Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10]([OH:14])[CH2:11][C:12]#[CH:13].C(N(CC)CC)C>CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:14][CH2:10][CH2:11][C:12]#[C:13][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: C#CCCO
Reactant: O=Cc1ccccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=Cc1ccccc1C#CCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a solution of 2-bromobenzaldehyde (10 g, 54 mmol) in anhydrous N,N-dimethylformamide (150 ml) was added 3-butyn-1-ol (6.13 ml, 81 mmol) and triethylamine (11.3 ml, 81 mmol), followed by copper (I) iodide (490 mg, 5.4 mmol) and Pd(PPh3)2Cl2 (1.9 g, 2.7 mmol), and the mixture degassed three times and stirred at room temperature overnight. The mixture was poured into water (600 ml) and extracted with EtOAc (3×150 ml); the combined EtOAc layers were washed with water (2×250 ml), sat NaCl (100 ml), then dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica eluting with 50% Et2O in isohexanes to give the title compound (8.5 g, 90%) as an orange oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][OH:9].[C:10]([O-:13])([O-])=[O:11].[K+].[K+]>C(Cl)Cl>[OH:9][N:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[C:10](=[O:11])[O:13][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1NO
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccccc1N(O)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2.5 g (20 mmol) of N-(2-methylphenyl)-hydroxylamine (crude product, obtained according to Bamberger et al., Anm. Chem. 316 (1901), 278), 3.5 g (25 mmol) of K2CO3 and 3.5 g (22 mmol) of phenyl Chlorooformate in 20 ml of CH2Cl2 is stirred for 2 hours at room temperature. The reaction mixture is then extracted with water, dried over MgSO4 and evaporated down. The residue is purified by column chromatography with mixtures of cyclohexane and ethyl acetate. There is obtained 2.0 g (8.2 mmol=42%) of the title compound as a colorless solid (mp=98° C.).
Reaction SMILES: [CH:1](/[C:9]1[CH:18]=[C:17]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[ClH:25].CCOCC.[H][H]>CO.[Pd]>[ClH:25].[CH2:1]([C:9]1[CH:18]=[C:17]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: OCC(O)CNc1cc(/C=C/c2ccccc2)nc2ccccc12
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: OCC(O)CNc1cc(CCc2ccccc2)nc2ccccc12
Temperature: 25 °C
Yield: 29 %

Procedure:
(E)-(RS)-3-(2-Styryl-quinolin-4-ylamino)-propane-1,2-diol (0.23 g, 0.718 mmol) was dissolved in MeOH (25 ml) and acidified with HCl/Et2O. The reaction mixture was refluxed for 2 hours in the presence of 10% Pd/C (0.02 g) under an atmospheric pressure of hydrogen. The mixture was cooled to room temperature, the catalyst was filtered, and the filtrate was concentrated. Addition of EtOH provided (RS)-3-(2-phenethyl-quinolin-4-ylamino)-propane-1,2-diol hydrochloride (0.075 g, 29%) as a light yellow solid, m. p. 143-145° C., MS: m/e=323.3 (M+H+).
Reaction SMILES: [NH:1]([C:8]1[S:9][CH:10]=[C:11]([CH:13]=O)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19])[CH3:16].O1CCCC1>O>[NH:1]([C:8]1[S:9][CH:10]=[C:11]([CH:13]=[CH:20][C:18]([O:17][CH2:15][CH3:16])=[O:19])[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1csc(Nc2ccccc2)n1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1csc(Nc2ccccc2)n1
Temperature: 60 °C

