Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8]CC)(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].[C:11]1([CH:21]=O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.[H-].[Na+].[OH-].[Na+]>C(O)C>[C:11]1([CH:21]=[C:3]([CH2:2][C:1]([OH:8])=[O:7])[C:4]([OH:6])=[O:5])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: CCOC(=O)CCC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC(=Cc1cccc2ccccc12)C(=O)O
Yield: 55.7 %

Procedure:
To a solution of 32.3 g of ethyl succinate and 29.0 g of 1-naphthaldehyde in 320 ml of absolute ethyl alcohol was added 10.7 g of a 50% sodium hydride (dispersion in mineral oil), and the mixture was heated under reflux for 0.5 hours. To the reaction mixture was added 230 ml of a 1N-aqueous sodium hydroxide solution, and the mixture was heated under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with diethyl ether to remove neutral materials. The aqueous layer was acidified by the addition of concentrated hydrochloric acid, and the acid solution was extracted with diethyl ether. The ethereal layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added benzene, and precipitated crystals were collected by filtration to obtain 26.5 g of 2-(1-naphthylmethylene)succinic acid.
Reaction SMILES: C(O[C:4](=O)[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])C.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[SH:26]>O>[S:26]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:4]1[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[C:12](=[O:17])[C:13]([F:14])([F:15])[F:16]
Reactant: CCOC(=O)CC1CCCCN1C(=O)C(F)(F)F
Reactant: Nc1ccccc1S
Solvent: O
Product: O=C(N1CCCCC1Cc1nc2ccccc2s1)C(F)(F)F
Temperature: 90 °C
Reaction time: 1 h

Procedure:
[1-(2,2,2-Trifluoroethanoyl)piperidin-2-yl] acetic acid ethyl ester, D28 (1.34 g) and 2-aminothiophenol (1.50 g) were suspended in polyphosphoric acid (30 ml) and heated to 90° C. for 2 h with vigorous stirring. After cooling, the reaction mixture was poured into iced water and stirred vigorously for 1 h. The aqueous solution was then extracted several times with ethyl acetate. After drying (MgSO4), the solvent was removed in vacuo and the residue chromatographed (silica gel) to afford the title compound as an oil (1.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[O:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH2:16][CH:15]1[CH2:24][NH2:25]>>[O:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH2:16][CH:15]1[CH2:24][NH:25][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:13]
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: NCC1COc2ccccc2O1
Product: O=C(NCC1COc2ccccc2O1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 2,3-dihydrobenzo[1,4]dioxin-2-ylmethylamine. The product was purified by mass directed purification to give the title compound as a yellow solid. δH (CD3OD): 3.69-3.73 (2H, m), 3.97-4.03 (1H, m), 4.32-4.42 (2H, m), 6.77-6.88 (4H, m), 7.10 (1H, s), 7.67 (1H, s), 8.58 (1H, s); m/z (ES+)=344 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[N:26]5[C:27](=[O:30])[NH:28][N:29]=[C:25]5[CH2:24][O:23][C:22]=4[N:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]#[N:48].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:38])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:20][C:21]4[N:26]5[C:27](=[O:30])[N:28]([CH2:46][C:47]#[N:48])[N:29]=[C:25]5[CH2:24][O:23][C:22]=4[N:31]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(n[nH]c3=O)CO4)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nn(CC#N)c3=O)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
To a solution of tert-butyl(1-(4-(1-oxo-8-phenyl-2,4-dihydro-1H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (70 mg, 0.14 mmol) in dry DMF (1 ml) was added potassium carbonate (57 mg, 0.41 mmol) and bromoacetonitrile (29 μl, 0.41 mmol) under nitrogen. The resulting mixture was stirred for 1 hour at room temperature. Water was added and the mixture was extracted with EtOAc (3×10 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 35% EtOAc in cyclohexane) to give the title compound (45 mg, 60%). 1H NMR (500 MHz, CDCl3): 8.43 (1H, s), 7.26-7.19 (7H,m), 7.14-7.12 (2H, m), 5.25 (2H, s), 4.96 (1H, br s), 4.72 (2H, s), 2.55-2.25 (4H, m), 2.10-2.03 (1H, m), 1.86-1.78 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[N+:7]([C:10]1[C:15](OC)=[CH:14][CH:13]=[CH:12][N:11]=1)([O-:9])=O.C1([C:24]2OC(=O)C[N:28]=2)C=CC=CC=1>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[OH:9][N:7]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][N:11]=2)[CH:24]=[N:28]1
Reactant: COc1cccnc1[N+](=O)[O-]
Reactant: O=C1CN=C(c2ccccc2)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Solvent: O
Product: On1ncc2cccnc21

