Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[C@H:6]1[C@H:11]([NH:12][C:13]([O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])[CH2:10][O:9][C:8]([CH3:23])([CH3:22])[CH2:7]1)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+].C([O-])(=O)C.[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:24]([C@H:6]1[CH2:7][C:8]([CH3:23])([CH3:22])[O:9][CH2:10][C@H:11]1[NH:12][C:13](=[O:14])[O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)C[C@@H](OS(C)(=O)=O)[C@H](NC(=O)OCC[Si](C)(C)C)CO1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)C[C@H](N=[N+]=[N-])[C@H](NC(=O)OCC[Si](C)(C)C)CO1
Temperature: 25 °C
Yield: 129.7 %

Procedure:
To a solution of (4R,5R)-2,2-dimethyl-5-((2-(trimethylsilyl)ethoxy)carbonylamino)-tetrahydro-2H-pyran-4-yl methanesulfonate (550 mg, 1.25 mmol) in N,N-dimethylformamide (10 mL) was added sodium azide (812 mg, 12.5 mmol) and sodium acetate (1.05 mg, 12.5 mmol) at room temperature. The resultant mixture was stirred at 95° C. for 2 days. After that, the mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The organic phase was washed with water (100 mL×8) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated to afford the title compound (510 mg, crude) as a yellow oil which was directly used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([F:14])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:17])=O>>[Br:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([F:14])[C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1Br
Product: O=C(Cl)c1c(F)c(F)c(F)c(F)c1Br

Procedure:
365 g (1.33 mol) of 2-bromo-3,4,5,6-tetrafluorobenzoic acid [Tetrahedron 2.3, 4719 (1967)] are introduced into 2 l of thionyl chloride and the mixture is heated under reflux for 11 hours until the evolution of gas stops. Excess thionyl chloride is stripped off in vacuo and the residue is distilled.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:42])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[CH:36]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:16]([N:14]([CH3:15])[C:12]1[C:11]([C:20]([F:23])([F:21])[F:22])=[CH:10][C:9]2[NH:24][C:25](=[O:42])[CH2:26][C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[CH:40]=[CH:39][N:38]=[C:37]([CH3:41])[CH:36]=4)[CH:30]=3)=[N:7][C:8]=2[CH:13]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)CC(C)C)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)CC(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (5-(isobutyl-methyl-amino)-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M275) (0.44 g, 0.73 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (186 mg, 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]([OH:17])=O)=[C:7]2[C:11]=1[O:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8]2.[CH3:18][N:19]1[C:23]([NH2:24])=[CH:22][CH:21]=[N:20]1>>[CH3:18][N:19]1[C:23]([NH:24][C:15]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:11]3[O:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8][C:7]=23)=[O:17])=[CH:22][CH:21]=[N:20]1
Reactant: Cn1nccc1N
Reactant: COCc1cc2c(C(=O)O)ccc(OC)c2o1
Product: COCc1cc2c(C(=O)Nc3ccnn3C)ccc(OC)c2o1
Yield: 34.6 %

Procedure:
Starting from 7-methoxy-2-methoxymethylbenzofuran-4-carboxylic acid (93 mg) and 2-methyl-2H-pyrazol-3-ylamine (40 mg). Purification by column chromatography on silica eluting with ethyl acetate afforded the title compound as a white solid (43 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[CH:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[C:14]([CH:17]=[O:18])=[CH:15][S:16][C@H:11]12)=[O:8].O1CCC[CH2:38]1.[Br].C[Mg].Cl>C(OCC)C.C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:35](=[O:36])[N:12]2[CH:13]([C:19]([O:21][CH:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:20])[C:14]([CH:17]([OH:18])[CH3:38])=[CH:15][S:16][C@H:11]12)=[O:8]
Reactant: O=CC1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: C[Mg]
Agent: Cl
Agent: [Br]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(O)C1=CS[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Yield: 63.9 %

