Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:41])([CH3:40])[C:3]([NH:5][C:6]1[NH:7][C:8](=[O:39])[C:9]2[CH2:15][CH:14]([CH2:16][CH2:17][C:18]3[S:22][C:21]([C:23]([NH:25][C@H:26]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:24])=[CH:20][CH:19]=3)[CH2:13][NH:12][C:10]=2[N:11]=1)=[O:4].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl>[CH3:41][C:2]([CH3:1])([CH3:40])[C:3]([NH:5][C:6]1[NH:11][C:10]2[N:12]=[CH:13][C:14]([CH2:16][CH2:17][C:18]3[S:22][C:21]([C:23]([NH:25][C@H:26]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:24])=[CH:20][CH:19]=3)=[CH:15][C:9]=2[C:8](=[O:39])[N:7]=1)=[O:4]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCC2CNc3nc(NC(=O)C(C)(C)C)[nH]c(=O)c3C2)s1)C(=O)OCC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2cnc3[nH]c(NC(=O)C(C)(C)C)nc(=O)c3c2)s1)C(=O)OCC
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
Dichloromethane (350 mL) was added to the 2:3 mixture of R-L and S-L diastereomers of N-[[5-[2-[2-[(2,2-dimethyl-1-oxopropyl)amino)-3,4,5,6,7,8-hexahydro-4-oxopyrido-(2,3-d)-pyrimidin-6-yl]ethyl]-2-thienyl]carbonyl]-L-glutamic acid, diethyl ester (17.0 g, 28.9 mmole) from Preparation 9 and stirred 30 minutes until a light yellow solution formed. As a solid, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (13.4 g, 59.2 mmol) was added. The solution initially turned purple, then with 30 minutes stirring at room temperature it transitioned to a light pink mixture. A pink solid was removed by filtration, washing three times with dichloromethane (25 mL). The filtrate was stirred three times for 30 minutes with a saturated solution of sodium bicarbonate (200 mL) and separated. The final organic layer was stirred for 30 minutes with sodium bicarbonate (100 mL) and water (100 mL) then separated. The organic layer was washed with brine (100 mL) and dried over magnesium sulfate. Removal of the solvent at reduced pressure gave 14.7 g (87.1%) of the title compound. mp 57° C.-87° C. IR(CHCl3): 3690-3025, 2978, 3000, 1736, 1677, 1629, 1558, 1449, 1245, 1147, 1022, 811 cm−1. MS(HR) calculated for C28H35N5O7S: 586.234100. Found: 586.233546.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[C:12]([NH:15][C:16]([NH2:18])=[NH:17])(=[O:14])[CH3:13]>C(#N)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:17]=[C:16]([NH:15][C:12](=[O:14])[CH3:13])[NH:18][CH:2]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)NC(=N)N
Reactant: O=C(CBr)c1ccc(F)cc1
Solvent: CC#N
Product: CC(=O)Nc1nc(-c2ccc(F)cc2)c[nH]1
Yield: 33.7 %

Procedure:
3.00 g (13.82 mmol) 2-bromo-4′-fluoroacetophenone, 2.80 g (27.64 mmol) acetylguanidine and 15 ml acetonitrile were combined and were together brought to reaction in the microwave (at 100 Watt) for 60 minutes at 40° C. by “heating by cooling”. After cooling, the solid formed was filtered off of the solvent. In addition, a total amount of 1.02 g N-[4-(4-fluorphenyl)-1H-imidazole-2-yl]acetamide were isolated by fractional crystallization with ethanol of the remainder of the mother liquor.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][S:7][CH2:8][CH:9]=[CH2:10].[CH2:12](O)[CH:13](C)[CH3:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:1]([O:2][C:3](=[O:11])[CH2:4][CH2:5][CH2:6][S:7][CH2:8][CH:9]=[CH2:10])[CH:13]([CH3:14])[CH3:12]
Reactant: CC(C)CO
Reactant: C=CCSCCCC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: C=CCSCCCC(=O)OCC(C)C
Temperature: 25 °C

