Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OC(OC(OC(C)(C)C)=O)=O)(C)C.[OH:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=1I.[CH3:28][N:29](C)C.O1CCOCC1>O>[C:28]([C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:17]=1[OH:16])[C:21]([O:23][CH3:24])=[O:22])#[N:29]
Reactant: CN(C)C
Reactant: COC(=O)c1ccc(O)c(I)c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(O)c(C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 154.5 %

Procedure:
(Boc)2O (44.7 g, 0.21mol) was added portion-wise over 10 min to a 0° C. solution of compound 2 (42 g, 0.19 mol), trimethyl amine (51.9 mL, 0.37 mol), dioxane (140 mL) and water (56 mL). After another 10 min, the ice bath was removed and the reaction mixture was stirred while warming to room temperature for another 2 hours. The reaction mixture was diluted in ethyl acetate (150 mL) and washed with 0.5 N HCl (200 mL×3). The organic layer was dried over magnesium sulfate, filtered, and the filtrate was concentrated in vacuo giving compound 3 (52 g, yield 97%) which was used directly in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:13][OH:14].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(O)C.O.CCCCCC>[OH:14][NH:13][C:8](=[NH:9])[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1
Reactant: NO
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CCO
Product: N=C(NO)c1ccc([N+](=O)[O-])cc1
Temperature: 85 °C
Yield: 97.4 %

Procedure:
To a stirred solution of 4-nitrobenzonitrile (1 g, 0.0068 mol) in ethanol (20 mL) and water (8 mL) was added hydroxylamine hydrochloride (1.9 g, 0.0272 mol) followed by sodium carbonate (2.2 g, 0.0204 mol). The resulting mixture was heated to reflux at 85° C. under an atmosphere of nitrogen for 2 hours The reaction was monitored by TLC (50% Ethyl acetate in Hexane). The volatiles were evaporated and the residue was extracted with ethyl acetate. The ethyl acetate was washed with brine solution, dried over Na2SO4 and concentrated under reduced pressure to get afford 1.2 g (98%) of N-hydroxy-4-nitro-benzamidine. 1H NMR (DMSO-d6): δ 10.2 (s, 1H), 8.24 (d, 2H), 7.97 (d, 2H), 6.03 (s, 2H). To a stirred solution of N-hydroxy-4-nitro-benzamidine (1.2 g, 0.0066 mol) in THF (15 mL) was added triethyl orthoformate (2.93 g, 0.0198 mol). The resulting mixture was cooled to between 0 and 5° C. Boron trifluoride dimethyl ether (0.9 g, 0.0079 mol) was then added dropwise and the resulting mixture was stirred at ambient temperature for 3 hours. Volatiles were evaporated under reduced pressure and the resulting residue was washed with ether and dried to afford 0.65 g (55%) of 3-(4-nitro-phenyl)-[1, 2, 4]oxadiazole. To a stirred solution of 3-(4-nitro-phenyl)-[1, 2, 4]oxadiazole (0.2 g, 0.001 mol) in THF (15 mL) was added ammonium chloride (0.214 g, 0.004 mol) in water (5 mL) followed by zinc powder (0.262 g, 0.004 mol) portionwise. The resulting mixture was stirred at ambient temperature for 1 hr and then heated to 65° C. for 5 hours. The mixture was then filtered through celite and the organic layers were concentrated under reduced pressure. The residue was extracted with ethyl acetate. The organic layers were washed with brine solution, dried over Na2SO4 and evaporated under reduced pressure to afford 0.155 g (92%) of 4-[1, 2, 4]oxadiazol-3-yl-phenylamine. 1H NMR (DMSO-d6): δ 9.5 (s, 1H), 7.7 (d, 2H), 6.7 (d, 2H), 5.8 (s, 2H).
Reaction SMILES: [CH2:1]([C:6]1[N:7]([CH2:34][CH2:35][CH3:36])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[N:19](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[CH2:2][CH2:3][C:4]#[CH:5].[OH-].[K+]>Cl.C(O)C>[CH2:1]([C:6]1[N:7]([CH2:34][CH2:35][CH3:36])[N:8]=[C:9]2[C:18]=1[C:17]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:11]=[C:10]2[NH2:19])[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C#CCCCc1c2c(nn1CCC)c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C#CCCCc1c2c(nn1CCC)c(N)nc1ccccc12
Temperature: 25 °C
Yield: 25.7 %

