Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:57])[C@H:4]([CH:54]([CH3:56])[CH3:55])[NH:5][C:6](=[O:53])[C@@H:7]([CH:50]([CH3:52])[CH3:51])[NH:8][C:9](=[O:49])[CH:10]([CH:12]1[CH2:18][CH2:17][N:16]([C@@H:19]([NH:21][C:22](=[O:33])[C@H:23]([CH3:32])[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH3:20])[CH2:15][CH:14]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:13]1[O:41][Si](C(C)(C)C)(C)C)[CH3:11].[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].CCOCC>C1COCC1>[CH3:1][O:2][C:3](=[O:57])[C@H:4]([CH:54]([CH3:56])[CH3:55])[NH:5][C:6](=[O:53])[C@@H:7]([CH:50]([CH3:52])[CH3:51])[NH:8][C:9](=[O:49])[CH:10]([CH:12]1[CH2:18][CH2:17][N:16]([C@@H:19]([NH:21][C:22](=[O:33])[C@H:23]([CH3:32])[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH3:20])[CH2:15][CH:14]([CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:13]1[OH:41])[CH3:11]
Reactant: COC(=O)[C@@H](NC(=O)[C@H](NC(=O)C(C)C1CCN([C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)CC(Cc2ccccc2)C1O[Si](C)(C)C(C)(C)C)C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)[C@@H](NC(=O)[C@H](NC(=O)C(C)C1CCN([C@H](C)NC(=O)[C@H](C)NC(=O)OC(C)(C)C)CC(Cc2ccccc2)C1O)C(C)C)C(C)C

Procedure:
One isomer of the protected alcohol (66) is dissolved in THF and treated with n-Bu4NF (1M in THF, 2 equivalents) at room temperature. After all of the ether disappears (tlc), the reaction mixture is evaporated at reduced pressure and the residue is purified by flash chromatography to give the title compound (67).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]1[N:11]2[CH:12]=[C:13]([O:16][C@H:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C@@H:20]([NH2:27])[CH2:19][CH2:18]3)[CH:14]=[CH:15][C:10]2=[N:9][N:8]=1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH2:50][CH2:51][O:52][CH:53]3[CH2:58][CH2:57][CH2:56][CH2:55][O:54]3)[CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([C@@H:3]5[CH2:4][CH2:5][CH2:6][N:2]5[CH3:1])=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([O:49][CH2:50][CH2:51][O:52][CH:53]3[CH2:58][CH2:57][CH2:56][CH2:55][O:54]3)[CH:44]=2)[N:36]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOC5CCCCO5)c4)c4ccccc43)cn12
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 76.2 %

Procedure:
A mixture of Intermediate 5c (150 mg, 0.410 mmol) and Intermediate 39b (230 mg, 0.430 mmol) in 1,4-dioxane (4 mL) and DIPEA (113 μL, 0.65 mmol) was stirred at 90° C. for 4.5 h. The mixture was concentrated in vacuo. The residue was purified by FCC twice, using 0-10% MeOH in DCM, to give the title compound as a pale yellow foam (234 mg, 76%). LCMS (Method 3): Rt 3.03 min, m/z 749.2 [MH+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][O:9][CH2:10][CH:11]2[CH2:14][C:13]([F:16])([F:15])[CH2:12]2)[CH:5]=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[CH2:18])[N:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[C:31]1[CH:36]=[C:35]([CH3:37])[N:34]=[N:33][CH:32]=1)[NH2:27].C(=O)([O-])[O-].[Cs+].[Cs+].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:15][C:13]1([F:16])[CH2:14][CH:11]([CH2:10][O:9][CH2:8][C:6]2[CH:5]=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[CH2:18])[N:3]=[C:2]([NH:27][C:26]3[CH:28]=[CH:29][C:30]([C:31]4[CH:36]=[C:35]([CH3:37])[N:34]=[N:33][CH:32]=4)=[C:24]([O:23][CH3:22])[CH:25]=3)[N:7]=2)[CH2:12]1
Reactant: COc1cc(N)ccc1-c1cnnc(C)c1
Reactant: C=C(OCC)c1cc(COCC2CC(F)(F)C2)nc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C=C(OCC)c1cc(COCC2CC(F)(F)C2)nc(Nc2ccc(-c3cnnc(C)c3)c(OC)c2)n1
Temperature: 120 °C
Yield: 104.3 %