Procedure:
Into a 25 cc micro flask equipped with spin bar, hot plate (having built in magnetic stirrer), thermometer and reflux condenser are placed 5 grams (0.2874 moles) methyl-4-(allylthio)butyrate; 8.5 grams (0.1149 moles) of isobutanol and 0.05 grams of para-toluene sulfonic acid. The reaction mass is heated to reflux and maintained at reflux for a period of 14.33 hours. At the end of the refluxing period, the reaction mass is cooled to room temperature and charged to a distillation flask and distilled on a micro Vigreux column yielding the following fractions:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[CH:25]=[CH:24][C:18]=1[CH:19]=[CH:20][C:21](O)=O>>[CH3:15][O:16][C:17]1[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[CH:25]=[CH:24][C:18]=1/[CH:19]=[CH:20]/[C:21]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1C
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(C)c3OC)nc2n(CC)c1=O

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.0 g (10.1 mmol) of 5,6-diamino-1,3 -diethyluracil and 2.04 g (9.19 mmol) of 2,4-dimethoxy-3-methylcinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.22 g (yield of Compound 76 as a yellow powder.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[C:8]1([NH:14][NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.N1C=CC=CC=1.Cl>CN(C=O)C>[C:8]1([NH:14][NH:15][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)C1CCC1
Reactant: NNc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(NNc1ccccc1)C1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.54 mL (31.0 mmol) cyclobutanecarboxylic acid chloride were added dropwise at RT to 3.00 mL (30.2 mmol) phenylhydrazine and 4.75 mL (60.0 mmol) pyridine in 30 mL DMF. The mixture was stirred for 1 h at RT and poured onto 200 mL of a 1M hydrochloric acid solution. The precipitated solid was suction filtered, washed with 50 mL water and dried i. vac. The product was extracted with 50 mL ether and suction filtered. The solid was washed with 20 mL ether and dried in the air.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([OH:19])[CH:9]=[C:10]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.B(Br)(Br)Br.[OH-].[Na+]>ClCCl>[OH:19][C:8]1[CH:9]=[C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])[C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]([OH:2])[CH:12]=2
Reactant: COc1ccc2cc(O)cc(CCNC(C)=O)c2c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)NCCc1cc(O)cc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Dissolve 0.2 g (0.771 mmol) of N-[2-(7-methoxy-3-hydroxynaphth-1-yl)ethyl]acetamide, according to Example 77, in 5 cm3 of anhydrous dichloromethane. Cool in a bath of ice and salt. Add dropwise 0.8 cm3 of 1M boron tribromide. Stir in ice at room temperature for 4 hours. Add a further 0.8 cm3 of 1M boron tribromide in CH2CL2. Allow to stir overnight at room temperature. Bring to pH 8 with 1N NaOH. Extract with CH2Cl2. Dry with MgSO4. Evaporate off the solvent. Recover the product. Extract with methyl ethyl ketone. Dry over MgSO4. Evaporate off the solvent. Purify the product on 30 g of silica. Elute with CH2Cl2 /MeOH: 95/5. The product of Example 78 is obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)=[CH:6][N:5]=[C:4]([N:15]2[CH2:20][C@H:19]([CH3:21])[O:18][C@H:17]([CH3:22])[CH2:16]2)[N:3]=1.[C:23]1([CH3:32])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].CC#N>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:22][C@H:17]1[O:18][C@@H:19]([CH3:21])[CH2:20][N:15]([C:4]2[N:3]=[C:2]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[CH3:32])[C:7]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=3)=[CH:6][N:5]=2)[CH2:16]1
Reactant: Cc1cc(-c2cnc(N3C[C@@H](C)O[C@@H](C)C3)nc2Cl)ccn1
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2cnc(N3C[C@@H](C)O[C@@H](C)C3)nc2-c2ccccc2C)ccn1
Temperature: 20 °C
Yield: 30.3 %