Procedure:
A solution of di(tert-butyl) 1-pent-4-ynyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-ylimidodicarbonate (prepared as described in Parts A-E of Example 57, 0.400 g, 0.812 mmol) in 6 M HCl in ethanol (3 mL) was heated at 60° C. for 1.7 hours. The solution was allowed to cool to room temperature, and then was concentrated under reduced pressure to yield an oil. The oil was treated with 1 M aqueous potassium hydroxide to generate a white precipitate, which was isolated by filtration. The crude product was purified by chromatography (silica gel, gradient elution with 5-10% CMA in chloroform) followed by crystallization from hexanes/ethyl acetate to afford 0.061 g of 1-pent-4-ynyl-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine as white crystals, mp 144.0-145.0° C.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:20](CC)CC)C.ClC(OCC)=O>C(Cl)Cl>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([NH2:20])=[O:17])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCC(OCc2ccccc2)CC1
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: NC(=O)C1CCC(OCc2ccccc2)CC1
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 96.9 %

Procedure:
To a solution of 4-(benzyloxy)cyclohexanecarboxylic acid (5.4 g, 23 mmol, 1.0 equiv) and triethylamine (4.82 mL, 34.57 mmol, 1.5 equiv) in DCM (dry, 40 mL) was added ethyl chloroformate (3.0 mL, 31.1 mmol, 1.35 equiv) dropwise between −20 and −10° C. under N2. The white precipitate appeared. The mixture was stirred at about −15° C. for 10 min, dried NH3 was bubbled rapidly into the liquid for 20 min. The mixture was stirred at −15° C. for 30 min, then put into the fridge (−20° C.) overnight. The flask was released the pressure and warm to room temperature. H2O (100 mL) was added. The layer was separated and the aqueous phase was extracted with DCM (3×100 mL). The combined organic solution was washed with brine (50 mL), dried over anhydrous Na2SO4, concentrated to give 5.2 g (96.7%) of 4-(benzyloxy)cyclohexanecarboxamide as a off-white solid.
Reaction SMILES: CN(C)C(N(C)C)=N.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:27][C:26]([C:28]3[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=3)=[N:25][CH:24]=2)=[CH:19][CH:18]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[C:36]([O:40][C:41]([NH:43][CH:44](P(OC)(OC)=O)[C:45]([O:47][CH3:48])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]>C1COCC1.C(Cl)Cl>[C:36]([O:40][C:41]([NH:43][C:44](=[CH:32][C:31]1[CH:30]=[CH:29][C:28]([C:26]2[S:27][C:23]([C:20]3[CH:21]=[CH:22][C:17]([O:16][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:18][CH:19]=3)=[CH:24][N:25]=2)=[CH:35][CH:34]=1)[C:45]([O:47][CH3:48])=[O:46])=[O:42])([CH3:37])([CH3:38])[CH3:39]
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C=O)cc3)s2)cc1
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C=C(NC(=O)OC(C)(C)C)C(=O)OC)cc3)s2)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
A stirring mixture of 1,1,3,3-tetramethylguanidine (86 μl, 0.69 mmol) was added to a suspension of 4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)benzaldehyde (260 mg, 0.685 mmol) and methyl 2-((tert-butoxycarbonyl)amino)-2-(dimethoxyphosphoryl)acetate (185 mg, 0.62 mmol) in anhydrous THF (10 mL) under nitrogen, at −70° C. The reaction mixture was stirred at −70° C. for 1 h then at RT for 18 h. The reaction mixture was diluted with DCM (50 mL), washed with water (50 mL), passed through a phase separation cartridge and the organic phase concentrated in vacuo to afford a yellow solid. The solid was triturated with EA/EtOH (20 mL) and the collected solid washed with EtOH (10 mL) and Et2O to afford 284 mg (79%) of methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(5-(4-(heptyloxy)phenyl)thiazol-2-yl)phenyl)acrylate as a yellow solid. LCMS-ESI (m/z) calculated for C31H38N2O5S: 550.7. found 551.0 [M+H]+, tR=3.11 min. (Method 8).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1B(O)O>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][C:26]=3[Cl:28])=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccc(Cl)cc3Cl)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 2,4-dichloro-phenylboronic acid (61 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound. Yield: 37 mg, 31%; LC/MS tr 1.76 min; MS(ES+) m/z 404, 406 (M+H)
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C([O:26][CH2:27][C:28]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=[CH:30][C:29]=1[N:43]1[CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[C:48]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:49]=2)[C:44]1=[O:56])(=O)C>>[C:52]([C:48]1[CH:49]=[C:50]2[C:45](=[CH:46][CH:47]=1)[C:44](=[O:56])[N:43]([C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([C:2]3[N:3]=[C:4]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)=[CH:13][CH:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=3)[C:28]=1[CH2:27][OH:26])[CH2:51]2)([CH3:55])([CH3:53])[CH3:54]
Reactant: Cn1cc(Br)nc(Nc2ccc(N3CCOCC3)cc2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Product: Cn1cc(-c2cccc(N3Cc4cc(C(C)(C)C)ccc4C3=O)c2CO)nc(Nc2ccc(N3CCOCC3)cc2)c1=O
Yield: 47 %

