Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][CH:5]=[C:4]([CH3:10])[N:3]=1.[I:11]N1C(=O)CCC1=O>CN(C=O)C>[CH2:8]([C:7]1[C:2]([NH2:1])=[N:3][C:4]([CH3:10])=[C:5]([I:11])[CH:6]=1)[CH3:9]
Reactant: O=C1CCC(=O)N1I
Reactant: CCc1ccc(C)nc1N
Solvent: CN(C)C=O
Product: CCc1cc(I)c(C)nc1N
Reaction time: 15 h
Yield: 81.3 %

Procedure:
To a solution of 2-amino-3-ethyl-6-methylpyridine (3.00 g, 21.6 mmol) in DMF (100 mL) was added N-iodosuccinimide (4.86 g, 21.6 mmol). The mixture was stirred in the dark for 15 hours and then partitioned between Et2O and H2O. The organic layer was washed with brine, dried over MgSO4, and concentrated to yield a brown solid (4.6 g, 79%). 1H NMR (300 MHz, CDCl3): δ 1.19 (t, J=7.5 Hz, 3H), 2.35 (q, J=7.4 Hz, 2H), 2.49 (s, 3H), 4.44 (s, 2H), 7.52 (s, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](=[O:24])[C:17]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)=[O:18].FC(F)(F)S(O[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]([C:17]1([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[O:18][CH:2]2[CH:3]=[CH:4][C:5]3[C:10]([N:1]2[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]1=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:24]
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: c1ccc2ncccc2c1
Reactant: O=C(C(=O)c1cccs1)c1cccs1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(c1cccs1)C1(c2cccs2)OC2C=Cc3ccccc3N2c2ccccc21
Yield: 56 %

Procedure:
Following the general procedure, treatment of quinoline (0.064 g, 59 μL, 0.50 mmol) and 1,2-di(thiophen-2-yl)ethane-1,2-dione (0.166 g, 0.75 mmol) with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.179 g, 146 μL, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in THF (2.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. ether/EtOAc=95/05) of the crude reaction mixture afforded thiophen-2-yl(5-(thiophen-2-yl)-5H,6aH-benzo[4,5][1,3]oxazino[3,2-a]quinolin-5-yl)methanone as inseparable mixture of diastereomers as a yellow solid (0.120 g, 56% yield, dr determined by 1H NMR analysis of crude reaction mixture is 1:1).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].C[C:8](P(OC)(O)=O)([C:10]([O-:12])=O)[CH3:9].C(OC([N:25]1[CH2:30][CH2:29]C(=O)[CH2:27][CH2:26]1)=O)(C)(C)C.[NH4+].[Cl-]>C1COCC1>[CH3:1][O:12][CH2:10][CH2:8][CH:9]1[CH2:29][CH2:30][NH:25][CH2:26][CH2:27]1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCC1CCNCC1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
8.4 g (74.9 mmol) of potassium t-butoxide were suspended in 200 mL of THF. To this mixture at rt was slowly added a solution of 13.7 g (75.4 mmol) of trimethylphosphonoacetate in 20 mL of THF. After stirring for 30 min, a solution of 10 g (50.2 mmol) of 1-t-butoxycarbonyl-4-piperidone in 50 mL of THF was added and the mixture was heated to 60° C. for 3.5 h. To the reaction mixture was added 250 mL of a sat'd aqueous NH4Cl solution and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. Chromatography on silica eluting with hexane:ethyl acetate=4:1 gave the title compound.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:9]=[C:10]([C:11]#[N:12])[C:5]2=[N:4][CH:3]=1.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>>[F:20][C:19]([F:22])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([C:8]2[CH:9]=[C:10]([C:11]#[N:12])[C:5]3[N:6]([C:2]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[CH:3][N:4]=3)[CH:7]=2)=[CH:14][CH:15]=1
Reactant: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(I)cnc12
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1cnc2c(C#N)cc(-c3ccc(C(F)(F)F)cc3)cn12
Yield: 65.2 %