Procedure:
A solution of Na2CO3 0.10 H2O (7.3 mmol) in H2O (10 ml) is emulsified under vigorous stirring at about room temperature or slightly elevated temperature with a solution of 2-nitro-3-methoxypyridine (4.25 mmol) and tetrabutylammonium bromide (10.06 mmol) as phase transfer catalyst in methylene chloride (~20mL). 2-phenyl-5(4H)-oxazolone (~60 mmol) is added in several portions during one hour. The layers are separated and the aqueous phase is washed with CH2Cl2. The combined organic solutions are dried with Na2SO4 and is evaporated under reduced pressure. The residue is chromatographed in silica gel starting with petroleum ether to which methylene chloride is gradually added. After recrystallizing, the complex is placed in refluxing methanol to which a catalytic amount of p-toluene sulfonic acid has been added. The sample is refluxed overnight. After cooling and evaporation of the solvent, the above-identified product is isolated.
Reaction SMILES: Cl[CH:2]=[CH:3][C:4]1[C:5]([C:11]([F:14])([F:13])[F:12])=[N:6][N:7]([CH3:10])[C:8]=1[CH3:9].CC(C)([O-])C.[K+].[Cl-].[NH4+]>C1COCC1>[C:3]([C:4]1[C:5]([C:11]([F:13])([F:14])[F:12])=[N:6][N:7]([CH3:10])[C:8]=1[CH3:9])#[CH:2]
Reactant: Cc1c(C=CCl)c(C(F)(F)F)nn1C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: C#Cc1c(C(F)(F)F)nn(C)c1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
1.27 g (5.67 mmol) of 4-(2-chloroethenyl)-1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazole from Example 1 are dissolved in 40 ml of dry THF and placed under a protective gas atmosphere. After cooling the reaction solution to 0° C., 1.91 (17.0 mmol) of potassium tert-butoxide are introduced and, after the addition is complete, the mixture is stirred at 20° C. for 3 hours. After the end of the reaction, a saturated ammonium chloride solution (25 ml) is added and the mixture is extracted twice with 30 ml each time of methylene chloride. The combined organic phases are dried over magnesium sulphate, the solvent is removed by distillation and 4-ethynyl-1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazole is isolated as a microcrystalline solid in a yield of 79% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH:14]([C:22]2([CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]2=[O:35])[C:15]([O:17]C(C)(C)C)=[O:16])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>ClCl.C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH:12][CH2:13][CH:14]([C:22]2([CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]2=[O:35])[C:15]([OH:17])=[O:16])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)NCC(C(=O)OC(C)(C)C)C2(CC(C)C)CCN(CCc3ccccc3)C2=O)cc1
Agent: ClCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: COc1ccc(S(=O)(=O)NCC(C(=O)O)C2(CC(C)C)CCN(CCc3ccccc3)C2=O)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.5 %

Procedure:
A cold (0° C.) solution of tert-butyl α-[[[(4-methoxyphenyl)sulfonyl]amino]methyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetate (374 mg, 0.669 mmol) in CH2 Cl2 (2 mL) is treated with TFA (2 mL). The solution is maintained at 0° C. for 40 min and then allowed to warm to room temperature under N2. After 1.5 hours, the solution is diluted with CH2Cl2 and stripped (5×). The residual foam is diluted with H2O (5 mL) and extracted into CH2Cl2 (3×20 mL). The extracts are combined, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to provide 301 mg (90%) of the title compound as a white, amorphous solid:
Reaction SMILES: [C:1]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:15][CH2:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:10][CH:9]=1)([O:3]CC)=O.[CH2:21]([NH2:24])[CH2:22][NH2:23]>>[NH2:23][CH2:22][CH2:21][NH:24][C:1]([CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH2:15][CH2:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:12][CH:13]=1)=[O:3]
Reactant: CCOC(=O)COc1ccc(C2=NNC(=O)CC2)cc1
Reactant: NCCN
Product: NCCNC(=O)COc1ccc(C2=NNC(=O)CC2)cc1
Temperature: 60 °C
Yield: 80.3 %

