Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Si:8]1(C2C=CC=CC=2)[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([F:26])[C:23]([OH:27])=[C:22]([F:28])[CH:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:35][C@@H:36](O)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>>[CH2:1]([Si@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]([F:28])[C:23]([O:27][C@@H:36]([CH3:35])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[C:24]([F:26])[CH:25]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCC[Si]1(c2ccccc2)CCC(c2ccc(-c3cc(F)c(O)c(F)c3)cc2)CC1
Reactant: CCCCCCC[C@@H](C)O
Product: CCCCCCC[C@H](C)Oc1c(F)cc(-c2ccc([C@H]3CC[Si@H](CCCCCCC)CC3)cc2)cc1F

Procedure:
The general procedure of Example 1 was repeated using 4-(4-(4-n-heptyl-4-phenyl-4-silacyclohexyl)phenyl) -2,6-difluorophenol and (R)-2-nonanol, thereby obtaining the intended compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2OC(=O)[S:10][N:9]=2)=[CH:4][CH:3]=1.[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:15]>ClC1C=CC=CC=1Cl>[CH2:19]([O:18][C:16]([C:14]1[S:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:15]=1)=[O:17])[CH3:20]
Reactant: O=c1oc(-c2ccc(Cl)cc2)ns1
Reactant: CCOC(=O)C#N
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2)ns1
Temperature: 150 °C
Yield: 84.8 %

Procedure:
To a solution of 5-(4-chlorophenyl)-[1,3,4]oxathiazol-2-one (1.35 g, 6.32 mmol) in 1,2-dichlorobenzene (5 ml) was added ethyl cyanoformate (2.50 ml, 25.27 mmol). The resulting reaction mixture was refluxed for 24 h at 150° C. After the completion of the reaction (TLC monitoring), added ice-cold water and extracted with ethyl acetate (3×100 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum, to get the desired product (1.44 g, 85%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH3:17])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([NH:22][C:23]([C@@H:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26]1)=[O:24])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([NH:22][C:23]([C@@H:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]1[C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:16][CH3:17])=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCCNC(=O)[C@@H]1Cc2ccccc2N1
Product: CCCCNC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@H](CC)NC(=O)OCc1ccccc1

Procedure:
The process is performed as in Example 15 c), using 0.646 g (2.73 mmol) of N-benzyloxycarbonyl-2(S)-aminobutyric acid prepared as in Example 3 a) and 0.595 g (2.73 mmol) of the amide prepared in step b). An oil is obtained which is recrystallized from CCl4.
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=O)=[C:9]([CH3:17])[N:8]=1.[CH3:19][C:20]1[C:21]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1>>[CH3:19][C:20]1[C:21]([N:27]2[CH2:28][CH2:29][N:30]([C:11]([C:10]3[C:9]([CH3:17])=[N:8][C:7]([N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:18])=[CH:16][CH:15]=3)=[O:13])[CH2:31][CH2:32]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1
Reactant: COC(=O)c1ccc(N2CCCS2(=O)=O)nc1C
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nc3C)CC2)c(C)c1
Yield: 67.2 %

Procedure:
Using methyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methylnicotinate (220 mg) described in Preparation Example 37 and 1-(3,5-dimethylpyridin-2-yl)piperazine (186 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (235 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][S:8](CCC(OC)=O)(=[O:10])=[O:9])=[N:4][CH:3]=1.C[O-].[Na+].CC([O-])=O.[Na+].[NH2:25]OS(O)(=O)=O>C1COCC1.O>[Br:1][C:2]1[S:6][C:5]([CH2:7][S:8]([NH2:25])(=[O:10])=[O:9])=[N:4][CH:3]=1
Reactant: NOS(=O)(=O)O
Reactant: COC(=O)CCS(=O)(=O)Cc1ncc(Br)s1
Agent: CC(=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)Cc1ncc(Br)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.2 %