Procedure:
To a cooled (-73°), stirred solution of 5.19 g. of benzhydryl 7-(2-thienylacetamido)-3-formyl-2-cephem-4-carboxylate in 60 ml. of tetrahydrofuran under an argon atmosphere was added 10 ml. of a cold (-10°) 3 molar solution of methylmagnesium bromine in ethyl ether. The reaction mixture was stirred with cooling for 4 minutes after which time 10 ml. of 1N.HCl was added. The solution was then allowed to warm to 0° in an ice bath. The reaction mixture was transferred to separatory funnel with the aid of cold ethyl acetate and 1N.HCl. The organic layer was separated and washed with cold 1N.HCl (2X) and brine (2X), and dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness gave a crude product which was chromatographed on silica gel using a toluene-ethyl acetate gradient to give 3.40 g. (63.9 percent) of the title product as a mixture of diastereoisomeric carbinols. Although both isomers have approximately the same rf value, careful fractionation of the column resulted in the isolation of the pure isomers. Isomer I (that which was eluded from the column first) crystallized from methylene chloride/hexane to provide white crystals (m.p. 133.5°-134.5°): ir (CHCl3) 1782 cm-1 (lactam C = O); nmr (CDCl3) δ1.17 (d, 3, J = 6.0 Hz,--CH(OH)CH3), 2.85 (broad s, 1, --OH), 3.79 (s, 2, side chain CH2), 4.27 (m, 1,--CH(OH)CH3), 5.10 (s, 1, C4 --H), 5.13 (d, 1, J = 4.0 Hz, C6 --H), 5.49 (q, 1, J = 4.0 and 8.0 Hz, C7 --H) and 6.31 (s, 1, C2 --H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[N:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([CH3:21])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:26]4[CH:25]=[N:24][C:23]([NH2:22])=[N:28][CH:27]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)=[CH:15][CH:16]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(Br)c2)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-phenyl)-6-methyl-pyrimidine (example E.44) (0.18 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a white solid (0.055 g, 29%). MS (ISP) 374.1 [(M+H)+]; mp 228° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[NH:11][C:10](=O)[C:9]=2[C:21]#[N:22])[CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)[Cl:25]>CCOC(C)=O>[Cl:25][C:10]1[C:9]([C:21]#[N:22])=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2[nH]c(=O)c(C#N)c(-c3cccc(F)c3)c2c1
Solvent: CCOC(C)=O
Product: COc1ccc2nc(Cl)c(C#N)c(-c3cccc(F)c3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(3-fluorophenyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbonitrile (1.10 g, 3.74 mmol) in 30 mL of phosphorus oxytrichloride was heated in a sealed pressure tube at 90° C. for 2 hours. The solution was cooled to room temperature and allowed to stand overnight. The mixture was diluted with EtOAc, cooled to 0° C., and quenched by the careful addition of saturated NaHCO3 solution. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the titled compound. ESI+ MS: 313.0 [M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:16][CH2:17][CH2:18][OH:19])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].CCN(CC)CC>C(Cl)Cl>[CH3:1][S:2]([O:19][CH2:18][CH2:17][CH2:16][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([O:7][CH3:6])[CH:9]=1)(=[O:4])=[O:3]
Reactant: COc1ccc(CCCO)cc1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCCOS(C)(=O)=O)cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under N2, methanesulfonyl chloride (129.7 g, 1.132 m, 87.6 cc) was added dropwise over 1-1.5 hours at -10° to 0° C. to a mechanically stirred solution of 3-(3,4-dimethoxyphenyl)-1-propanol (202 g, 1.03 mole) and Et3N (158.3 g, 1.56 mole, 218 cc) in CH2Cl2 (1.5 1) contained in a 5 1, 3-neck flask. The reaction mixture was stirred at 0° C. for 1 hour and then washed successively with icewater (1×700 cc), cold 3N HCl (1×700 cc), saturated NaHCO3 solution (1×700 cc) and brine (1×700 cc). The organic solution was dried (Na2SO4) and concentrated in vacuo to an orange syrup; yield: 282 g (100%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)=[CH:4][CH:3]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH2:26]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:10]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:9]=2)=[CH:6][CH:7]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: Oc1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Reactant: CCCCCCCCBr
Product: CCCCCCCCOc1ccc(-c2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)cc1
Yield: 63.1 %