Procedure:
A mixture of 2.85 g (10.3 mmol) of 6-(4-carboethoxymethoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (prepared as described in Example 13) and 9.3 g (155 mmol) of ethylenediamine is heated at 60° C. under N2 for 30 min. Volatile materials are removed in vacuo, and the residue is recrystallized from methanol-EtOAc to give 2.40 g of 6-[4-[2-aminoethylcarbamoylmethoxy]phenyl]-4,5-dihydro-3(2H)-pyridazinone as a white solid, m.p. 176°-177.5° C. Yield, 80%.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][N+:7]([CH3:10])=[CH:8][Cl:9].[Cl-].C[Si](CC(N)=O)(C)C.[CH3:20][C:21]([O:23][CH2:24][C:25]1[CH2:34][S:33][C@@H:28]2[C@H:29](N)[C:30](=[O:31])[N:27]2[C:26]=1[C:35]([OH:37])=[O:36])=[O:22]>C(OCC)(=O)C.O1CCCC1.O.CN(C)C=O>[CH3:6][N+:7]([CH3:10])=[CH:8][Cl:9].[Cl-:3].[CH3:20][C:21]([O:23][CH2:24][C:25]1[CH2:34][S:33][C@@H:28]2[CH2:29][C:30](=[O:31])[N:27]2[C:26]=1[C:35]([OH:37])=[O:36])=[O:22]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: C[N+](C)=CCl
Agent: C[Si](C)(C)CC(N)=O
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1
Reaction time: 0.5 h

Procedure:
Vilsmeier reagent was prepared from phosphorus oxychloride (1.1 g) and N,N-dimethylformamide (0.5 g) in ethyl acetate (2.0 ml) in a conventional manner. 2-[2-(2,2,2-Trifluoroacetamido)-5-chlorothiazol-4-yl]-2-propargloxyiminoacetic acid (syn isomer, 2.2 g) was added to the stirred suspension of Vilsmeier reagent in tetrahydrofuran (22 ml) under ice cooling and stirred for 20 minutes at same temperature [Solution A]. Trimethylsilylacetamide (5.1 g) was added to the stirred suspension of 7-aminocephalosporanic acid (1.5 g) in tetrahydrofuran (30 ml); and the mixture was stirred for 30 minutes at 35° to 40° C. To the solution was added the solution [Solution A] at -10° C., and the resulting solution was stirred at the same temperature for 30 minutes. Water and ethyl acetate were added to the reaction mixture at -10° C. The organic layer was separated and added to water. The mixture was adjusted to pH 7.5 with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was separated and adjusted to pH 2.0 with 10% hydrochloric acid, and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure to give 7-[2-(2,2,2-trifluoroacetamido)-5-chlorothiazol-4-yl]-2-propargyloxyiminoacetamido]cephalosporanic acid (syn isomer, 2.51 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=1[F:38].C(OCC)(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:29][C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=2[F:38])[C@H:12]([CH2:16][CH2:17][C:18]([F:21])([F:19])[F:20])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: NC(=O)[C@@H](CCC(F)(F)F)NS(=O)(=O)c1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(CN([C@H](CCC(F)(F)F)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)c(F)c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 78.1 %