Procedure:
A mixture of 2-chloro-4-(((3,3-difluorocyclobutyl)methoxy)methyl)-6-(1-ethoxyvinyl)pyrimidine (0.068 g, 0.21 mmol), 3-methoxy-4-(6-methylpyridazin-4-yl)aniline (0.046 g, 0.21 mmol), cesium carbonate (0.139 g, 0.43 mmol), palladium (II) acetate (7 mg, 0.03 mmol) and (2-biphenylyl)dicyclohexylphosphine (0.011 g, 0.03 mmol) in dioxane (2 mL) was heated under argon at 120° C. for 90 min in microwave reactor. The mixture was filtered through a short silica plug and was eluted with 10% MeOH in EtOAc. The solvents were evaporated to give the title compound (0.109 g, quant).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([NH:11][C@H:12]([C:19]([OH:21])=O)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:35][NH:36][O:37][CH3:38].[Cl-].[NH4+]>ClCCl.CCOC(C)=O>[CH2:7]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:19](=[O:21])[N:36]([O:37][CH3:38])[CH3:35])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: CNOC
Reactant: O=C(N[C@H](C(=O)O)c1ccccc1)OCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CON(C)C(=O)[C@@H](NC(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
To a solution of Z-L-phenylglycine (5.0 g, 17.5 mmol) in dichloromethane (35 mL) is added 1,1′-carbonyldimidazole (3.13 g, 19.3 mmol), and the solution is stirred at rt for 0.5 h. To the solution is added N,O-dimethylhydroxylamine hydrochloride (1.88 g, 19.3 mmol), and the mixture is stirred at rt overnight. To the reaction mixture is added ammonium chloride solution and EtOAc, and the organic layer is separated, washed with brine, dried (MgSO4), and filtered. The filtrate is evaporated to give 5.65 g of the product 482. 1H NMR (CDCl3) δ 7.50-7.20 (m, 10H), 6.10 (d, 1H), 5.78 (d, 1H), 5.20-5.00 (m, 2H), 3.43 (s, 3H), 3.18 (s, 3H); MS: m/z 329 (M++1).
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[CH3:24][CH:25]([CH2:28][CH3:29])[CH2:26][OH:27]>CCCCCC>[Si:1]([O:27][CH2:26][CH:25]([CH3:24])[CH2:28][CH3:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCC(C)CO
Agent: c1c[nH]cn1
Solvent: CCCCCC
Product: CCC(C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A 250 ml, three-necked flask was fitted with a large magnetic, egg-shaped stir bar, a small pressure-equalizing addition funnel, a thermocouple connected to a THERM-O-WATCH®, a reflux condenser, and an argon inlet. This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon. The flask was charged with 46.27 grams (0.168 mole, 1.01 equivalents) of t-butyldiphenylsilyl chloride, 11.69 grams (0.172 mole, 1.03 equivalents) of imidazole, and 100 mls of hexane. 2-Methyl-1-butanol, 14.69 grams (0.167 mole, 1.00 equivalent), was then added dropwise to the resultant slurry. A very mild exotherm was detected. The total feed time was twelve minutes. A fine white precipitate formed almost immediately. The reaction mixture was stirred at room temperature, and monitored by GC analysis. An aliquot of the clear supernatant was injected into the GC. After seven hours, both starting materials were still present. Therefore, the reaction mixture was heated to 60° C. with a heating mantle, controlled by the THERM-O-WATCH®. The reaction mixture was stirred overnight at 60° C. The sample after 23.5 hours indicated all the starting material had been consumed, with the formation of a single, higher boiling component. The reaction mixture was allowed to cool to room temperature, then it was transferred to a small, dry, Chemglass pressure filter. The filtrate was collected in a dry, 500 ml flask. The filter cake was rinsed with additional hexane (2×100 ml). The solvent was removed on the rotary evaporator, with the bath temperature set at 40° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[CH2:11][NH:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[CH:4][CH:3]=1.Cl.[CH:23](O)=O>C=O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[CH2:11][N:12]([CH2:13][CH:14]2[CH2:16][CH2:15]2)[CH3:23])=[CH:4][CH:3]=1
Reactant: O=CO
Reactant: Clc1ccc(COc2cccc(CNCC3CC3)c2)cc1
Agent: C=O
Agent: Cl
Product: CN(Cc1cccc(OCc2ccc(Cl)cc2)c1)CC1CC1
Temperature: 25 °C