Procedure:
2-(4-Hydroxyphenyl)-4,5-diphenylimidazole (5 g) (J. Org. Chem., 1964, 29, 1926) was reacted with 8-bromooctane (6.2 g) in a method similar to Example 9. Work-up and recrystallisation from ethanol and water gave 2-(4-octyloxyphenyl)-4,5-diphenylimidazole (4.29 g, 63%) as a white solid, m.p. 178°. Found: C, 82.31; H, 7.66; N, 6.73%; C29H32N2O requires C, 82.04; H, 7.60; N, 6.60%.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14]N2C3C=CC=CC=3N=N2)=O)=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.Br.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([F:47])[C:31]=1[N:32]1[CH2:37][CH2:36][CH:35]([C:38]([N:40]2[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]2)=[O:39])[CH2:34][CH2:33]1.CCN(C(C)C)C(C)C>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([C:12]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[C:30]([F:47])[C:31]=2[N:32]2[CH2:33][CH2:34][CH:35]([C:38]([N:40]3[CH2:41][CH2:42][N:43]([CH3:46])[CH2:44][CH2:45]3)=[O:39])[CH2:36][CH2:37]2)=[O:14])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)On1nnc2ccccc21
Reactant: CN1CCN(C(=O)C2CCN(c3c(N)cncc3F)CC2)CC1
Agent: Br
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)C2CCN(c3c(F)cncc3NC(=O)c3c(N)nn4cc(F)cnc34)CC2)CC1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 56.5 %

Procedure:
A suspension of benzotriazol-1-yl 2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate 6a (6.271 g, 20.02 mmol), [1-(3-amino-5-fluoro-4-pyridyl)-4-piperidyl]-(4-methylpiperazin-1-yl)methanone hydrobromide 17a (6.98 g, 16.68 mmol) and DIPEA (2.802 g, 3.776 mL, 21.68 mmol) in pyridine (63 mL) were placed in a sealed tube and heated at 100° C. for 24 h. The mixture cooled to room temperature then concentrated in vacuo. The resulting solid was loaded onto silica and purified by chromatography (330 g SiO2, 0.5-7.5% MeOH (containing 10% ammonium hydroxide)/DCM). The residue was stirred in ethanol for 5 mins and the solid that formed was collected by filtration, washed with minimal ethanol, dried by suction for 2 h, affording desired product as a pale yellow solid (4.71 g, 56.5%). MS (ES+) 500.2; 1H NMR (DMSO-d6) δ 10.63 (s, 1H), 9.67 (s, 1H), 9.47 (dd, J=4.8, 2.5 Hz, 1H), 9.25 (dd, J=2.6, 0.7 Hz, 1H), 8.25 (d, J=2.4 Hz, 1H), 6.79 (s, 2H), 3.60 (t, J=5.0 Hz, 2H), 3.55 (t, J=4.9 Hz, 2H), 3.19 (m, 2H), 3.03 (m, 2H), 2.95 (tt, J=11.7, 3.6 Hz, 1H), 2.34 (t, J=5.0 Hz, 2H), 2.29 (t, J=5.1 Hz, 2H), 2.20 (s, 3H), 2.13 (qd, J=12.4, 3.9 Hz, 2H), 1.75-1.72 (m, 2H).
Reaction SMILES: C(Cl)Cl.[F:4][C:5]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:6]=1[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH2:17][OH:18])[C:11]=2[N:10]=[C:9]1[C:19]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=1[F:26]>N1C=CC=CC=1.N1C=CC=CC=1.C(Cl)Cl>[F:4][C:5]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:6]=1[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH:17]=[O:18])[C:11]=2[N:10]=[C:9]1[C:19]1[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=1[F:25]
Reactant: OCc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=Cc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Reaction time: 6 h
Yield: 78 %

Procedure:
To CrO3 (1.26 g) dissolved in pyridine (1.0 mL) and CH2Cl2 (9.0 mL) was added 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-hydroxylmethylbenzimidazole (Example 112) (0.49 g, 1.27 mmol) dissolved in pyridine:CH2Cl2 (1:1) (2 mL). After stirring for 6 h, the reaction was filtered. The filtrate was diluted with CH2Cl2, and washed with NaHCO3 (sat. soln) and NaCl (sat. aq). The combined washings were dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash chromatography eluting with 1% methanol/CH2Cl2. Recrystallization from diethylether:hexane (3:1) yielded white crystals of 1-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-benzimidazole-4-carbaldehyde (0.38 g, 0.99 mmol, 78% yield). M.p. 151-153° C. 1H-NMR (300 MHz, CD2Cl2): δ10.82 (d, J=0.6 Hz, 1H, CHO), 7.83 (dd, J=7.5, 1.1 Hz, 1H, H7), 7.78 (dd, J=8.1, 1.1 Hz, H5), 7.58 (m, 1H, H4′), 7.44 (ddd, J=8.1, 7.5, 0.6 Hz, 1H, H6), 7.27 (m, 1H, H4″), 7.11 (m, 2H, H3′,5′), 6.84 (m, 2H, H3″,5″), 5.42 (s, 2H, CH2PhF2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH2:24][C:25]([OH:27])=O)[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[N:11]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:10]=1.[CH3:36][NH:37][CH3:38].C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:19]=[C:20]([CH2:24][C:25]([N:37]([CH3:38])[CH3:36])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:16]=2)[N:11]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:10]=1
Reactant: CNC
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(CC(=O)O)c3)cc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(CC(=O)N(C)C)c3)cc12
Temperature: 60 °C