Procedure:
To a suspension of cis-4-(4-chloro-5-(2-methylpyridin-4-yl)pyrimidin-2-yl)-2,6-dimethylmorpholine (0.100 g, 0.314 mmol), o-tolylboronic acid (0.064 g, 0.471 mmol) and potassium carbonate (0.138 g, 1 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) stirred in air at 20° C. was added solid tetrakis(triphenylphosphine)palladium(0) (0.058 g, 0.0500 mmol). The reaction mixture was stirred under nitrogen at 100° C. overnight. The reaction mixture was allowed to cool to room temperature, diluted with water and extracted with ethyl acetate (×3). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The crude product was purified by pre-HPLC, (Gilson GX-281; Shimadzu 15 um 250*19 mm; A:10 mMol NH4HCO3/Water B: CH3CN; 0-7 min 85-95%, 7-14 min 95%; 214 nm; 30 mL/min) to obtain the title compound (35.4 mg, 0.095 mmol, 30.1% yield). LC/MS [M+H]+=375; 1H NMR (400 MHz, CDCl3): δ 8.41 (1H, s), 8.27-8.25 (1H, s), 7.29-7.25 (1H, m), 7.17-7.14 (2H, m), 7.10-7.09 (1H, m), 6.81 (1H, s), 6.69-6.67 (1H, d), 4.69-4.65 (2H, d), 3.72-3.63 (2H, m), 2.69-2.63 (2H, m), 2.43 (3H, s), 2.07 (3H, s), 1.27-1.26 (6H, d).
Reaction SMILES: [Na].[CH3:2][CH:3]([OH:17])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([CH3:16])[CH2:14][CH3:15])=[CH:8][CH:7]=1.Cl[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH3:2][CH:3]([O:17][C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([CH3:16])[CH2:14][CH3:15])=[CH:8][CH:7]=1
Reactant: Clc1ncccn1
Reactant: CCC(C)Oc1ccc(OCC(C)O)cc1
Agent: [Na]
Product: CCC(C)Oc1ccc(OCC(C)Oc2ncccn2)cc1

Procedure:
In the same manner, the sodium salt of 1-methyl-2-[4-(1-methylpropoxy)phenoxy]ethanol and 2-chloropyrimidine are reacted together to give 2-{1-methyl-2-[4-(1-methylpropoxy)phenoxy]ethoxy}pyrimidine, MS m/e 320 (M+ +NH4).
Reaction SMILES: [OH:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18].[C:19](Cl)(=[O:23])[CH2:20][CH2:21][CH3:22]>>[C:19]([O:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18])(=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: CC1=C2C[C@@]3(C)C(=CC[C@H](O)[C@@H]3C)C=C2OC1=O
Reactant: CCCC(=O)Cl
Product: CCCC(=O)O[C@H]1CC=C2C=C3OC(=O)C(C)=C3C[C@]2(C)[C@H]1C

Procedure:
The title compound was prepared in the same manner as in Example B2, except that the compound prepared in Example B1 was reacted with butyryl chloride.
Reaction SMILES: [O-]CC.[Na+].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]#[N:14])=[CH:8][CH:7]=1.[CH2:15]([O:17][CH2:18][C:19](OCC)=[O:20])[CH3:16]>C(O)C>[CH2:15]([O:17][CH2:18][C:19](=[O:20])[CH:12]([C:9]1[CH:10]=[CH:11][C:6]([CH3:5])=[CH:7][CH:8]=1)[C:13]#[N:14])[CH3:16]
Reactant: Cc1ccc(CC#N)cc1
Reactant: CCOCC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOCC(=O)C(C#N)c1ccc(C)cc1
Reaction time: 1 h
Yield: 70 %