Procedure:
In a mixture of 150 ml of formic acid and 150 ml of 37% formaldehyde was dissolved 80 g of 3-(4-chlorobenzyloxy)-N-cyclopropylmethylbenzylamine. The solution was refluxed with heating, for 3 hours. The reaction mixture was cooled to room temperature, and 150 ml of concentrated hydrochloric acid was added thereto. The mixture was subjected to vacuum distillation to remove the solvent. The resulting residue was treated with chloroform-aqueous sodium hydroxide solution. The resulting chloroform layer was separated, washed with water, dried with anhydrous sodium sulfate, and subjected to vacuum distillation to remove the solvent, whereby 86 g of 3-(4-chlorobenzyloxy)-N-cyclopropylmethyl-N-methylbenzylamine was obtained as a brown oil.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH:23]1[CH2:29][CH:28]2[N:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:25]([CH2:26][CH2:27]2)[CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH:23]1[CH2:24][CH:25]2[N:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:28]([CH2:27][CH2:26]2)[CH2:29]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(ON)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1CC(ONC(=O)[C@@H]1CC[C@@H]3CN1C(=O)N3OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.15 g, 0.54 mmol) in dry DCM (20 mL) were added tert-butyl 3-(aminooxy)-8-azabicyclo[3.2.1]octane-8-carboxylate 45 (0.15 g, 0.62 mmol, J. Med. Chem. 2008, 51, 4601-4608), 1-hydroxybenzotriazole (0.11 g, 0.81 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.16 g, 0.81 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was purified by column chromatography to give tert-butyl 3-[({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)oxy]-8-azabicyclo[3.2.1]octane-8-carboxylate 46 (0.26 g, 96%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=O)[CH3:18])=[CH:13][C:12]=2[Br:20])[CH:7]=[N:6][CH:5]=1.CO.C([BH3-])#[N:25].[Na+]>>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([NH2:25])[CH3:18])=[CH:13][C:12]=2[Br:20])[CH:7]=[N:6][CH:5]=1
Reactant: [BH3-]C#N
Reactant: COC(=O)c1cncc(Oc2ccc(C(C)=O)cc2Br)c1
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cncc(Oc2ccc(C(C)N)cc2Br)c1
Yield: 96.4 %

Procedure:
To a solution of the compound from step 1 (630 mg, 1.79 mmol) in MeOH (30 mL) ammonium acetate (1.39 g, 17.9 mmol) was added. After stirring at ambient temperature overnight sodium cyanoborohydride (135.7 mg, 2.16 mmol) was added and the reaction was refluxed for 6 h. The solvent was evaporated and the solid, dissolved in ethyl acetate, was extracted with water. The organic layer was separated, washed with brine, dried over sodium sulphate, filtered and evaporated to give 606 mg (yield: 96%) of the crude product. LC/MS (method D) (M+H)+: 352
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH2:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)=[C:9]([Br:17])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:18]1(=O)[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH2:19]1.Cl.CN(C)CCCN=C=NCC.CN(C1C=CC=CN=1)C>C(Cl)Cl>[Br:1][C:2]1[C:10]([O:11][CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16]2)=[C:9]([Br:17])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:18]1[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH:19]=1)=[O:5]
Reactant: O=C(O)c1ccc(Br)c(OCC2CCC2)c1Br
Reactant: O=C1CCCC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: O=C1C=C(OC(=O)c2ccc(Br)c(OCC3CCC3)c2Br)CCC1

Procedure:
1.150 g (3.20 mmol) of 2,4-dibromo-3-(cyclobutylmethoxy)benzoic acid, 0.39 g (3.50 mmol) of cyclohexane-1,3-dione, 0.618 g (3.20 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 0.004 g of dimethylaminopyridine were stirred for 10 hours at room temperature in 30 ml of methylene chloride. The mixture was subsequently diluted with methylene chloride and washed with 0.5 N HCl, with water, with saturated NaHCO3 solution and again with water. After the combined organic phases had been dried over Na2SO4 and evaporated completely on a rotary evaporator, 3-oxo-1-cyclohexenyl 2,4 dibromo-3-cyclobutylmethoxybenzoate was obtained in the form of a yellow resin.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:12][CH:11]([O:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:15]=2)[CH2:10][CH:9]1[C:28](=[O:40])[NH:29][C:30]1([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:32][CH:31]1[CH:33]=[CH2:34])=[O:7])(C)(C)C.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:38]([O:37][C:35]([C:30]1([NH:29][C:28]([CH:9]2[CH2:10][CH:11]([O:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:15]=3)[CH2:12][CH:8]2[C:6]([OH:7])=[O:5])=[O:40])[CH2:32][CH:31]1[CH:33]=[CH2:34])=[O:36])[CH3:39]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(OC)nc(-c3ccccc3)n2)CC1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(OC)nc(-c3ccccc3)n2)CC1C(=O)O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.4 %