Procedure:
To a solution of {3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid (100 mg, 0.19 mmol), dimethylamine (2 N solution in THF, 0.19 mL, 0.38 mmol), diisopropylethylamine (49 mg, 0.38 mmol) in THF was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluromiumhexafluorophosphate (110 mg, 0.29 mmol). The resulting suspension was heated to 60° C. with stirring till the O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluromiumhexafluorophosphate completely dissolved. The THF was evaporated and the residue was used in the next step reaction without further purification. MS: m/z 517 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C@@H:9]([OH:12])[CH2:10][OH:11])=[CH:4][C:3]=1[F:13].O.[C:15]1(C)[CH:20]=CC(S(O)(=O)=O)=C[CH:16]=1>COC(OC)(C)C>[Cl:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([CH2:8][C@@H:9]2[CH2:10][O:11][C:15]([CH3:20])([CH3:16])[O:12]2)=[CH:6][N:7]=1
Reactant: OC[C@H](O)Cc1cnc(Cl)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC1(C)OC[C@@H](Cc2cnc(Cl)c(F)c2)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 967.5 %

Procedure:
A suspension of 3 (2.50 g, 12.2 mmol) in dimethoxypropane (25 mL) was cooled with an ice bath and treated with paratoluene sulfonic acid monohydrate (0.23 g, 1.22 mmol). The ice bath was removed and the solution was stirred at room temperature for 16 hrs, cooled to 5° C. and treated with aqueous sat. NaHCO3 and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated to afford 2.90 g of 31 (97%) as an oil. 1HNMR (CDCl3) δ 1.34 (3 H, s), 1.42 (3 H, s), 2.87 (2 H, d, J=6.0 Hz), 3.62 (1 H, t, J=7.0 Hz), 4.08 (1 H, t, J=6.0 Hz), 4.30 (1 H, q, J=6.0 Hz), 7.46 (1 H, d, J=9.0 Hz), 8.12 (1 H, s). LC/MS (M+1) 247.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[OH:29][C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:39][C:40]2[C:41]([O:55][CH3:56])=[N:42][CH:43]=[C:44](B3OC(C)(C)C(C)(C)O3)[CH:45]=2)(=[O:38])=[O:37])=[CH:32][CH:31]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[NH2:1][C:2]1[C:3]([C:44]2[CH:45]=[C:40]([NH:39][S:36]([C:33]3[CH:32]=[CH:31][C:30]([OH:29])=[CH:35][CH:34]=3)(=[O:38])=[O:37])[C:41]([O:55][CH3:56])=[N:42][CH:43]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(O)cc1
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ncc(-c2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1NS(=O)(=O)c1ccc(O)cc1
Yield: 52.6 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.11 mmol) was treated with 4-hydroxy-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (70 mg, 0.17 mmol) and bis(pinacolato)diboron according to the method described at Preparation 119b), cesium carbonate (2M, 120 μl, 0.24 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (10 mg, 0.01 mmol) according to the method described in Example 3 to give 37 mg (51% yield) of the title compound. Purity 100%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][C:3]=1[CH2:19][OH:20].[OH-].[K+].I[CH2:24][CH3:25]>CS(C)=O.O>[Br:1][C:2]1[C:3]([CH2:19][O:20][CH2:24][CH3:25])=[CH:4][C:5]([O:10][CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:18])[CH3:17])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)c(CO)cc1OCOCC[Si](C)(C)C
Reactant: CCI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCOCc1cc(OCOCC[Si](C)(C)C)c(OC)cc1Br
Reaction time: 16 h
Yield: 92 %