Procedure:
Sodium ethoxide (2 eq) is dissolved in ethanol (200 mL) and 4-methylphenylacetonitrile (10.0) and ethyl ethoxyacetate (1.5 eq) are slowly added. The reaction mixture is stirred for 1 hour under reflux. Upon completion of the reaction, ethanol is removed under reduced pressure and water (100 mL) and ethyl acetate are added. The organic layer is removed and the aqueous layer is acidified by adding acetic acid (10 mL) and extracted 3 times with ethyl acetate. The extracted organic layer is collected, washed with water and dehydrated with MgSO4. After concentration under reduced pressure, the produced solid is recrystallized with Hx:EA=20:1 to obtain the target compound (70-95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[C:9]([NH:22][C@@H:23]3[CH2:28][CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]3)=[N:10][C:11]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[N:12][C:13]=2[O:14]C)=[N:6][CH:7]=1.[Na+].[I-].[Si](Cl)(C)(C)C>CC#N>[F:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[C:13](=[O:14])[NH:12][C:11]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[N:10][C:9]=2[NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)=[N:6][CH:7]=1
Reactant: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1ncc(F)cn1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: O=c1[nH]c(N2CCOCC2)nc(N[C@@H]2CCCNC2)c1-c1ncc(F)cn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To (R)-tert-butyl 3-((5-fluoro-6′-methoxy-2′-morpholino-[2,5′-bipyrimidin]-4′-yl)amino)piperidine-1-carboxylate (0.025 g, 0.051 mmol) in MeCN (1 mL) was added NaI (0.011 g, 0.077 mmol) followed by TMS-Cl (9.79 μl, 0.077 mmol). The reaction was stirred at room temperature for 15 min. then heated to 50° C. for 3 h. The solvent was removed in vacuo and the residue was purified via semi-preparative HPLC to afford the desired product as a white solid. MS (m/z)=376 (M+H). IRAK4 IC50=220 nM
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[CH:41]=[N:42][CH:43]=[C:44]([CH:49]=1)[C:45]([NH:47][CH3:48])=[O:46]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:40]2[CH:41]=[N:42][CH:43]=[C:44]([CH:49]=2)[C:45]([NH:47][CH3:48])=[O:46])=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CNC(=O)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CNC(=O)c1cncc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Yield: 45.3 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.0 g), 5-bromo-N-methylnicotinamide (1.01 g) and tetrakis(triphenylphosphine)palladium(0) (0.177 g), the title compound (1.26 g) was obtained as colorless powder crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[CH3:21])=[CH:18]/[CH2:19][OH:20])=[CH:13][CH:12]=1.[CH2:22]([O:24][C@@H:25]([CH2:31][C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:23]>>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:11]1[CH:12]=[CH:13][C:14](/[C:17](/[CH3:21])=[CH:18]/[CH2:19][O:20][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][C@H:25]([O:24][CH2:22][CH3:23])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:37][CH:36]=2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: COc1cccc(OC)c1-c1ccc(/C(C)=C/CO)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3c(OC)cccc3OC)cc2)cc1)OCC
Yield: 46.2 %

Procedure:
The title compound (0.41 g, 80% yield) was prepared from (E)-3-(2′,6′-dimethoxy-biphenyl-4-yl)-but-2-en-1-ol (0.50 g, 1.76 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.44 g, 1.85 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [N:1]([C@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][C@@H:5]1[F:17])=[N+]=[N-]>[Pd].CCO>[NH2:1][C@H:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:6][C@@H:5]1[F:17]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N=[N+]=[N-])[C@@H](F)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H](N)[C@@H](F)C1