Procedure:
The product of Step 3 (1.244 g, 3.79 mmol) was taken up in THF (50 mL) at room temperature, and NaOMe (25% in MeOH, 0.819 g, 3.79 mmol) was added. After 30 min at room temperature, the suspension was evaporated to dryness, providing a yellow solid. The solid was taken up in water (25 mL), and a solution of NaOAc (1.710 g, 20.85 mmol) and hydroxylamine-O-sulfonic acid (2.143 g, 18.95 mmol) in water (12.5 mL) was added while cooling the reaction (0° C.). The reaction was vigorously stirred at room temperature overnight. The reaction was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. Flash chromatography (dry load, 10-100% EtOAc/hexanes) afforded 1-(5-bromo-1,3-thiazol-2-yl)methanesulfonamide (470 mg, 48%) as a colorless solid. MS ESI: [M+H]+ m/z 256.9/258.9.
Reaction SMILES: [C:1]([C:3]1[N:4]=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].Cl.[NH2:11][OH:12].C(N(CC)CC)C>CO>[OH:12][N:11]=[C:1]([C:3]1[N:4]=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)[NH2:2]
Reactant: Cc1ccc(C#N)nn1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1ccc(C(N)=NO)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Cyano-6-methyl pyridazine (U.S. Pat. No. 5,914,319) (0.77 g, 6.4 mmol) was dissolved in methanol (20 mL), then hydroxylamine hydrochloride (0.66 g, 9.6 mmol) and triethylamine (1.3 mL, 9.6 mmol) were added and the mixture was stirred at room temperature overnight. The mixture was chilled in an ice-bath, then the solid was collected by filtration, washed with methanol and dried to give the title compound as a pale yellow solid (0.84 g).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[CH:11]2.[OH-].[Na+].[BrH:18]>O>[Br:18][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][N:10]=[CH:11]2
Reactant: Nc1cccc2cnccc12
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Brc1cccc2cnccc12
Temperature: 75 °C
Reaction time: 1 h

Procedure:
Add a solution of sodium nitrite (9.6 g, 139 mmol) in water (50 mL) cautiously to 5-aminoisoquinoline (20 g, 139 mmol) in hydrobromic acid (48%, 100 mL) at 0° C. Transfer this mixture to a vessel containing CuBr (25 g, 174 mmol) in hydrobromic acid (48%, 200 mL) at 75° C. After complete addition, stir the mixture at 75° C. for one hour, cool to room temperature and stir overnight. Place the mixture in an ice bath, add ice to the reaction mixture, and then add sodium hydroxide aqueous solution (20%, 250 mL). Filter the slurry and extract the filtrate with diethyl ether. Combine the solid and the extract sonicate for one hour in chloroform Filter the suspension through a plug of Celite™, and concentrate the filtrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with chloroform.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)[C:5]([F:14])=[CH:4][N:3]=1.[NH2:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1>>[F:14][C:5]1[C:6]([NH:8][N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)=[N:7][C:2]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)=[N:3][CH:4]=1
Reactant: Nc1cccc(O)c1
Reactant: Fc1cnc(Cl)nc1Nn1cccc1
Product: Oc1cccc(Nc2ncc(F)c(Nn3cccc3)n2)c1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(1H-pyrrol-1-yl)-4-pyrimidineamine was reacted with 3-aminophenol to produce 5-fluoro-N2-(3-hydroxyphenyl)-N4-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.68 (s, 1H), 9.04 (s, 1H), 9.00 (s, 1H), 8.08 (d, 1H, J=4.11 Hz), 7.01 (d, 1H, J=8.2 Hz), 6.84-6.75 (m, 4H), 6.22 (dd, 1H, J=1.2 and 8.2 Hz), 6.08 (t, 2H, J=2.3 Hz). LCMS: ret. time: 16.24 min.; purity: 94%; MS (m/e): 286 (MH+).
Reaction SMILES: [BH3-]C#N.[Na+].[CH2:5]([O:7][CH:8]([O:10][C:11]1[CH:19]=[CH:18][C:14]2[O:15][CH2:16][O:17][C:13]=2[C:12]=1[CH:20]=O)[CH3:9])[CH3:6].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(O)(=O)C>CC#N>[CH2:5]([O:7][CH:8]([O:10][C:11]1[CH:19]=[CH:18][C:14]2[O:15][CH2:16][O:17][C:13]=2[C:12]=1[CH2:20][N:26]1[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]1)[CH3:9])[CH3:6]
Reactant: CCOC(C)Oc1ccc2c(c1C=O)OCO2
Reactant: CN1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(C)Oc1ccc2c(c1CN1CCN(C)CC1)OCO2
Reaction time: 3 h
Yield: 74 %