Procedure:
(R)-2-(4-Chlorophenylsulfonamido)-5,5,5-trifluoropentanamide (3.444 kg), potassium carbonate (2.774 kg), tetrabutylammonium bromide (0.484 kg), and 4-(bromomethyl)-3-fluorobenzonitrile (2.092 kg) were charged to a reactor. Ethyl acetate (17.2 L) and water (3.44 L) were then charged and the batch was heated to 50° C. until complete by HPLC (<1 relative Aβ starting material). The reaction is usually complete in about 15 hours. The batch was cooled to 15-20° C. and water (6.88 L) was charged and the bottom aqueous phase was separated. A solution of sodium phosphate monobasic (0.2 M in water, 20.66 L) was charged and the bottom aqueous phase was separated and the pH was tested to ensure that it was <6.5. (Note: If the pH is >6.5, an additional 20.66 L of 0.2 M sodium phosphate monobasic solution may be charged and the extraction and pH measurement repeated.) The solvent was then exchanged by a constant volume vacuum distillation. The reactor was placed under vacuum (270 mmHg) and the jacket was heated to 75-80° C. Once distillation of ethyl acetate started, isopropanol (41.34 L) was added at the same rate of distillate collection, and the overall batch volume was maintained at a constant level. Once all of the isopropanol was added, the vacuum was released and water (13.76 L) was charged. The batch temperature was maintained at approximately 50° C. during the water addition. The batch was then cooled to 15-20° C. and filtered. The wet cake was washed with 50% (v/v) aqueous isopropanol (4×21.6 kg) and then dried under vacuum at 50° C. to give the title compound as an off-white solid (3.648 kg, 78% yield.) 1H NMR (300 MHz, DMSO-d5) δ ppm 1.42-1.55 (m, 1H) 1.80-1.93 (m, 1H) 2.00-2.15 (m, 2H) 4.44 (dd, J=7.91, 1.13 Hz, 1H) 4.68 (d, J=17.71 Hz, 1H) 4.99 (d, J=17.71 Hz, 1H) 7.26 (s, 1H) 7.50 (s, 1H) 7.63-7.73 (m, 4H) 7.78-7.87 (m, 3H). 13C NMR (75 MHz, DMSO-d6) ppm 22.58-22.97 (m, 1C) 29.96 (d, J=29.09 Hz, 1C) 41.46 (d, J=5.49 Hz, 1C), 57.86, 110.97, 111.45 (d, J=10.43 Hz, 1C), 117.58, 119.11 (d, J=25.80 Hz, 1C), 124.89, 128.53, 128.56, 129.21, 131.17, 131.98, 137.44, 138.32, 158.99 (d, J=247.54 Hz, 2C), 170.25. 19F NMR, (CDCl3, 282 MHz) δ: −116.5, −65.9. IR (KBr): 3443, 3342, 3210, 2955, 2245, 1699, 1577, 1476, 1163 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:18][NH2:19])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=1.Cl[C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][C:24]([I:30])=[CH:23][N:22]=1.C(N(CC)C(C)C)(C)C>C(#N)C.O>[I:30][C:24]1[CH:25]=[C:26]([N+:27]([O-:29])=[O:28])[C:21]([NH:19][CH2:18][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]3[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:22][CH:23]=1
Reactant: COc1cc(CN)ccc1OCc1ccc(C)nc1
Reactant: O=[N+]([O-])c1cc(I)cnc1Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CNc2ncc(I)cc2[N+](=O)[O-])ccc1OCc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.8 %

Procedure:
To a stirred solution of (3-methoxy-4-((6-methylpyridin-3-yl)methoxy)phenyl)methanamine (7.30 g, 28.26 mmol) in acetonitrile (200 mL) was added 2-chloro-5-iodo-3-nitropyridine (8.44 g, 29.67 mmol) and N,N-diisopropylethylamine (5.48 g, 42.39 mmol). The brown mixture was heated to reflux. After 5 h, the brown mixture was allowed to cool to room temperature and was diluted with water (600 mL). The resulting precipitate was isolated by filtration and washed with water (200 mL). The moist solids were dissolved in ethyl acetate (300 mL), and this solution was washed with water (100 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated to provide 13.57 g (95%) of 5-iodo-N-(3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzyl)-3-nitropyridin-2-amine as a bright yellow solid.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][O:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.[OH-].[Na+].O>CO.O1CCOCC1>[NH2:26][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][O:20][CH2:19]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCCC3CCCOC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CCCC3CCCOC3)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.3 %

Procedure:
To a solution of N2-butyl-8-(methoxy)-9-[3-(tetrahydro-2H-pyran-3-yl)propyl]-9H-purine-2,6-diamine (198 mg) in dry methanol (20.8 ml) was added 4.0M hydrochloric acid in 1,4-dioxane (3.6 ml) in one go. The reaction was left to stir at room temperature for 4 hours. The reaction was neutralised by the addition of 2.0M sodium hydroxide solution and concentrated in vacuo. to give an off-white solid. To this solid was added water, triturated, and the solid filtered under vacuum until dry. This afforded the title compound as an off-white solid (151 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH2:16][C:17]([N:19]([C:21]2[C:22]([CH3:30])=[C:23]([CH2:28]O)[C:24]([CH3:27])=[CH:25][CH:26]=2)[CH3:20])=[O:18])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.S([Cl:42])(C)(=O)=O.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]([NH:15][CH2:16][C:17]([N:19]([C:21]2[C:22]([CH3:30])=[C:23]([C:24]([CH3:27])=[CH:25][CH:26]=2)[CH2:28][Cl:42])[CH3:20])=[O:18])=[O:14])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(/C=C/C(=O)NCC(=O)N(C)c2ccc(C)c(CO)c2C)cn1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(/C=C/C(=O)NCC(=O)N(C)c2ccc(C)c(CCl)c2C)cn1
Reaction time: 1 h