Procedure:
Compound 7a (1.48 g, 2.68 mmol) was dissolved in 35 ml DCM. Triethylsilane (1.07 ml, 6.7 mmol) and 35 ml TFA were added and the mixture was stirred at RT for 45 minutes. The solvent was evaporated and co evaporated with toluene which gave the title product (1.32 g, 99%), MS (M+H)+496.
Reaction SMILES: [CH3:1][C:2]([N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:16][C:17]([F:33])([F:32])[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][NH2:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[CH3:1][C:2]([N:9]1[CH2:14][CH2:13][CH:12]([NH:31][CH2:30][C:27]2[CH:26]=[CH:25][C:24]([C:21]3[CH:22]=[CH:23][C:18]([C:17]([F:16])([F:32])[F:33])=[CH:19][CH:20]=3)=[CH:29][CH:28]=2)[CH2:11][CH2:10]1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)(C)N1CCC(=O)CC1
Reactant: NCc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A mixture of ethyl 2-methyl-2-(4-oxo-1-piperidinyl)propanoate (Int. A4) (25.6 g, 1.2 equiv), {[4′-(trifluoromethyl)-4-biphenylyl]methyl}amine (Int. A1) (31.1 g, 1.0 equiv), DCE (400 ml) and acetic acid (6.3 ml, 1.1 equiv) was stirred at room temperature under nitrogen. Sodium triacetoxyborohydride (33.5 g, 1.5 equiv) was added and stirring continued for 19 hours. Aqueous sodium carbonate (2M solution, excess) was added and stirred for 1.5 h, then the mixture was extracted with a mixture of diethyl ether and THF. The organic extracts were backwashed with water and brine, filterered through a pad of silica gel, dried over sodium sulfate and evaporated in vacuo. The desired product was obtained as a white solid (44.2 g) which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[CH3:20][O:21][CH2:22][C:23](OC)=[O:24].Cl>C(OCC)C>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:23](=[O:24])[CH2:22][O:21][CH3:20])=[CH:6][CH:7]=1
Reactant: COCC(=O)OC
Reactant: Brc1ccc(Br)nc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COCC(=O)c1ccc(Br)nc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 32.6 %

Procedure:
To a suspension of 2,5-dibromopyridine (50.0 g) in diethyl ether (1 L) was added under nitrogen atmosphere a 1.6M n-butyllithium hexane solution (140 mL) at −70° C. over 20 min. The reaction mixture was stirred at −70° C. for 30 min, methyl methoxyacetate (44.0 g) was added at −70 to −45° C. over 15 min. The reaction mixture was warmed to room temperature, 2M hydrochloric acid (110 mL) was added, and the diethyl ether layer was separated. The aqueous layer was extracted with ethyl acetate, the ethyl acetate layer was combined with the diethyl ether layer, and the layers were washed with saturated brine, dried (MgSO4) and concentrated. Cold ether was added to the obtained residue, and the resulting crystals were collected by filtration, washed with cold ether and dried to give the title compound (15.85 g, yield 33%) as colorless crystals. melting point 110-112° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O)(=[O:3])[CH3:2].[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1CC([O-])=O.[OH-].[Na+].Cl>CO>[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[C:15]1[C:2]1[C:1](=[O:3])[O:4][CH2:5][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C([O-])Cc1nc2ccccc2s1
Reactant: CC(=O)OCC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1OCC(c2ccccc2)=C1c1nc2ccccc2s1
Temperature: 25 °C

Procedure:
A solution of 2-acetoxyacetophenone (from Example 1) (8.9 g, 0.05M) and α-(benzothiazol-2-yl)-acetate (from Example 3) dissolved in methanol (40 mL) by stirring at room temperature was treated at room temperature with a solution prepared by dissolving sodium hydroxide pellets (2.5 g) in methanol (30 mL) by stirring. A slight exothermic reaction was observed. After being stirred at about room temperature for about 1.0 hour, the reaction mixture was acidified to a pH of about 4 by the dropwise addition of concentrated HCl. The product which was a dark brown colored semi-crystalline mass was washed by decantation and dried in air (yield--12.0 g (81.9% of the theoretical yield). Mass spectrometry indicated that the product largely consisted of the following desired compound: ##STR16##
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([O:11]COCCOC)=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[N:8]=[C:7]([CH2:22][CH:23]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)O)[N:6]=1)([CH3:4])[CH3:3].C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH3:21][C:18]([C:9]1[C:10]([OH:11])=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[N:6]=[C:7]([CH:22]=[CH:23][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[N:8]=1)([CH3:19])[CH3:20]
Reactant: COCCOCOc1c(C(C)(C)C)nc(CC(O)c2cccnc2)nc1C(C)(C)C
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1nc(C=Cc2cccnc2)nc(C(C)(C)C)c1O
Temperature: 190 °C
Yield: 49.8 %