Procedure:
Using the same general procedure as Example 105, reaction of 108a (296 mg, 0.810 mmol) with 103f (413 mg, 0.891 mmol) afforded 108 in 47% yield (205 mg) as an amorphous yellow solid: mp 225-227° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.08 (s, 1H), 7.83 (d, J=9.0 Hz, 2H), 7.73 (d, J=8.5 Hz, 2H), 7.62 (dd, J=8.0, 1.5 Hz, 1H), 7.58 (dd, J=8.0, 1.5 Hz, 1H), 7.50 (t, J=7.5 Hz, 1H), 7.42 (dd, J=8.0, 1.0 Hz, 1H), 7.34 (s, 1H), 6.89 (d, J=9.0 Hz, 2H), 4.92 (s, 2H), 4.83 (t, J=5.0 Hz, 1H), 4.43 (d, J=5.0 Hz, 2H), 3.72 (t, J=5.5 Hz, 4H), 3.54 (s, 3H), 3.03 (t, J=5.5 Hz, 4H), 1.37 (s, 9H); MS (ESI+) m/z 580.3 (M+H).
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[C:17]([C:22]2([CH:25]4[CH2:28][C:27]([F:30])([F:29])[CH2:26]4)[CH2:24][CH2:23]2)[N:16]=3)=[C:9]([F:31])[CH:8]=1.Cl.[OH-].[Na+]>C1COCC1>[F:30][C:27]1([F:29])[CH2:26][CH:25]([C:22]2([C:17]3[N:16]=[C:15]4[S:14][C:13]([C:10]5[CH:11]=[CH:12][C:7]([CH:2]=[O:1])=[CH:8][C:9]=5[F:31])=[N:21][C:20]4=[CH:19][CH:18]=3)[CH2:23][CH2:24]2)[CH2:28]1
Reactant: Fc1cc(C2OCCCO2)ccc1-c1nc2ccc(C3(C4CC(F)(F)C4)CC3)nc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2nc3ccc(C4(C5CC(F)(F)C5)CC4)nc3s2)c(F)c1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-(3,3-difluoro-cyclobutyl)cyclopropyl)thiazolo[5,4-b]pyridine (151.5 mg, 0.339 mmol) and hydrochloric acid (5.0N, aq.) (3.0 mL, 15.00 mmol) in THF (6.7 mL) was stirred at 65° C. for 3 h. Ther reaction mixture was then cooled on an ice bath, and NaOH (5.0N, aq.; 3.0 mL) was added. THF was removed in vacuo, and the resulting mixture was partitioned between EtOAc (100 mL) and water (30 mL). The organic layer was separated, sequentially washed with water (30 mL) and brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-60% EtOAc/hexanes) furnished 4-(5-(1-(3,3-difluoro-cyclobutyl)cyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-3-fluorobenzaldehyde as a light-yellow solid. MS (ESI) m/z: Calculated: 388.1; Observed: 389.0 (M++1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([NH:10][CH:11]=[O:12])=[CH:4][CH:3]=1.[I-].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:22][C:23](=[O:25])[CH3:24]>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N:10]([CH2:22][C:23](=[O:25])[CH3:24])[CH:11]=[O:12])=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: COc1nc(Br)ccc1NC=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1nc(Br)ccc1N(C=O)CC(C)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
To a mixture of N-(6-bromo-2-methoxypyridin-3-yl)formamide (5.69 g, 24.63 mmol), potassium iodide (0.450 g, 2.71 mmol) and cesium carbonate (28.1 g, 86 mmol) in 66 mL of DMF was added 1-chloropropan-2-one (4.90 mL, 61.6 mmol). The reaction mixture was stirred at rt for 3 days. The reaction mixture was poured into icewater and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuum to give N-(6-bromo-2-methoxypyridin-3-yl)-N-(2-oxopropyl)formamide (7.07 g, 24.62 mmol, 100% yield) as brown solid. LC-MS (M+Na)+=310.9.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14](O)=[O:15])[CH2:9]1)=[O:7])([CH3:4])[CH3:3].B>C1COCC1>[OH:15][CH2:14][CH:10]1[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(CO)C1
Temperature: 25 °C
Yield: 39 %