Procedure:
A mixture comprising 3.5 g of 2-anilinothiazole-4-carbaldehyde, 6.5 g of (ethoxycarbonylmethylene)triphenylphosphorane and 35 ml of tetrahydrofuran was heated at 60 ° C. for 2 hours. The reaction mixture was poured into water and extracted with benzene. The benzene extract was dried over anhydrous sodium sulfate, and the solvent was evaporated off under reduced pressure, giving an oil. This oil was purified by silica gel column chromatography. using as eluent a 9:1 mixture of benzene and ethyl acetate, giving the desired compound as yellow crystals.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[F:6][C:7]1[CH:19]=[C:18]2[C:10]([C:11]3C[C:13]4C=C[C:23]([O:26]C)=[CH:22][C:14]=4[C:15]([CH3:21])([CH3:20])[C:16]=3[NH:17]2)=[CH:9][CH:8]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH-].[Na+]>C(OCC)C.O>[F:6][C:7]1[CH:19]=[C:18]2[C:10]([C:11]3[C:23](=[O:26])[C:22]4[CH:2]=[CH:1][C:5]([O:4][CH3:3])=[CH:13][C:14]=4[C:15]([CH3:20])([CH3:21])[C:16]=3[NH:17]2)=[CH:9][CH:8]=1
Reactant: C1CCOC1
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(F)ccc3c1C2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3cc(F)ccc3c1C2=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Under nitrogen atmosphere, to the THF (1.8 mL)-water (0.18 mL) solution of 3-fluoro-8-methoxy-6,6-dimethyl-6,11-dihydro-5H-benzo[b]carbazole (Compound V2, 72.4 mg, 0.245 mmol), DDQ (122.4 mg, 0.539 mmol) was added and the mixture was stirred at room temperature for 5 hr. The reaction mixture was added with diethyl ether and 0.5 N aqueous solution of sodium hydroxide (2 mL), and the resulting mixture was extracted twice with diethyl ether. The organic layer was washed twice with 0.5 N aqueous solution of sodium hydroxide (2 mL) and subsequently twice with brine (2 mL), and dried over sodium sulfate. After concentration under reduced pressure, hexane/ethyl acetate (5:1) and diethyl ether were added to the obtained crude product, and the solid was triturated. After removing the supernatant and drying under reduced pressure, the title compound was obtained (yellow solid, 57.0 mg, 75%).
Reaction SMILES: CCN(CC)CC.[CH2:8]([O:15][C:16](=[O:36])[C:17]([C:22](=O)[CH2:23][O:24][C:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2)=[CH:18]N(C)C)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[C:38]1([CH3:46])[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[NH:44][NH2:45]>CC#N>[CH2:8]([O:15][C:16]([C:17]1[C:22]([CH2:23][O:24][C:25]23[CH2:26][CH:27]4[CH2:33][CH:31]([CH2:30][CH:29]([CH2:28]4)[CH2:34]2)[CH2:32]3)=[N:45][N:44]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[CH3:46])[CH:18]=1)=[O:36])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccccc1NN
Reactant: CN(C)C=C(C(=O)COC12CC3CC(CC(C3)C1)C2)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccccc1-n1cc(C(=O)OCc2ccccc2)c(COC23CC4CC(CC(C4)C2)C3)n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
NEt3 (0.2 mL, 1.43 mmol) was added to a mixture of 2-[2-(adamantan-1-yloxy)-acetyl]-3-dimethylamino-acrylic acid benzyl ester (0.539 g, 1.4 mmol), and o-tolylhydrazine hydrochloride (0.222 g, 1.4 mmol) in MeCN (8 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 17 h. The precipitated solid was filtered off, washed with MeCN and dried to afford the product, (0.359 g, 56%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9](=[O:11])C)=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1.[OH-:20].[Na+].BrBr>O1CCOCC1.O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([OH:11])=[O:20])=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]=1
Reactant: [OH-]
Reactant: CC(=O)c1cc(C)c(Br)cc1OCc1ccccc1
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C(=O)O)c(OCc2ccccc2)cc1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-{4-bromo-5-methyl-2-[(phenylmethyl)oxy]phenyl}ethanone (may be prepared as described in Description 11; 607 mg, 1.90 mmol) in 1,4-dioxane (10 ml) was added sodium hydroxide (761 mg, 19.02 mmol) in water (10 ml). The solution was cooled to 0° C. and bromine (0.29 ml, 5.71 mmol) was added. The mixture was stirred for 10 minutes at 0° C. and then at room temperature for one hour. The dioxane was removed under reduced pressure and the residue acidified to pH=2 using 2N HCl. The mixture was extracted with ethyl acetate (3×20 ml), dried (MgSO4) and the solvent removed in vacuo to yield the title compound. 611 mg.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][C@:5]([C:8]2[S:12][C:11]([S:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[N:10][CH:9]=2)([CH3:7])[CH2:4][O:3]1.Cl.[NH2:25][OH:26]>>[CH3:1][C:2]1([CH3:23])[O:6][C@:5]([C:8]2[S:12][C:11]([S:13][C:14]3[CH:19]=[CH:18][C:17](/[C:20](=[N:25]/[OH:26])/[CH3:21])=[CH:16][CH:15]=3)=[N:10][CH:9]=2)([CH3:7])[CH2:4][O:3]1
Reactant: CC(=O)c1ccc(Sc2ncc([C@@]3(C)COC(C)(C)O3)s2)cc1
Reactant: NO
Agent: Cl
Product: C/C(=N\O)c1ccc(Sc2ncc([C@@]3(C)COC(C)(C)O3)s2)cc1
Yield: 82 %