Procedure:
Prepared from 3-iodo-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-8-carbonitrile (example C.23 step 4) (1.3 g, 4 mmol) and trimethylsilylacetylene (0.87 mL, 6 mmol) as described in example C.20 step 4. Obtained the title compound as a light brown solid (1.0 g, 82%). MS (ISP) 384.1 [(M+H)+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][N:17]=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].O1CCCC1>CO.[C].[Pd]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][N:17]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)c(Oc2ccc([N+](=O)[O-])cn2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(F)c(Oc2ccc(N)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
A suspension of tert-butyl{4-fluoro-3-[(5-nitropyridin-2-yl)oxy]phenyl}carbamate (3.75 g, 10.7 mmol) and 10% palladium-carbon (0.5 g) in methanol (10 mL)-tetrahydrofuran (10 mL) was vigorously stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was poured into water (100 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined and dried over anhydrous sodium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was triturated with diethyl ether to give the title compound (2.50 g, 73%) as a pale-yellow amorphous.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.Cl[CH2:10][C:11](=O)[CH3:12].C(OCC)(=O)C>CC(O)C.CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([CH:10]=[C:11]([CH3:12])[N:8]=2)[CH:7]=1
Reactant: Nc1ncc(Br)cn1
Reactant: CC(=O)CCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1cn2cc(Br)cnc2n1
Temperature: 10 °C
Reaction time: 16 h

Procedure:
To a solution of 5-bromopyrimidin-2-amine (170.0 g, 0.98 mol) in i-PrOH (2 L) and DMF (500 mL) was added 1-chloropropan-2-one (606 g, 6.53 mol), then the mixture was stirred at 10° C. for 16 h. TLC (petroleum ether:ethyl acetate=1:2) showed the reaction was complete. The reaction mixture was quenched by Na2CO3 and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (petroleum ether:ethyl acetate=5:1) to afford compound B-8-2 (10.0 g, 4.8%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[Cl:8].[F:11][C:12]([F:19])([F:18])[CH:13]([OH:17])[C:14](O)=O.Cl.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:14]([CH:13]([OH:17])[C:12]([F:19])([F:18])[F:11])=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C(O)C(O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: OC(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 108 °C