Procedure:
A solution of 4-{[(1,1-dimethylethyl)oxy]carbonyl}-2-morpholinecarboxylic acid (2.0 g, 21.6 mmol) in THF (45 mL) was cooled to 0° C. A solution of borane (39 mL, 39.0 mmol, 1M in THF) was added over 25 min via addition funnel. After warming to RT, the reaction was quenched by dropwise addition of methanol/acetic acid (18 mL, 9:1 v/v). The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and 1N HCl. The aqueous layer was extracted with ethyl acetate and combined extracts were washed with water, 1N NaOH, water, brine and dried over sodium sulfate. Removal of the solvent under reduced pressure afforded 1.83 g (97%) of the desired material. 1H NMR (400 MHz, CDCl3) δ ppm 1.49 (s, 9H) 2.30 (br d, J=11.37 Hz, 1H) 2.69-2.79 (m, J=9.51, 6.41, 3.28, 3.28 Hz, 1H) 2.84 (ddd, J=13.77, 10.86, 3.16 Hz, 2H) 3.27-3.38 (m, 1H) 3.47 (br s, 1H) 3.63-3.75 (m, 2H) 4.10-4.19 (m, 1H) 4.27 (br s, 1H).
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]([CH3:19])[C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]=[N:9][C:4]=2[CH:3]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:22]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C(=O)C.C(O)C.O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[C:22]=1[C:2]1[CH:18]=[C:17]([CH3:19])[C:5]2[N:6]=[C:7]([NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]=[N:9][C:4]=2[CH:3]=1
Reactant: Cc1cc(Br)cc2nnc(Nc3ccccc3)nc12
Reactant: COc1cccc(F)c1B(O)O
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: CCO
Solvent: O
Product: COc1cccc(F)c1-c1cc(C)c2nc(Nc3ccccc3)nnc2c1
Yield: 17.3 %