Procedure:
Using an analogous procedure to that described in Example 68, 4'-{5-[(4R)-2,2,4-trimethyl-1,3-dioxolan-4-yl]thiazol-2-ylthio}acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-{5-[(4R)-2,2,4-trimethyl-1,3-dioxolan-4-yl]thiazol-2-ylthio}acetophenone oxime in 82% yield as a gum.
Reaction SMILES: [CH:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[CH:14]3)=[O:10])=[CH:5][CH:4]=1)=O.[C:23]1([NH2:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([NH:29][CH2:1][C:3]2[CH:22]=[CH:21][C:6]([CH2:7][NH:8][C:9]([C:11]3[CH:12]=[C:13]4[C:18](=[CH:19][CH:20]=3)[N:17]=[CH:16][CH:15]=[CH:14]4)=[O:10])=[CH:5][CH:4]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1ccccc1
Reactant: O=Cc1ccc(CNC(=O)c2ccc3ncccc3c2)cc1
Product: O=C(NCc1ccc(CNc2ccccc2)cc1)c1ccc2ncccc2c1

Procedure:
The title compound (13.8 mg) was obtained according to an analogous method to Example E-26 using quinoline-6-carboxylic acid 4-formyl-benzylamide described in Preparation Example E+-6 (50 mg, 0.172 mmol) instead of formalin, and phenylamine (31 μl, 10.34 mmol) instead of quinoline-6-carboxylic acid 4-benzyl amino-benzylamide. Trifluoroacetic acid salt of the title compound was obtained by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used).
Reaction SMILES: [H-].[Na+].[CH:3]1([C:7]([O-:9])=O)[CH2:6][CH2:5][CH2:4]1.[C:10](#[N:12])[CH3:11].Cl>C1COCC1.O>[CH:3]1([C:7](=[O:9])[CH2:11][C:10]#[N:12])[CH2:4][CH2:5][CH2:6]1
Reactant: CC#N
Reactant: O=C([O-])C1CCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CCC(=O)C1CCC1