Procedure:
4,5-Dichloro-benzene-1,2-diamine (8.50 g; 48.0 mmoles) and 3,3,3-trifluoro-2-hydroxy-propionic acid (10.59 g; 73.52 mmoles) were suspended in 6N HCl (19 mL; 114 mmoles) under a nitrogen atmosphere. The reaction was stirred vigorously and heated to 108° C. for 18 hrs, then cooled to room temperature. The reaction was diluted with water (200 mL) and with ethyl acetate (200 mL), then sodium bicarbonate (6.05 g; 72.0 mmoles) was added slowly and in portions to quench the reaction. The aqueous layer was separated and extracted with ethyl acetate (3×80 mL). The extracts were combined, washed with water (60 mL) and brine (60 mL), then dried over Na2SO4. The filtrate was concentrated in vacuo to yield a crude brown solid which was then purified by column chromatography (SiO2; 30% ethyl acetate/CH2Cl2) to yield the title compound as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]3[CH2:13][S:12][CH2:11][C:10]3=[C:6]2[N:5]=[C:4]([C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[CH3:22])[C:3]=1[C:23]#[N:24].Cl.CO>O1CCCC1>[NH2:24][CH2:23][C:3]1[C:4]([C:14]2[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=2[CH3:20])=[N:5][C:6]2[N:7]([N:8]=[C:9]3[CH2:13][S:12][CH2:11][C:10]=23)[C:2]=1[NH2:1]
Reactant: Cc1cc(C)c(-c2nc3c4c(nn3c(N)c2C#N)CSC4)c(C)c1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C)c(-c2nc3c4c(nn3c(N)c2CN)CSC4)c(C)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A suspension of 81 mg (0.24 mmol) of 4-amino-2-mesityl-7H,9H-thieno[3′,4′:3,4]pyrazolo[1,5-a]pyrimidine-3-carbonitrile from Step A in 1.2 mL of anhydrous tetrahydrofuran was stirred under nitrogen in an ultrasound bath as 1.2 mL (1.2 mmol) of 1M borane-tetrahydrofuran complex in tetrahydrofuran was added gradually by syringe. The mixture was stirred overnight with intermittent sonication. Next, the mixture was quenched by cautious gradual addition of 0.36 mL (4.32 mmol) of concentrated hydrochloric acid (gas evolution) followed by addition of 1.2 mL of methanol. The resulting solution was stirred in a sealed tube with heating in an oil bath at 80° C. for 4 h. The solution was evaporated to dryness and re-concentrated twice from methanol. The residue was converted to free base form by passage through a pre-washed SCX ion exchange cartridge. After flushing the column with methanol to remove trifluoroacetic acid, elution with 1M ammonia in methanol afforded the crude product. Further purification by flash chromatography on silica gel (elution with 98:2:0.4 dichloromethane:methanol:concentrated ammonium hydroxide) yielded the title compound. LC-MS 340 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[NH2:18][CH2:19][CH2:20][NH:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][N:23]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCCNc1ccc([N+](=O)[O-])cn1
Solvent: COCCOC
Product: N#Cc1c(NCCNc2ccc([N+](=O)[O-])cn2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 2-(2-aminoethylamino)-5-nitropyridine in DME. ES-MS m/e (%): 389 (M+Na+, 15), 367 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[F:12])=[O:3].[CH3:13][Mg]Cl.C(O)(=O)C.O>O1CCCC1>[F:12][C:5]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=1[C:2]([OH:3])([CH3:13])[CH3:1]
Reactant: C[Mg]Cl
Reactant: COc1ccc(C(C)=O)c(F)c1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)O)c(F)c1
Temperature: 30 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
A solution of 2-fluoro-4-methoxyacetophenone (78.1 g, 460 mmol) in tetrahydrofuran (58.6 ml) was added to 3M methylmagnesium chloride solution in THF (199 ml, 598 mmol) at 20 to 35° C. under a nitrogen atmosphere over 30 min without cooling. Additional THF (19.53 ml) was used to rinse all starting material into the vessel. After complete addition, the mixture was stirred at 30° C. for 10 min., then was quenched into acetic acid (52.6 ml, 920 mmol) and water (273 ml) at 5-25° C. THF (20 ml) was used to rinse the vessel. Heptane (156 ml) was then added. The biphasic mixture was stirred at 20-25° C. for 30 min, and then the organic layer was separated. The organic layer was assayed and was found to contain 83.0 g of the desired product, which corresponds to 98% yield. The organic layer was concentrated under vacuum to remove THF, then was flushed with IPAC (200 ml), and the volume was increased to 500 ml by addition of more IPAC. This was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH3:20])=[C:9]([C:12]([O:14][C:15](C)(C)C)=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[Cl:30][C:31]1[CH:53]=[C:52]([N+:54]([O-:56])=[O:55])[CH:51]=[CH:50][C:32]=1[O:33]C1C2C(=CC(OC)=C(C(OC)=O)C=2)N=CC=1>CN1CCCC1=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH3:20])=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:53]=[C:52]([N+:54]([O-:56])=[O:55])[CH:51]=[CH:50][C:32]=1[OH:33]
Reactant: COc1cc2nccc(Cl)c2cc1C(=O)OC(C)(C)C
Reactant: COC(=O)c1cc2c(Oc3ccc([N+](=O)[O-])cc3Cl)ccnc2cc1OC
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2c(Cl)ccnc2cc1OC
Product: O=[N+]([O-])c1ccc(O)c(Cl)c1

Procedure:
Similar to the synthesis of compound 1a, from methyl 4-chloro-7-methoxyquinoline-6-carboxylate (350 mg), 2-chloro-4-nitrophenol (240 mg), N,N-diisopropylethylamine (484 μL), and N-methylpyrrolidin-2-one (1.5 mL), compound 48a was yielded (130 mg, yield: 24%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.Cl>O1CCOCC1>[NH3:9].[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]([OH:18])=[O:17])[CH2:13][CH2:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CN1CCN(C(c2ccccc2)c2cccc(Br)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N
Product: O=C(O)CN1CCN(C(c2ccccc2)c2cccc(Br)c2)CC1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl 2-(4-((3-bromophenyl)(phenyl)methyl)piperazin-1-yl)acetate (2.0 g, 4 mmol) in dioxane (10 mL) was added 4N HCl solution in 1,4-dioxane (30 mL, 823 mmol) followed by concentrated HCl (2.0 mL, 55 mmol). The reaction was stirred at 50° C. for 6 h and concentrated under vacuum. The crude product was purified by SCX column eluting with methanol then 2N NH3 in MeOH solution to give the title compound as a racemate (1.62 g, 93%). MS (ESI, pos. ion) m/z: 389.1 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:11]([CH3:10])(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: NCc1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ccc(Br)cc1
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a stirred solution of (4-bromophenyl)methanamine (500 mg, 2.687 mmol) in pyridine were added methanesulfonyl chloride (0.4 mL, 5.106 mmol) at 0° C. The reaction mixture was stirred for 1 h, then diluted with dichloromethane. The mixture was washed with water. The organic layer was dried (MgSO4) and filtered. The solvent removed in vacuo. The crude product was purified by CC. N-(4-bromobenzyl)methanesulfonamide (675 mg) was obtained (95% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[CH:4][CH:3]=1.[S-:10][C:11]#[N:12].[K+].BrBr.[C:16](#[N:23])C1C=CC=CC=1>C(O)(=O)C.O>[NH2:12][C:11]1[S:10][C:3]2[CH:4]=[C:5]([CH2:6][C:16]#[N:23])[CH:8]=[CH:9][C:2]=2[N:1]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: N#C[S-]
Reactant: N#Cc1ccccc1
Agent: BrBr
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: N#CCc1ccc2nc(N)sc2c1
Temperature: 16 °C
Reaction time: 16 h