Procedure:
To a solution of 3-[N-[(E)-3-(6-acetylaminopyridin-3-yl)acryloylglycyl]-N-methylamino]-1-hydroxymethyl-2,6-dimethylbenzene (200 mg) in dimethylformamide (2 ml) were added triethylamine (136.1 μl) and mesyl chloride (52.9 μl) at 0° C., and the mixture was stirred for 1 hour at the same temperature and then for 1 hour at ambient temperature. Chloroform and saturated sodium bicarbonate solution were added to the reaction mixture, and the separated organic layer was washed with water, saturated sodium bicarbonate solution and brine, and dried over magnesium sulfate. The solvent was removed in vacuo to give 3-[N-[(E)-3-(6-acetylaminopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dimethylbenzyl chloride (191.0 mg) as pale yellow solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])O.[Na+].[BH4-].[Na+]>CO.O>[CH2:21]([NH:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2ccccc2)cc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc([C@@H]2C[C@H]2NCc2ccccc2)cc1)c1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of N-[4-(trans-2-aminocyclopropyl)phenyl]benzamide hydrochloride (70 mg) in methanol (2 mL) were added benzaldehyde (25 μL) and sodium hydrogen carbonate (30.5 mg). The reaction mixture was stirred at 70° C. for 1 hr, and ice-cooled to 0° C. and sodium borohydride (13.8 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized (hexane/ethyl acetate) to give the title compound (49.1 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:12])([CH3:11])[C:9]#[N:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N:19]([Si](C)(C)C)=[N+:20]=[N-:21].C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([C:8]([C:9]2[N:19]=[N:20][NH:21][N:10]=2)([CH3:12])[CH3:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(C)(C#N)c1ccc(-c2ccccc2)c(F)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(c1ccc(-c2ccccc2)c(F)c1)c1nn[nH]n1
Temperature: 150 °C

Procedure:
A mixture of 2-(2-fluoro-biphenyl-4-yl)-2-methyl-propionitrile (100 mg, 0.418 mmol), azidotrimethylsilane (222 μL, 1.672 mmol) and dibutyltin oxide (20 mg) in dry toluene (2.5 mL) was heated under microwave irradiation in a sealed vessel at 150° C. for 1000 seconds. The solution was then diluted with EtOAc, washed with water, the organics separated, dried (MgSO4), filtered and evaporated to dryness. The residue was purified by column chromatography (EtOAc) to afford the title compound, 5-[1-(2-Fluoro-biphenyl-4-yl)-1-methyl-ethyl]-2H-tetrazole as a colorless powder. 1H NMR (500 MHz, CD3OD) δ 7.50 (2H, m), 7.40-7.46 (3H, m), 7.35 (1H, m), 7.05-7.12 (2H, m), 1.87 (6H, s). LCMS(EI) 283.1 (M+H)+, 324.2 (M+Na+H3O)+.
Reaction SMILES: [CH3:1][C@H:2]([CH2:8][CH3:9])[CH2:3][CH2:4][C:5](=O)[CH3:6].[CH3:10][C:11]([S@@:14]([NH2:16])=[O:15])([CH3:13])[CH3:12]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Na+].O.[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[CH3:6]/[C:5](=[N:16]\[S@:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15])/[CH2:4][CH2:3][C@H:2]([CH3:1])[CH2:8][CH3:9]
Reactant: CC[C@@H](C)CCC(C)=O
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@@H](C)CC/C(C)=N/[S@@](=O)C(C)(C)C
Temperature: 50 °C
Reaction time: 20 h

Procedure:
A solution of (5R)-5-methylheptan-2-one (3 g, 23.4 mmol) in tetrahydrofuran (10 ml) was added to a solution of (S)-2-methylpropane-2-sulfinamide and titanium tetraethoxide (9.8 ml, 46.8 mmol) in tetrahydrofuran. The solution was stirred at 50° C. for 20 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate (50 ml) and then poured into brine (100 ml).