Procedure:
A 50 mL three necked round bottom flask containing NaH (980 mg, 60%, 24.50 mmol, 1.57 eq.) and THF (10 mL) was heated to reflux under nitrogen for about 30 min. Then a mixture of cyclobutanecarboxylate [CCLXVII] (2 g, 15.6 mmol, 1.00 eq.) and acetonitrile (1 g, 24.3 mmol, 1.56 eq.) in 20 mL of THF was added dropwise to the refluxing suspension. After addition, the resulting mixture was refluxed for 16 h and worked up with water. The pH value of the reaction solution was adjusted to 4 with aqueous HCl solution and extracted with ethyl acetate. The combined organic phases were dried and concentrated, the residue was applied onto a silica gel column with ethyl acetate/petroleum ether as the eluent to give Compound [CCLXVIII] as a yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 3.40-3.60 (m, 1H), 3.43 (s, 2H), 2.25-2.36 (m, 4H), 2.01-2.15 (m, 1H), 1.82-1.96 (m, 1H).
Reaction SMILES: [H-].[K+].[CH2:3]([O:5][C:6](=[O:15])[CH:7]([CH2:13][CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([I:27])[CH:25]=2)[N:20]=[CH:19][C:18]=1[C:28]#[N:29]>CCCCCC.O1CCCC1>[CH2:3]([O:5][C:6](=[O:15])[C:7]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([I:27])[CH:25]=2)[N:20]=[CH:19][C:18]=1[C:28]#[N:29])([CH2:13][CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(CC)C(=O)OCC
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Agent: [H-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(CC)(C(=O)OCC)c1c(C#N)cnc2ccc(I)cc12
Reaction time: 0.17 h
Yield: 83.8 %

Procedure:
Potassium hydride (35% oil dispersion, 220 mg, 1.91 mmol) was washed with newly opened hexane for two times under Argon. Then anhydrous tetrahydrofuran (55 mL) was added, followed by addition of 2-ethyl-malonic acid diethyl ester (480 mg, 2.54 mmol). The reaction mixture was stirred at about room temperature for 10 min. Then 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c, 200 mg, 0.64 mmol) in anhydrous tetrahydrofuran (3 mL) was added to the above reaction mixture, and then reaction continued at room temperature for another 30 min. The reaction was quenched with ice water, and then extracted with ethyl acetate. The organic layers were collected, washed with brain, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 20% ethyl acetate in hexane in 25 min) afforded 2-(3-cyano-6-iodo-quinolin-4-yl)-2-ethyl-malonic acid diethyl ester (250 mg, 85%) as colorless viscous oil. LC-MS m/e 467 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Br[C:29]1[CH:34]=[C:33]([CH3:35])[N+:32]([O-:36])=[C:31]([CH3:37])[CH:30]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:29]4[CH:34]=[C:33]([CH3:35])[N+:32]([O-:36])=[C:31]([CH3:37])[CH:30]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: Cc1cc(Br)cc(C)[n+]1[O-]
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)cc(C)[n+]1[O-]

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 4-bromo-2,6-dimethylpyridine-N-oxide in Step 4. LC-MS Method 2 tR=1.092, m/z=479.1; 1H NMR (CDCl3) 1.38 (m, 1H), 1.56 (d, 3H), 1.71 (m, 1H), 1.95 (m, 2H), 2.19-2.31 (m, 3H), 2.58 (s, 3H), 2.61 (s, 3H), 2.95 (m, 1H), 3.58 (m, 1H), 5.71 (m, 1H), 7.05 (m, 4H), 7.21-7.32 (m, 4H), 7.38 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH3:12][N:13]([CH:15]=O)[CH3:14].COC(OC)N(C)C.S([O-])(O)(=O)=O.[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](/[N:11]=[CH:12]/[N:13]([CH3:15])[CH3:14])(=[O:10])=[O:9]
Reactant: NS(=O)(=O)c1ccccc1Br
Reactant: CN(C)C=O
Agent: COC(OC)N(C)C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: CN(C)/C=N/S(=O)(=O)c1ccccc1Br