Procedure:
NaCNBH3 (6.4 g, 101.8 mmol) was added to a stirred solution of 5-(1-ethoxyethoxy)-4-formyl-1,3-benzodioxole (16.0 g, 67.2 mmol) and 1-methylpiperazine (20.2 g, 201.7 mmol) in CH3CN (150 ml). Acetic acid (10 ml) was added dropwise to the solution in one hour at room temperature, to keep the pH neutral (pH=7). After 3 hours of additional stirring, most of the CH3CN was evaporated in vacuo. Aqueous NaOH (2N, 300 ml) was added and the resulting mixture was extracted with diethyl ether (3 times). The combined ether extracts were washed with an aqueous solution of Na2CO3, dried over Na2SO4, filtered and evaporated to yield 26 g of a crude oil. This oil was purified by flash chromatography (eluent gradient; dichloromethane/methanol/25% aqueous ammonia=95/4.5/0.5 to 85/14/1 (v/v) to give 5-(1-ethoxyethoxy)-4-(4-methyl-piperazinylmethyl)-1,3-benzodioxole (16.0 g, 74% yield, compound No. 4) as a colorless oil.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.[Cl:15][C:16]1[CH:21]=[C:20]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)[CH:19]=[C:18]([Cl:30])[C:17]=1[C:31]1[N:35]2[CH:36]=[C:37](F)[CH:38]=[CH:39][C:34]2=[N:33][N:32]=1>CN(C=O)C>[Cl:15][C:16]1[CH:21]=[C:20]([CH2:22][N:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]2)[CH:19]=[C:18]([Cl:30])[C:17]=1[C:31]1[N:35]2[CH:36]=[C:37]([O:14][C@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:38]=[CH:39][C:34]2=[N:33][N:32]=1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CN1CCN(Cc2cc(Cl)c(-c3nnc4ccc(F)cn34)c(Cl)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(Cc2cc(Cl)c(-c3nnc4ccc(O[C@@H]5CC[C@H](N)c6ccccc65)cn34)c(Cl)c2)CC1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 18.6 %

Procedure:
A suspension of sodium hydride (60% dispersion in oil, 56 mg, 1.39 mmol) in dry DMF (2.0 mL) under nitrogen was treated with Intermediate 1 (46 mg, 0.28 mmol) and the mixture was stirred for 20 min. Intermediate 13d (110 mg, 0.28 mmol) was added and the mixture was heated to 60° C. for 1.75 h then quenched with MeOH. The mixture was further diluted with MeOH and applied to a pre-conditioned (MeOH) SCX-2 cartridge (10g). The cartridge was eluted with MeOH then 2M NH3 in MeOH. The relevant fractions were combined and concentrated in vacuo. The residue was dissolved in DCM containing a few drops of MeOH and purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (28 mg, 19%). LCMS (Method 3): Rt 2.08 min, m/z 537, 539 [MH+].
Reaction SMILES: FC(F)(F)[C:3]1[N:16]=[C:15]2[C:17]3=[C:18]4[C:8]([N:9]=[C:10](C(F)(F)F)[N:11]=[C:12]4[CH:13]=[C:14]2Br)=[C:7](Br)[CH:6]=[C:5]3[N:4]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32]([C:7]2[C:8]3[C:18]4[C:12](=[CH:13][C:14]([C:32]5[CH:33]=[CH:34][C:29]([C:28]([F:39])([F:38])[F:27])=[CH:30][CH:31]=5)=[C:15]5[C:17]=4[C:5]([CH:6]=2)=[N:4][CH:3]=[N:16]5)[N:11]=[CH:10][N:9]=3)=[CH:31][CH:30]=1
Reactant: FC(F)(F)c1nc2cc(Br)c3nc(C(F)(F)F)nc4cc(Br)c(n1)c2c43
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: FC(F)(F)c1ccc(-c2cc3ncnc4c(-c5ccc(C(F)(F)F)cc5)cc5ncnc2c5c34)cc1
Temperature: 101 °C
Reaction time: 48 h
Yield: 23.1 %