Procedure:
The crude benzyl alcohol was stirred with a solution of potassium hydroxide (800 mg, 14.4 mmol) in DMSO (8 mL). Iodoethane (580 mL, 7.2 mmol) was added, and the reaction stirred for 16 h before it was diluted with H2O (30 mL) and extracted with ether (2×30 mL). Organics were washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo. Purification by silica gel chromatography (15% EtOAc/hexanes) gave 1.30 g (92%) of the title compound as a clear oil. 1H NMR (300 MHz, CDCl3) δ 7.29 (s, 1H), 7.03 (s, 1H), 5.26 (s, 2H), 4.48 (s, 2H), 3.85 (s, 3H), 3.79 (t, 2H, J=8.4 Hz), 3.58 (q, 2H, J=6.9 Hz), 1.26 (t, 3H, J=6.9 Hz), 0.95 (t, 2H, J=8.4 Hz), −0.01 (s, 9H).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.Cl.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]1[N:38]=[C:37]([CH:39]2[CH2:44][CH2:43][NH2+:42][CH2:41][CH2:40]2)[O:36][N:35]=1>ClCCl>[C:2]1([C:1]([N:42]2[CH2:43][CH2:44][CH:39]([C:37]3[O:36][N:35]=[C:34]([C:30]4[S:29][CH:33]=[CH:32][CH:31]=4)[N:38]=3)[CH2:40][CH2:41]2)=[O:9])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1csc(-c2noc(C3CC[NH2+]CC3)n2)c1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCC(c2nc(-c3cccs3)no2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
67.40 mg (1 eq.) of benzoic acid, 106 mg (1 eq.) of EDCI and 165 μl (2 eq.) of triethylamine were dissolved in 2 ml of dichloromethane. 150 mg (1 eq.) of 4-(3-thiophen-2-yl[1,2,4]oxadiazol-5-yl)piperidinium hydrochloride dissolved in 2 ml of dichloromethane and 165 μl (2 eq.) of triethylamine were added to the reaction medium, which was stirred at room temperature overnight. The reaction medium was evaporated under reduced pressure and the residue was chromatographed on a thick layer (eluent: CH2Cl2/MeOH (98/2: v/v)) to give 98 mg (52%) of the expected product.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.Cl.[NH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>C(O)(C)C.O1CCOCC1>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([N:26]4[CH:27]=[CH:28][C:23](=[NH:22])[CH:24]=[CH:25]4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1ccncc1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccc(=N)cc3)nc2N1C1CCCC1
Temperature: 160 °C

Procedure:
To a solution of the Intermediate B (400 mg, 1.36 mmol) in 5 mL of isopropanol in a microwave vial, 4N HCl in dioxane (0.43 mL) and 4-aminopyridine (320 mg, 2 eq) were added and the vial was heated in a microwave oven at 160° C. for 1 hour. Solvent was removed under reduced pressure and the resulting yellow solid was purified by reversed phase HPLC to give the title compound. 1H NMR (CDCl3) δ: 9.62 (bs, 1H), 8.91 (d, J=7.7 Hz, 2H), 7.81 (s, 1H), 7.37 (d, J=7.8 Hz, 2H), 4.44-4.36 (m, 2H), 3.41 (s, 3H), 2.08-1.71 (m, 10H), 0.89 (t, J=7.5 Hz, 3H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si](C(C)(C)C)(C)C)=[CH:11][CH:10]=1)[C:3]([NH2:5])=O.B>C1COCC1.CO>[NH2:1][C@@H:2]([CH2:3][NH2:5])[CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCC[C@@H](N)C(N)=O)cc1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: NC[C@H](N)CCCc1ccc(O)cc1
Temperature: 5 °C

Procedure:
A solution of (R)-2-Amino-5-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-pentanoic acid amide (7.74 g, 24 mmol) in THF is stirred at 5° C. and borane (96 ml of a 1 M solution in THF, 96 mmol) is added. The mixture is stirred at 5° C. until a homogeneous mixture is obtained and then stirred at room temperature for 30 minutes and 35° C. for 3 hours. After this time, further borane (24 ml of a 1 M solution in THF, 24 mmol) is added and the reaction is heated at 35° C. for 18 hours. After this time, a further portion of borane (24 ml of a 1 M solution in THF, 24 mmol) is added and the reaction heated at 35° C. for a further 24 hours. After this time, the reaction is cooled to 10° C., and quenched by adding dropwise to MeOH (50 ml) at −5° C. After allowing to warm to room temperature the solvent is removed in vacuo to afford a yellow oil. The oil is dissolved in MeOH (250 ml) and SCX-2 silica (180 g, 0.63 mmol/g, 120 mmol) is added. The silica suspension is shaken for 18 hours, the silica is removed by filtration, washed with MeOH (3×100 ml), then suspended in 7M NH3 in MeOH and shaken for 18 hours. The silica is removed by filtration and the 7M NH3 in MeOH is removed in vacuo to afford the title compound as a yellow oil; [M+H]+ 195