Procedure:
2 grams of 4-aminobenzonitrile is dissolved in about 40 mL acetic acid and the solution is cooled to about 16° C. About 3.3 g of potassium thiocyanate is added and the flask is equipped with an addition funnel. The addition funnel is charged with about 2.7 g bromine and about 5 ml acetic acid. This dark solution is then added to the benzonitrile solution in a dropwise fashion under good agitation and allowed to stir for about 16 hours. The slurry is then drowned into water and filtered. The presscake is washed well with water, reslurried in dilute aqueous alkali and filtered. Again the presscake is washed well with water. After drying in vacuo, about 2 grams is isolated.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11].Br[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:15])[CH2:13][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: COCCOCCOCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCCOCCOCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethyleneglycol monomethyl ether (10 mmol) and benzyl bromoacetate (11 mmol) are added to a suspension of anhydrous K2CO3 (15 mmol) in 50 ml anhydrous DMF. The suspension is stirred at room temperature overnight. Water is added and the emulsion is extracted with ethyl acetate (3×200 ml), washed with water, brine, and dried with MgSO4. The solvent is evaporated and the residual oil purified by flash chromatography to give the title compound.
Reaction SMILES: [CH2:1](O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]=1[OH:25])([CH3:14])([CH3:13])[CH3:12].O>C(O)=O.C(O)(=O)C>[C:21]([C:17]1[CH:18]=[C:19]([CH2:1][CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:20]=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:16]=1[OH:25])([CH3:24])([CH3:23])[CH3:22]
Reactant: OCC=Cc1ccccc1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Solvent: CC(=O)O
Solvent: O
Solvent: O=CO
Product: CC(C)(C)c1cc(CC=Cc2ccccc2)cc(C(C)(C)C)c1O

Procedure:
Cinnamyl alcohol (134 g.) was added to a suspension of 2,6-di-t-butylphenol (206 g.) in 88% aqueous formic acid (470 ml.) and glacial acetic acid (200 ml.), and the mixture was refluxed for 1.5 hours. Warm water (2000 ml.) was added and the oily layer which formed on top of the mixture was collected. The oil was distilled and gave a fraction (179 g.), b.p. 190°-200°C. at 0.5 mm Hg. The oil crystallized upon treatment with Skelly F (a mixture of petroleum hydrocarbons boiling between 30°-60°C.) to give glistening, colorless needles, m.p. 93°C. (Found: C, 85.7; H, 9.20. Calc. for C23H30O: C. 85.7; H, 9.38). The nuclear magnetic resonance (nmr) spectrum of this compound at 100 MHz in deuterated chloroform (CDCl3) exhibited absorbances as follows: a singlet (9 protons) at δ 1.41; a singlet (9 protons) at δ 1.45; a singlet (2 protons) at δ 3.48; a singlet (1 proton) at δ 5.07; a multiplet (2 protons) at δ 6.18-6.58; and a multiplet (7 protons) at δ 6.96-7.46.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])[CH:3]([CH3:5])[CH3:4].[NH:17]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:18][C:19]([NH:21][CH2:22][C:23](O)=[O:24])=[O:20].CN1CCOCC1.CN(C=O)C>CCOC(C)=O>[NH:17]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:18][C:19]([NH:21][CH2:22][C:23]([NH:1][C@H:2]([C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:24])=[O:20]
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)C(C)C)C(=O)O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(C)C)C(=O)O
Temperature: 25 °C