Procedure:
An oven-dried Schlenk tube was loaded with 130 mg (0.26 mmol) 2,7-bis-(trifluoromethyl)-4,9-dibromo-1,3,6,8-tetraazapyrene, 197 mg (1.04 mmol) 4-trifluoromethylphenylboronic acid, 508 mg (1.56 mmol) caesium carbonate and 19 mg (0.03 mmol) Pd(dppf)Cl2 and evacuated and refilled with argon for three times. 20 ml abs. 1,4-dioxane were added, the Schlenk tube was sealed with a glass cap and the reaction mixture was stirred at 101° C. for 48 h. The mixture was allowed to cool to room temperature, the solvent was evaporated and the solid residue was extracted with chloroform. The organic phase was washed with water and brine, dried over sodium sulphate and evaporated in vacuo. The solid was washed with methanol and pentane to yield 35 mg (0.06 mmol, 23%) of the compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([CH2:7][N:8]2[CH:17]=[C:11]3[N:12]=[CH:13][CH:14]=[C:15](I)[C:10]3=[N:9]2)[CH2:4][O:3]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[F:61][C:62]1[C:63]([C:69]2[CH:74]=[C:73]([NH2:75])[CH:72]=[CH:71][N:70]=2)=[N:64][C:65]([CH3:68])=[CH:66][CH:67]=1.CC([O-])(C)C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:18][C:2]1([CH3:1])[O:6][C@@H:5]([CH2:7][N:8]2[C:17]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[NH:75][C:73]3[CH:72]=[CH:71][N:70]=[C:69]([C:63]4[C:62]([F:61])=[CH:67][CH:66]=[C:65]([CH3:68])[N:64]=4)[CH:74]=3)[CH:10]=[N:9]2)[CH2:4][O:3]1
Reactant: Cc1ccc(F)c(-c2cc(N)ccn2)n1
Reactant: CC1(C)OC[C@H](Cn2cc3nccc(I)c3n2)O1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1ccc(F)c(-c2cc(Nc3ccnc4cnn(C[C@H]5COC(C)(C)O5)c34)ccn2)n1
Temperature: 120 °C

Procedure:
(S)-2-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)-7-iodo-2H-pyrazolo[4,3-b]pyridine (51 mg, 0.142 mmol), Tris(dibenzylideneacetone)dipalladium(0) (3.25 mg, 3.55 μmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (20.54 mg, 0.035 mmol), 3′-fluoro-6′-methyl-2,2′-bipyridin-4-amine (28.9 mg, 0.142 mmol) and sodium 2-methylpropan-2-olate (40.9 mg, 0.426 mmol) were combined in dioxane (5 mL). The mixture was heated at 120° C. for 2 hours, then cooled and purified by preparative HPLC using a Phenomenex Gemini Prep 5 μm C18, 75×30 mm column eluting with a gradient of 5-40% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) to give (S)-1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-N-(3′-fluoro-6′-methyl-2,2′-bipyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine which was combined with methanol (5 mL) and 1N HCl (2 mL) and stirred at room temperature for 30 minutes before evaporation to afford the title compound (12.5 mg, 22.32% yield) as a HCl salt. 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.57 (s, 3H) 3.41 (m, 1H) 3.49 (m, 1H) 3.97-4.10 (m, 1H) 4.51 (m, 1H) 4.69 (m, 1H) 7.51 (dd, J=8.59, 3.54 Hz, 1H) 7.64 (d, J=6.32 Hz, 1H) 7.71 (dd, J=11.24, 8.72 Hz, 1H) 8.01 (d, J=5.05 Hz, 1H) 8.53 (s, 1H) 8.63 (d, J=6.32 Hz, 1H) 8.66-8.71 (m, 2H). MP 182-184° C. MS [M+H] found 395.3.
Reaction SMILES: [CH:1](I)([CH3:3])[CH3:2].[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:1]([CH3:3])[CH3:2])=[CH:21][CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)I
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)[C@H](Cc1ccc(OC(C)C)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 74.1 %

