73 (dd,1H), 8.36 (d,1H).