Procedure:
Palladium on carbon 10% (0.1 g) was added to a solution of tert-butyl (3S,4S)-4-azido-3-fluoropiperidine-1-carboxylate, 4.4 (0.4 g, 0.00163 mol) dissolved in EtOH (60 mL). The reaction was placed under a hydrogen atmosphere (40 psi pressure) for 16 h. The mixture was filtered through celite-bed and concentrated under reduced pressure to obtain the title compound tert-butyl (3S,4S)-4-amino-3-fluoropiperidine-1-carboxylate, 4.6 (0.4 g crude).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH2:10])=O)=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.N1C(Cl)=NC(Cl)=NC=1Cl>CN(C)C=O>[Cl:1][C:2]1[C:7]([C:8]#[N:10])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12
Reactant: NC(=O)c1cnc2ccsc2c1Cl
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: N#Cc1cnc2ccsc2c1Cl
Temperature: 0 °C
Yield: 90.7 %

Procedure:
To a solution of 7-chlorothieno[3,2-b]pyridine-6-carboxamide (10.8 g, 51 mmol) in 80.0 mL of N,N-dimethylformamide is added cyanuric chloride (5.72 g, 31 mmol). After 30 minutes the suspension is poured into ice water. The solid is filtered, washed with ice water and dried in vacuo to give 9.0 g of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile as an off white solid, mp 105–107° C.; 1H NMR (DMSO-d6) δ 7.83 (s, 1H), 8.61 (s, 1H), 9.12 (s, 1H); MS 195.0, 197.0 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.[CH:11]([O:14][C:15]([NH:17][C@@H:18]([C:22]([S:25][CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23])[C:19](O)=[O:20])=[O:16])([CH3:13])[CH3:12]>>[CH3:2][O:3][C:4]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:19](=[O:20])[C@@H:18]([NH:17][C:15]([O:14][CH:11]([CH3:13])[CH3:12])=[O:16])[C:22]([S:25][CH:26]([CH3:28])[CH3:27])([CH3:23])[CH3:24])=[O:10]
Reactant: CC(C)OC(=O)N[C@H](C(=O)O)C(C)(C)SC(C)C
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)C)C(C)(C)SC(C)C
Yield: 88.2 %

Procedure:
Reaction of 0.54 g of (L)-proline methyl ester hydrochloride and 0.89 g of 2-(R)-isopropoxycarbonylamino-3-isopropylsulfanyl-3-methyl-butyric acid according to the procedure described for example 91b afforded 1.10 g (88%) of the title compound as a colorless oil. (+)-APCI-MS: 389 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[N:4]([CH2:12][CH2:13][CH2:14][CH2:15][P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[C:3]1=[O:24].[CH2:25](I)[CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:25]([N:7]1[C:6]2[C:5](=[O:11])[N:4]([CH2:12][CH2:13][CH2:14][CH2:15][P:16](=[O:23])([O:17][CH2:18][CH3:19])[O:20][CH2:21][CH3:22])[C:3](=[O:24])[N:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1)[CH3:26]
Reactant: CCOP(=O)(CCCCn1c(=O)c2[nH]cnc2n(C)c1=O)OCC
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(CCCCn1c(=O)c2c(ncn2CC)n(C)c1=O)OCC
Temperature: 60 °C

Procedure:
7.2 g (0.02 mol) of diethyl [4-(3-methylxanthin-1-yl)-butyl]phosphonate were suspended in 100 ml of DMF, treated with 4.7 g (0.03 mol) of ethyl iodide and 4.1 g (0.03 mol) of activated potassium carbonate and heated at 60° C. for 4 hours. The solid was filtered off, the filtrate was concentrated under reduced pressure and the oily residue which remained was taken up in ethyl acetate, filtered again and crystallized from diisopropyl ether.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH:27]([CH3:29])[CH3:28])=[C:13]([C:15]2[NH:25][C:18]3=[N:19][C:20]([CH2:23]O)=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:32])=O>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:26][CH:27]([CH3:29])[CH3:28])=[C:13]([C:15]2[NH:25][C:18]3=[N:19][C:20]([CH2:23][Cl:32])=[CH:21][CH:22]=[C:17]3[N:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2ccc(CO)nc2[nH]1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)Oc1ccc(OCc2ccccc2)cc1-c1nc2ccc(CCl)nc2[nH]1
Yield: 95.5 %