Procedure:
Isopropyl iodide (30 uL, 0.3 mmol) was added to a mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxyphenyl)propanoate (50 mg, 0.2 mmol) (Aldrich, Cat. #469106) and potassium carbonate (35 mg, 0.25 mmol) in acetonitrile (2 mL). The reaction was heated at 60° C. overnight. The reaction was partitioned between water and ethyl acetate. The organic phase was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product (S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-isopropoxyphenyl)propanoate (50 mg, 90%) as a white solid. Analytical LCMS (M+H-Boc)+: m/z=238.0.
Reaction SMILES: [CH:1]1([Li:6])[CH:5]=[CH:4][CH:3]=[CH:2]1.[N:7](OS(C)(=O)=O)([CH3:9])[CH3:8].C([Li])CCC>C1COCC1.CCCCCC>[CH3:8][N:7]([C:1]1([Li:6])[CH:5]=[CH:4][CH:3]=[CH:2]1)[CH3:9]
Reactant: [Li]C1C=CC=C1
Reactant: CN(C)OS(C)(=O)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Li]C1(N(C)C)C=CC=C1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of 3 g of cyclopentadienyllithium (0.042 moles) in 30 ml of THF was added slowly at −30° C. to a solution of 5.9 g of compound 6 (0.042 moles) in 20 ml of THF. The mixture was then heated to −20° C. and stirred for 30 min. Hexane was then added and the solution was filtered. 1.8 ml of a 2.3 molar solution of butyllithium (0.042 moles) in hexane were then added at −20° C. to produce a precipitate. The precipitate was filtered off and washed with twice 20 ml of hexane. After drying under vacuum, 2.0 g (40% of the theoretical yield) of compound 7 were obtained in the form of a white powder; cf. Angew. Chem., Int. Ed. Engl. 19, (1980), 1010. 1H NMR (400 MHz, THF): δ=5.34 (bd, J=2.2 Hz, 2H); 5.15 (bd, J 2.2 Hz, 2H); 2.56 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][CH:7]=[CH:6][N:5]2[CH:18]=1.C(Cl)(Cl)Cl.Cl.[N:24]([O-])=[O:25].[Na+]>O>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][CH:7]=[CH:6][N:5]2[C:18]=1[N:24]=[O:25]
Reactant: O=N[O-]
Reactant: Cc1cn2cccc(OCc3ccccc3)c2n1
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1nc2c(OCc3ccccc3)cccn2c1N=O
Temperature: 25 °C

Procedure:
To a stirred mixture of 10.0 g (42.2 mmol) of 2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine, 150 ml of water and 150 ml of chloroform is added cautiously (EXOTHERM) 179.5 ml (2.15 moles) of concentrated hydrochloric acid and the resultant mixture is heated to an internal temperature of approximately 55° C. To this stirred and heated mixture is added at a rate of approximately 7 ml/minute a solution of of 151 g (2.11 moles) sodium nitrite (97%) in 660 ml of water to produce a vigorous, but manageable, reflux. When the addition is complete,the reaction mixture is allowed to cool to room temperature. The lower (CHCl3) layer is drawn off and the aqueous layer extracted with three--150 ml portions of chloroform. The combined chloroform extracts arewashed with two--450 ml volumes of 2.4 M sodium carbonate solution, then with a single 500 ml portion of saturated aqueous sodium chloride. The extracts are concentrated in vacuo (rotary evaporator, 45°) to lessthan one-half the original volume, dried over anhydrous sodium sulfate and evaporated to a viscous oil. Chromatography of the oil on silica gel, eluting with chloroform/ethyl acetate (1/1) yields the title compound as acrystalline solid, mp 147.5°-149.5° C. (dec).
Reaction SMILES: CO[C:3](OC)([CH3:5])[CH3:4].CS(O)(=O)=O.[Cl:13][CH2:14][C@@H:15]([OH:29])[CH2:16][C@@H:17]([OH:28])[CH2:18][C:19]([N:21]([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[O:20]>CC(C)=O>[Cl:13][CH2:14][C@H:15]1[O:29][C:3]([CH3:5])([CH3:4])[O:28][C@@H:17]([CH2:18][C:19]([N:21]([CH:22]([CH3:23])[CH3:24])[CH:25]([CH3:27])[CH3:26])=[O:20])[CH2:16]1
Reactant: COC(C)(C)OC
Reactant: CC(C)N(C(=O)C[C@H](O)C[C@H](O)CCl)C(C)C
Agent: CS(=O)(=O)O
Solvent: CC(C)=O
Product: CC(C)N(C(=O)C[C@H]1C[C@@H](CCl)OC(C)(C)O1)C(C)C
Temperature: 30 °C
Reaction time: 3 h