Procedure:
On one hand, H-Val-Leu-OH (1 eq.) was added to a solution of MSA (2.72 eq.) in AcOEt. The slurry was stirred at 25° C. until a solution was obtained. The solution was then cooled to −15° C. On the other hand, Boc-Gly-Gly-OH (1.05 eq., commercially available) was added together with NMM (1.0 eq.), AcOEt and DMF. The slurry was stirred until complete dissolution and then cooled to −25° C. IBCF (1.0 eq.) was added to the Boc-Gly-Gly-OH solution to activate the carboxylic function. The silylated Val-Leu was then added and left to stir at least 30 min. The reaction mixture was conditioned to 25° C. before being quenched by the addition of water. The mixture was then diluted with AcOEt and washed with a solution of KHSO4 under stirring. The aqueous phase was discarded and the organic layer was washed again with a solution of NaCl. The organic phase was finally concentrated and the tetrapeptide crystallized under gentle stirring for at least 8 h at 5° C. The solid was recovered by filtration, once washed with cold AcOEt at 5° C. After drying under vacuum, 85% of Boc-Gly-Gly-Val-Leu-OH (SEQ ID NO 19) was recovered.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[N:20][C:19]([CH3:22])=[CH:18][N:17]=1)=[O:14])[C:6]([OH:8])=O.CN(C(ON1N=[N:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:47]([NH:49]C1C=CC=CN=1)C.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[N:20][C:19]([CH3:22])=[CH:18][N:17]=1)=[O:14])[C:6]([NH:49][CH2:47][CH2:32][C:37]1[CH:36]=[CH:35][CH:34]=[CH:33][N:38]=1)=[O:8]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1NC(=O)Nc1cnc(C)cn1
Reactant: CCNc1ccccn1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)NCCc2ccccn2)ccc1NC(=O)Nc1cnc(C)cn1
Reaction time: 0.25 h
Yield: 71 %

Procedure:
To a stirred solution of 3-methoxy-4-[3-(5-methyl-pyrazin-2-yl)-ureido]-benzoic acid (30 mg, 0.1 mmol) in 1 mL NMP at RT in a capped reaction vial was added HBTU (42 mg, 0.11 mmol). The suspension was stirred for 15 minutes and then treated with 2-ethylaminopyridine (13.2 μL, 0.11 mmol) followed by Hunigs Base (35 μL, 0.2 mmol). After stirring overnight, NMP was removed by bulb to bulb transfer at 70 ° C. under high vacuum and the residue stirred with a mixture of CH2Cl2 (10 mL) and 10% Na2CO3 (10 mL) until complete dissolution occurred. The organics were isolated, dried (MgSO4), filtered and concentrated. The residue was triturated with EtOAc to produce a solid which was isolated by filtration (71 % yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[C:16]([CH:20]4[C:29]([CH3:31])([CH3:30])[CH2:28][C:27]5[C:22](=[CH:23][CH:24]=[C:25]([C:32](O)=[O:33])[CH:26]=5)[NH:21]4)[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:35][S:36]([NH2:39])(=[O:38])=[O:37]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[CH:15]=[C:16]([CH:20]4[C:29]([CH3:30])([CH3:31])[CH2:28][C:27]5[C:22](=[CH:23][CH:24]=[C:25]([C:32]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:33])[CH:26]=5)[NH:21]4)[CH:17]=[CH:18][CH:19]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CCN(c3ccc(Cl)cc3)CC2)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)Cc2cc(C(=O)NS(C)(=O)=O)ccc2NC1c1cccc(N2CCN(c3ccc(Cl)cc3)CC2)c1
Yield: 25.8 %

Procedure:
A mixture of 2-{3-[4-(4-chloro-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.21 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (60.5 mg, 0.32 mmol), 4-dimethylaminopyridine (39 mg, 0.32 mmol), methane sulfonamide (60 mg, 0.63 mmol) in dichloromethane (10 mL) was refluxed for 12 hours. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-(2-{3-[4-(4-chloro-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carbonyl)-methanesulfonamide (30 mg, 26%) as a light yellow solid: LC/MS m/e calcd for C29H33ClN4O3S M+: 553.13, observed: 553.2.