Procedure:
To a solution of (7-Bromo-5-methyl-benzo[1,2,4]triazin-3-yl)-phenyl-amine (10 mg, 0.032 mmol) dissolved in 2 ml N,N-Dimethylacetamide in a 20 ml vial, 2-Fluoro-6-methoxy-phenylboronic acid (22 mg, 0.128 mmol) dissolved in 1 ml ethanol and potassium carbonate (6.4 mg, 0.06 mmol) dissolved in 1 ml water were added. Triphenylphosphine (1 mg, 0.0038 mmol) and tris(dibenzylideneacetone) dipalladium (0) (1 mg, 1.09 umol) were added to the mixture. The mixture was reflux overnight. The crude product was filtered and purified by preparative HPLC. 2 mg [7-(2-Fluoro-6-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-yl]-phenyl-amine was isolated. Yield: 17.5%; ESI-MS: [M+H]+, 361; 1H NMR (CDCl3): δ 2.73 (s, 3 H), 3.83 (s, 3 H), 6.83–6.86 (m, 2H), 7.14 (m, 1 H), 7.34 (m, 1 H), 7.45 (m, 2 H), 7.75(s, 1 H), 7.92(m, 2 H), 8.24(s, 1 H).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([O:11]C)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[Cl-].[NH+]1C=CC=CC=1>O>[OH:2][C:3]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: COc1ccc(C#N)c(OC)c1
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Solvent: O
Product: N#Cc1ccc(O)cc1O
Reaction time: 2 h
Yield: 70.6 %

Procedure:
2,4-dimethoxybenzonitrile (2 g) was mixed with pyridinium chloride (5.67 g) and the reaction mixture was fused at 210° C. for 2 hours. After being left to stand at room temperature overnight, the mixture was diluted with water and extracted into diethyl ether. The ether extracts were washed with water, dried over magnesium sulphate and concentrated to give a pink solid which was washed with petrol and air dried to give 2,4-dihydroxybenzonitrile (1.17 g) (m pt 176°-178° C.).
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH:16]=[CH:17][N+:18]([O-])=O)=[CH:11][C:10]=1[CH3:21])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[Si:5]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][CH2:17][NH2:18])=[CH:11][C:10]=1[CH3:21])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7]
Reactant: Cc1cc(C=C[N+](=O)[O-])cc(C)c1O[Si](C)(C)C(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1cc(CCN)cc(C)c1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
A solution of tert-butyl-[2,6-dimethyl-4-(2-nitrovinyl)phenoxy]dimethylsilane (0.20 g) in 15 mL diethyl ether was cooled to 0° C. Lithium aluminum hydride (0.20 g) was added in portions to the stirring nitroalkene solution. The resulting slurry was refluxed for 3 h and then cooled to 0° C. The mixture is carefully quenched by the sequential addition of 0.2 mL of water, followed by 0.2 mL of 3 N sodium hydroxide and 0.6 mL of water. The mixture was stirred for 15 min, then filtered to remove the aluminum salts. The filtrate was collected and the volatile material was removed by a rotary evaporator to give 100 mg of 2-[4-(tert-butyldimethylsilanyloxy)-3,5-dimethylphenyl]ethylamine.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[NH:30][C:31]([CH:33]1[CH2:35][CH2:34]1)=[NH:32]>>[CH:33]1([C:31]2[N:32]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:19][CH:20]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][S:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:27][N:30]=2)[CH2:35][CH2:34]1
Reactant: O=C(O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Reactant: N=C(NO)C1CC1
Product: O=C(N1CCSCC1)N1CC(c2ccc(CC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
According to General Method 6A, 300 mg (0.720 mmol) of the compound from Example 45A and 79.3 mg (0.792 mmol) of N-hydroxycyclopropanecarboximidamide were reacted Yield: 160 mg (45% of theory)
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:55])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[C:30]([O:32][C:33]([F:36])([F:35])[F:34])[CH:29]=[CH:28][C:27]=5[O:37][C@H:38]([CH2:40][CH:41]=C)[CH3:39])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[C:14]([CH3:43])=[C:13]([CH3:44])[C:12]=2[C@H:45]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:46]([O:48][CH3:49])=[O:47])[CH2:7][CH2:6]1)[CH:2]=C.O.[BH4-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C(Cl)Cl>[C:51]([O:50][C@@H:45]([C:12]1[C:13]([CH3:44])=[C:14]([CH3:43])[C:15]2=[N:19][C:18]3=[CH:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:55])([O:4][CH2:1][CH2:2][CH2:41][CH2:40][C@H:38]([CH3:39])[O:37][C:27]2[CH:28]=[CH:29][C:30]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:31][C:26]=2[C:22]2[CH:21]=[C:20]3[CH:25]=[CH:24][CH:23]=2)[CH2:6][CH2:7]1)[C:46]([O:48][CH3:49])=[O:47])([CH3:52])([CH3:53])[CH3:54]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(-c5cc(OC(F)(F)F)ccc5O[C@@H](C)CC=C)c4)cn23)CC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [BH4-]
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(OC(F)(F)F)cc1-c1cccc-3c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.3 %