Procedure:
The starting material, 2-bromobenzene-1-sulfonamide, is commercially available. Reaction of 2-bromobenzene-1-sulfonamide in a solvent such as DMF, with 1,1-dimethoxy-N,N-dimethylmethanamine, followed by the addition of sodium hydrogen sulfate in water, yields 2-bromo-N-[1-dimethylaminometh-(E)-ylidene]benzenesulfonamide. This compound is reacted with 4-methylphenylboronic acid to yield 4′-methylbiphenyl-2-sulfonic acid 1-dimethylaminometh-(E)-ylideneamide, then the —(CH2)r-L moiety is added, for example, by a halogenation reaction, to form compound (1b).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)(=O)=O)[N:12]=3)[S:10][C:5]=2[C:4](=[O:21])[NH:3]1.[NH3:23].CO>O1CCOCC1>[NH2:23][C:13]1[N:12]=[C:11]([C:9]2[S:10][C:5]3[C:4](=[O:21])[NH:3][C:2]([CH3:22])([CH3:1])[NH:7][C:6]=3[CH:8]=2)[CH:16]=[CH:15][N:14]=1
Reactant: N
Reactant: CC1(C)NC(=O)c2sc(-c3ccnc(S(C)(=O)=O)n3)cc2N1
Solvent: C1COCCO1
Solvent: CO
Product: CC1(C)NC(=O)c2sc(-c3ccnc(N)n3)cc2N1
Yield: 53 %

Procedure:
A mixture of 2,2-dimethyl-6-[2-(methylsulfonyl)pyrimidin-4-yl]-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (0.044 g, 0.13 mmol) and 7 M ammonia in methanol (2.0 mL, 14 mmol) in 1,4-dioxane (8 mL) was microwave-irradiated at 120° C. for 75 min. Then, the reaction mixture was cooled, and concentrated with silica gel, and the residue was purified twice by flash chromatography (Combiflash, silica gel, ethyl acetate to 90:10 ethyl acetate/methanol) to give the title compound (0.019 g, 53%) as a yellow solid:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2OS(C(F)(F)F)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([Sn](CCCC)(CCCC)CCCC)=[CH2:29].[Cl-].[Li+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]2[CH:28]=[CH2:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)c2cccc(OCc3ccccc3)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=Cc1cc(C)nc2c(OCc3ccccc3)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
A mixture of 8-benzyloxy-2-methyl-4-(trifluoromethanesulfonyloxy)quinoline (300 mg), vinyltributyltin (263 mg), tetrakis(triphenylphosphine)palladium (0) (43.6 mg) and lithium chloride (96 mg) in 1,4-dioxane (6 ml) was refluxed for three hours and then left at ambient temperature overnight. The mixture was diluted with ethyl acetate and was added silica gel (70-230 mesh, 5 g) and stirred at ambient temperature for half an hour. The silica gel was removed by filtration and the filtrate was concentrated in vacuo. The residue was chromatographed on a silica gel column eluting with ethyl acetate-n-hexane (1:4, V/V) to give a solid. This solid was crystallized from diisopropyl ether to give 8-benzyloxy-2-methyl-4-vinylquinoline (110 mg) as pale yellow solid.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[OH-].[K+].Cl[CH2:17][C:18]([O:20][CH3:21])=[O:19]>C(OCC)(=O)C>[C:1]1([C:7]2[N:11]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:10]=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nnn[nH]2)cc1
Reactant: COC(=O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)Cn1nnnc1-c1ccccc1
Yield: 18.1 %