Procedure:
A solution of {2-[5-(benzyloxy)-2-isopropoxyphenyl]-3H-imidazo[4,5-b]pyridin-5-yl}methanol (0.11 g) and thionyl chloride (0.1 g) in chloroform (10 ml) was heated under reflux for 3 hr. The reaction mixture was concentrated, and saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated to give the title compound (0.11 g, yield 96%) as colorless crystals. purity 85%. M+H: 408. 1H NMR (CDCl3) δ: 1.51 (6H, d, J=6.0 Hz), 3.97-4.15 (2H, m), 4.72-4.81 (1H, m), 5.16 (2H, s), 7.00-7.06 (1H, m), 7.07-7.12 (1H, m), 7.31-7.51 (6H, m), 8.07 (1H, d, J=7.9 Hz), 8.20 (1H, s).
Reaction SMILES: [OH:1][C@@H:2]([C:4]1[N:15]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][C:23]([O:25]CC)=[O:24])[CH2:18][CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3].O.[OH-].[Li+].CO.Cl>O.O1CCCC1>[OH:1][C@@H:2]([C:4]1[N:15]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][CH2:17]2)[C:7]2=[C:8]3[S:14][CH:13]=[CH:12][C:9]3=[N:10][CH:11]=[C:6]2[N:5]=1)[CH3:3]
Reactant: CCOC(=O)C[C@H]1CC[C@H](n2c([C@@H](C)O)nc3cnc4ccsc4c32)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl (trans-4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}cyclohexyl)acetate (0.15 g, 0.39 mmol) and lithium hydroxide, monohydrate (0.079 g, 1.9 mmol) in water (0.7 mL)/methanol (1.7 mL)/tetrahydrofuran (1.7 mL) was stirred at room temperature overnight. The reaction was acidified with 1N aq. HCl solution to pH=4, extracted with methylene chloride. The combined organic layers were dried over MgSO4 and concentrated to give the desired product (0.11 g, 79%) to be used in the next step directly. LCMS calculated for C18H22N3O3S (M+H)+: m/z=360.1. Found: 360.1.
Reaction SMILES: C[Al](C)C.[C:5]([N:9]1[C:13]([NH2:14])=[CH:12][C:11]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[N:10]1)([CH3:8])([CH3:7])[CH3:6].[N:25]1([C:31]2[CH:41]=[CH:40][C:34]([C:35](OCC)=[O:36])=[CH:33][CH:32]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[C:5]([N:9]1[C:13]([NH:14][C:35](=[O:36])[C:34]2[CH:33]=[CH:32][C:31]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:41][CH:40]=2)=[CH:12][C:11]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[N:10]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: COc1cccc(CCc2cc(N)n(C(C)(C)C)n2)c1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: COc1cccc(CCc2cc(NC(=O)c3ccc(N4CCNCC4)cc3)n(C(C)(C)C)n2)c1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 22.5 %

Procedure:
A 2M solution of trimethylaluminium in toluene (6.25 mL, 12.50 mmol) was added dropwise to a stirred solution of and 1-tert-butyl-3-(3-methoxyphenethyl)-1H-pyrazol-5-amine (1.367 g, 5.00 mmol) and ethyl 4-(piperazin-1-yl)benzoate (1.171 g, 5 mmol) in toluene (20 mL) at 4° C., over a period of 5 mins under nitrogen. The resulting solution was stirred at 20° C. for 18 h. The reaction mixture was quenched with methanol (20 mL), filtered and evaporated to afford tan solid. The crude product was purified by silica column chromatography, eluting with a gradient of 0 to 10% MeOH in DCM and 0.1% ammonia. Pure fractions were evaporated to dryness to afford N-(1-tert-butyl-3-(3-methoxyphenethyl)-1H-pyrazol-5-yl)-4-(piperazin-1-yl)benzamide (0.520 g, 22.53%) as a white solid.