Procedure:
A mixture of 4,6-bis(1,1-dimethylethyl)-5-[(2-methoxyethoxy)methoxy]-α-(3-pyridinyl)-2-pyrimidine-ethanol (350 mg), sodium acetate (10 g) and acetic anhydride (7 mL) in toluene (100 mL) is heated at reflux for 8 hours. The reaction mixture is cooled and the solvent is evaporated. Dichlorobenzene (30 mL) is added and the reaction mixture is heated at 190° C. for 30 minutes. The reaction mixture is cooled and partitioned between ethyl acetate and water. The aqueous layer is adjusted to pH 4 with 1 N HCl. The organic layer is collected and evaporated. Purification of the residue by flash chromatography (silica, 1:1 ethyl acetate/hexane) followed by recrystallization from hexane gives pure 4,6-bis(1,1-dimethylethyl)-2-[[2-(3 pyridinyl)]ethenyl]-5-pyrimidinol (130 mg, 40%); mp 150°-151° C.
Reaction SMILES: [C:1]([C:5]1[CH:40]=[CH:39][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=2)[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N:45]=[N+:46]=[N-:47])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:40]=[CH:39][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2/[CH:17]=[CH:18]/[CH:19]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[NH:47][N:46]=[N:45][N:38]=3)=[CH:33][CH:32]=2)[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCOC(=O)CCCCC(/C=C/c1ccccc1OCc1ccc(C(C)(C)C)cc1)CCc1ccc(C#N)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCC(/C=C/c1ccccc1OCc1ccc(C(C)(C)C)cc1)CCc1ccc(-c2nnn[nH]2)cc1
Temperature: 80 °C

Procedure:
A solution of 1 g (1.86 mmol) of ethyl (7E)-8-{2-[(4-tert-butylbenzyl)oxy]phenyl}-6-[2-(4-cyanophenyl)ethyl]-oct-7-enoate in 70 ml of toluene is mixed with 3.7 ml (27.9 mmol) of trimethylsilyl azide and 694 mg (2.79 mmol) of di-n-butyltin oxide and heated at 80° C. for 12 hours. After cooling to room temperature, the mixture is washed with saturated sodium bicarbonate solution. The organic phase is separated off, washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate is concentrated to dryness. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1→1:1). 622 mg (1.1 mmol, 34% of theory) of a white foam are obtained.
Reaction SMILES: Cl[C:2]1[C:3]([C:27]#[N:28])=[C:4]([N:11](CC2C=CC(OC)=CC=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C@H:29]1([NH2:36])[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31][CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(O)(C(F)(F)F)=O>CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:35][C@H:32]1[CH2:33][CH2:34][C@H:29]([NH:36][C:2]2[C:3]([C:27]#[N:28])=[C:4]([NH:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:30][CH2:31]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: COc1ccc(CN(c2ccccc2)c2c(C#N)c(Cl)nn3ccnc23)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c(N[C@H]2CC[C@H](N)CC2)nn2ccnc2c1Nc1ccccc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
In a 1 dram vial was added 6-chloro-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-7-carbonitrile (0.019 g, 0.049 mmol) from (1e), (trans)-cyclohexane-1,4-diamine (0.011 g, 0.097 mmol), cesium carbonate (0.048 g, 0.146 mmol), Pd(OAc)2 (0.547 mg, 2.437 μmol), (R)-(−)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphospine [JOSI-Phos] (1.351 mg, 2.437 μmol) and the solids were pump/purged with argon (3×). Dioxane (1.0 ml, 0.05 M) was added and the reaction was heated at 100° C. overnight. Upon cooling, the mixture was filtered through a frit and the resulting solution was concentrated to dryness. To this residue was added TFA (1.0 ml) and the solution was stirred for 18 hours, concentrated and purified by HPLC to provide the titled compound (0.0031 g, 18% yield) as a TFA salt. 1H NMR (500 MHz, MeOH) δ ppm 7.78 (1H, s), 7.57 (1H, s), 7.43-7.51 (2H, m), 7.31-7.40 (3H, m), 3.77-3.89 (1H, m), 3.06-3.20 (1H, m), 2.18-2.29 (2H, m), 2.09 (2H, m), 1.36-1.62 (4H, m). LC/MS, m/z 348 (M+1). HPLC Rt, 1.78 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.