Procedure:
A solution of (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-7,8-dimethyl-2-(2′-((S)-pent-4-en-2-yloxy)-5′-(trifluoromethoxy)-[1,1′-biphenyl]-3-yl)imidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate (0.20 g, 0.262 mmol, 1 equiv) and TsOH monohydrate (50 mg, 0.262 mmol, 1 equiv) in DCE (100 mL) was heated to 80° C. The Hoveyda Grubbs 2nd generation catalyst (16 mg, 0.026 mmol, 0.1 equiv) was added. The pale green brown solution was stirred for 3 h. Upon cooling to ambient temperature, the reaction was washed with saturated aqueous NaHCO3, dried (Na2SO4), and concentrated in vacuo. The crude product was taken up in 20:1 DCE:water (2.8 mL) and tetrabutylammonium borohydride (135 mg, 0.524 mmol, 2 equiv) was added. After 1 h, the reaction mixture was diluted with DCM, washed with water, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by silica gel flash column chromatography (0-100% EtOAc [2% TEA]/hexane) to provide the product (74 mg, 38%) as a tan foam. LCMS (ESI, M+1): 738.80.
Reaction SMILES: [CH:1]1([N:4]2[C:13]([C:14]#[N:15])=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:23])[CH:10]=3)[C:5]2=[O:24])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].O([CH2:39][C:40]([F:43])([F:42])[F:41])S(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH:1]1([N:4]2[C:13]([C:14]#[N:15])=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:23][CH2:39][C:40]([F:43])([F:42])[F:41])[CH:10]=3)[C:5]2=[O:24])[CH2:2][CH2:3]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: N#Cc1c(-c2cccc(F)c2)c2cc(O)ccc2c(=O)n1C1CC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1c(-c2cccc(F)c2)c2cc(OCC(F)(F)F)ccc2c(=O)n1C1CC1
Temperature: 50 °C

Procedure:
A mixture of the phenol 62 (64 mg, 0.2 mmol), K2CO3 (83 mg, 0.6 mmol) and trifluoroethyl triflate (70 mg, 0.3 mmol) in DMF (3 mL) was heated at 50° C. for 30 min. The reaction was cooled, poured into saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic extracts were washed once with 1N HCl and brine, dried with Na2SO4, filtered and concentrated in vacuo. Trituration of the residue with EtOAc/Hexane provided desired product 63.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[N:13][C:12]([NH:15][NH2:16])=[C:11]([CH2:17][CH3:18])[C:10]=1[CH3:19].[N:20]#[C:21]Br.C(=O)([O-])[O-].[K+].[K+]>CCO.O>[Cl:8][C:9]1[C:10]([CH3:19])=[C:11]([CH2:17][CH3:18])[C:12]2[N:13]([C:21]([NH2:20])=[N:16][N:15]=2)[N:14]=1
Reactant: CCc1c(NN)nnc(Cl)c1C
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCc1c(C)c(Cl)nn2c(N)nnc12
Reaction time: 8 h
Yield: 112.8 %

Procedure:
(6-Chloro-4-ethyl-5-methylpyridazin-3-yl)hydrazine trifluoroacetic acid salt (W3.008; 340 mg) was initially charged in a mixture of EtOH (12 ml) and water (2 ml) at RT while stirring. Thereafter, cyanogen bromide (240 mg), dissolved in 3 ml of EtOH and 1 ml of water, was cautiously added dropwise and the mixture was stirred for 8 h. After standing overnight, 0.5 eq. of cyanogen bromide solution was added and the mixture was stirred again at RT for 4.5 h and then at 55° C. for 2 h. After standing overnight, the solvent was drawn off and the residue was admixed with water. Once it had been alkalized with saturated potassium carbonate solution, the mixture was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 270 mg of the title compound were obtained.