Procedure:
Two grams of 5-phenyltetrazole (13.68 mM) were slowly added to 5 ml of a methanol solution containing 770 mg (13.68 mM) of potassium hydroxide at room temperature. Two milli liters of a methanol solution containing 1.48 g (13.68 mM) of methyl chloroacetate were dropwise added to the resultant solution at room temperature. After the completion of the addition, the reaction solution was refluxed for 20 hours and cooled. The reaction solution was diluted with ethyl acetate and washed with water. The organic phase was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (elute is chloroform), to give 0.54 g of methyl 5-phenyl-1-tetrazoleacetate (yield: 18.1%).
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]3[CH2:33][CH2:34][C:35](=[O:38])[NH:36][N:37]=3)=[CH:31][C:26]=2[N:25]=[N:24]1>>[CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][N:23]3[C:27]4[CH:28]=[CH:29][C:30]([C:32]5[CH2:33][CH2:34][C:35](=[O:38])[NH:36][N:37]=5)=[CH:31][C:26]=4[N:25]=[N:24]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NCCn1nnc2cc(C3=NNC(=O)CC3)ccc21
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CCC1
Product: O=C1CCC(c2ccc3c(c2)nnn3CCNCC(O)COc2ccc(CCOCC3CCC3)cc2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6- [1-(2-aminoethyl)benztriazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19](=[O:21])[CH3:20])[C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[BrH:23].BrBr>C(O)(=O)C>[Br:23][CH2:20][C:19]([C:18]1[C:13]2[CH:12]=[CH:11][N:10]([S:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:22])=[CH:6][CH:5]=3)(=[O:9])=[O:8])[C:14]=2[N:15]=[CH:16][N:17]=1)=[O:21]
Reactant: CC(=O)c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C(=O)CBr)ncnc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.4 %

Procedure:
[5.95 g, 18.88 mmol] of 1-[7-(Toluene-4-sulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-ethanone was dissolved/suspended in 90 mL of glacial acetic acid and [7.53 mL, 10.197 g, 37.76 mmol] of 30% hydrogen bromide in acetic acid. Added dropwise to this stirring mixture at ambient temperature, was [0.970 mL, 3.02 g, 18.88 mmol] of bromine in 10 mL of glacial acetic acid over 1.0 hour. The reaction was stirred an additional 4.0 hours at ambient temperature during which time a yellow precipitate forms. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane and saturated sodium hydrogen carbonate solution. The organic phase was washed with water, brine, and dried with anhydrous sodium sulphate and the solvent was removed under reduce pressure. The crude solid was triturated/stirred with MTBE overnight and the solid isolated via suction filtration and airdried to yield 4.2 g of pale yellow solid, a 56.6% yield.
Reaction SMILES: O.C(OC([NH:12][C@@H:13]([C:17]([NH:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:21]=1[C:22]([OH:24])=[O:23])=[O:18])[CH:14]([CH3:16])[CH3:15])=O)C1C=CC=CC=1>[Pd].CO>[CH3:29][C:25]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]([NH:19][C:17](=[O:18])[C@@H:13]([CH:14]([CH3:15])[CH3:16])[NH2:12])[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cccc(NC(=O)[C@H](NC(=O)OCc2ccccc2)C(C)C)c1C(=O)O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: Cc1cccc(NC(=O)[C@H](N)C(C)C)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
10% Pd-C (70 mg) was added to a 1% water-containing methanol solution (30 ml) of 2-(N-benzyloxycarbonyl-D-valyl)amino-6-methylbenzoic acid (669 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for two hours. After the catalyst was filtered off, the filtrate was concentrated to obtain 6-methyl-2-(D-valylamino)benzoic acid (347 mg).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:26]=[CH:25][CH:24]=[CH:23][C:8]=2[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].C[O:28][C:29](=[O:39])[CH:30]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)O>>[CH2:1]([C:5]1[O:6][C:7]2[CH:26]=[CH:25][CH:24]=[CH:23][C:8]=2[C:9]=1[C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:30]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:29]([OH:39])=[O:28])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1-c1ccc(-c2ccc(O)cc2)cc1
Reactant: COC(=O)C(O)Cc1ccccc1
Product: CCCCc1oc2ccccc2c1-c1ccc(-c2ccc(OC(Cc3ccccc3)C(=O)O)cc2)cc1

Procedure:
The title compound was prepared from 4′-(2-butyl-benzofuran-3-yl)-biphenyl-4-ol, and 3-phenyllactic acid methyl ester, in substantially the same manner, as described in Example 1, steps g-h , and was obtained as a white solid, mp 169-170° C.; MS m/e 491 (M+H)+;