Procedure:
2,2-dimethoxy propane (1050 ml) and 2.6 ml of methane sulfonic acid added to a solution of 280 grams of (3R,5S)-6-chloro-3,5-dihydroxy-N,N-diisopropylhexanamide, 1500 ml of acetone. Stirred the reaction mixture for 3 hours at 25-35° C. Quenched the reaction mixture with sodium bicarbonate solution. Separated the organic and inorganic phases. Extracted the aqueous layer with petroleum ether and washed the organic layer with brine solution. Dried the organic layer over sodium sulfate. Distilled the solvent completely under reduced pressure to get the title compound as a residue.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH3:10][C:11]([C:16]1[O:17][C:18]([CH3:21])=[CH:19][CH:20]=1)([CH3:15])[CH2:12][CH:13]=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:13]/[CH2:12][C:11]([CH3:15])([C:16]1[O:17][C:18]([CH3:21])=[CH:19][CH:20]=1)[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(C)(C)CC=O)o1
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: Cc1ccc(C(C)(C)C/C=N/CC(=O)OC(C)(C)C)o1
Yield: 101.4 %

Procedure:
Step F In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.79 g, 6 mmol) was reacted with 3-methyl-3-(5-methyl-furan-2-yl)-butyraldehyde 1 g, 6 mmol) in CH2Cl2 at room temperature for 5 h to give [3-methyl-3-(5-methyl-furan-2-yl)-but-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.7 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:46][CH2:47][C:48]1[C:49]([OH:56])=[N:50][C:51]([CH3:55])=[CH:52][C:53]=1[CH3:54]>ClCCl>[OH:56][C:49]1[C:48]([CH2:47][NH:46][C:10](=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([C:3]([O:2][CH3:1])([CH3:4])[CH3:5])=[CH:14][CH:13]=2)=[C:53]([CH3:54])[CH:52]=[C:51]([CH3:55])[N:50]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: COC(C)(C)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(C)(C)c1ccc(C(=O)NCc2c(C)cc(C)nc2O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
To a solution of 4-(2-methoxypropan-2-yl)benzoic acid (0.09 g, 0.46 mmol) and O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.23 g, 0.61 mmol) in dichloromethane (10 mL) was added triethylamine (0.15 g, 1.5 mmol). The reaction mixture was stirred for 15 minutes at room temperature, then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.08 g, 0.53 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction, the mixture was washed with water (20 mL), concentrated and purified by column chromatography (silica gel:dichloromethane:methanol=30:1) to give the pure product N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(2-methoxypropan-2-yl)benzamide (0.09 g, 61%) as a white solid. LRMS (M+H+) m/z: calcd for 328.18. found 328. HPLC Purity (214 nm) 99.8%. 1H NMR (300 MHz, DMSO-d6) δ: 11.47 (s, 1H), 8.32 (d, J=1.5 Hz, 1H), 7.81 (d, J=8.1 Hz, 2H), 7.43 (d, J=8.4 Hz, 2H), 5.86 (s, 1H), 4.30 (d, J=4.8 Hz, 2H), 2.97 (s, 3H), 2.17 (s, 3H), 2.11 (s, 3H), 1.44 (s, 6H).
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][CH2:56][CH:57]2[CH2:59][O:58]2)=[CH:51][CH:50]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[S:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[CH2:23][CH2:22][CH2:21][NH:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:59][C@H:57]([OH:58])[CH2:56][O:55][C:52]3[CH:53]=[CH:54][C:49]([OH:48])=[CH:50][CH:51]=3)=[CH:30][CH:29]=2)[CH2:13][CH2:14]1)=[O:19]
Reactant: NCCc1ccc(NC2CCN(C(=O)NCCCc3cccs3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O=CO
Product: O=C(NCCCc1cccs1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 34.3 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-[3-(2-thienyl)propyl]-1-piperidinecarboxamide formate (0.33 g, 0.67 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.275 g, 0.686 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.182 g, 0.230 mmol).