Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Br:6][C:7](=[CH2:11])[C:8]([OH:10])=[O:9].B.O1CCCC1.O>O1CCCC1.C(Cl)(Cl)Cl>[Br:6][C:7]1([C:8]([OH:10])=[O:9])[CH2:11][CH:2]2[O:1][CH:5]1[CH:4]=[CH:3]2
Reactant: C=C(Br)C(=O)O
Reactant: c1ccoc1
Agent: B
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(Br)CC2C=CC1O2
Temperature: 2 °C
Reaction time: 10 h
Yield: 70 %

Procedure:
Distilled furan (6.8 g, 100 mmol) and 2-bromoacrylic acid (1.0 g, 6.6 mmol) were charged in a similar reactor as in Example 7, and the mixture was cooled to an inner temperature of 2° C. To this mixed solution was added dropwise a solution (0.7 ml, 0.7 mmol) of a borane-tetrahydrofuran complex (BH3.THF) in 0.93 M tetrahydrofuran over 5 min., while maintaining the inner temperature at not more than 2° C. After the completion of the dropwise addition, the mixture was stirred at the same temperature for 10 hr. Water (10 ml) and chloroform (10 ml) were added to the reaction mixture and the organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with chloroform (10 ml) and the extract was combined with the organic layer separated earlier. The mixture was dried over anhydrous sodium sulfate, concentrated and dried under reduced pressure for 2 hr. to give 2-bromo-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid as a pale-yellow oily substance (1.3 g, main component:minor component=2:1, purity 77% (containing 23% of unreacted 2-bromoacrylic acid), yield 70% based on 2-bromoacrylic acid) being a mixture of an endo form and an exo form.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[CH:4]=[N:3][CH:2]=1.[H-].[Na+].ClCOCC[Si:17]([CH3:20])([CH3:19])[CH3:18].C1[CH2:25][O:24][CH2:23][CH2:22]1>>[CH3:18][Si:17]([CH3:20])([CH3:19])[C:2]1[N:3]=[C:4]([CH2:25][O:24][CH2:23][CH3:22])[C:5]2[CH:9]=[CH:8][NH:7][C:6]=2[N:1]=1
Reactant: c1ncc2cc[nH]c2n1
Reactant: C[Si](C)(C)CCOCCl
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCOCc1nc([Si](C)(C)C)nc2[nH]ccc12
Temperature: 25 °C

Procedure:
7H-Pyrrolo[2,3-d]pyrimidine (1.16 g, 9.74 mmol), was dissolved in 100 ml anhydrous THF under N2. At 0° C., a 60% dispersion of NaH 0.51 g in mineral oil was added. The mixture was stirred at ambient temperature and 2.93 ml (9.8 mmol) (2-chloromethoxy-ethyl)-trimethyl-silane dissolved in 15 ml anhydrous THF was added. The reaction mixture was stirred at room temperature for 2 hour and subsequently concentrated in vacuo. Ethyl acetate was added to the mixture and the organic layer was washed three times with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether) to afford 7-(2-trimethylsilanyl-ethoxymethyl-7H-pyrrolo[2,3-d]pyrimidine (compound 91), (amorphous, 0.84 g, 35%). 1H-NMR (400 MHz, CDCl3): δ 9.1 (bs, 1H), 9.0 (bs, 1H), 7.43 (bd, J=4 Hz, 1H), 6.68 (bd, J=4 Hz, 1H), 5.73 (s, 1H), 3.6 (t, J=8 Hz, 2H), 0.97 (t, J=8 Hz, 2H), 0.1 (s, 9H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[CH3:6][C:7]1[CH:8]=[C:9]([S:21](Cl)(=[O:23])=[O:22])[CH:10]=[CH:11][C:12]=1[NH:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15]>O1CCCC1>[CH2:1]([N:3]([CH2:4][CH3:5])[S:21]([C:9]1[CH:10]=[CH:11][C:12]([NH:13][S:14]([C:17]([F:20])([F:18])[F:19])(=[O:16])=[O:15])=[C:7]([CH3:6])[CH:8]=1)(=[O:23])=[O:22])[CH3:2]
Reactant: CCNCC
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Product: CCN(CC)S(=O)(=O)c1ccc(NS(=O)(=O)C(F)(F)F)c(C)c1
Reaction time: 8 h
Yield: 58.3 %

Procedure:
A solution of diethylamine (1 g) and 3-methyl-4-(trifluoromethanesulfonamido)benzenesulfonyl chloride (1.5 g) in tetrahydrofuran (20 ml) was allowed to stand overnight. The resultant mnixture was concentrated and shaken with chloroform and 5% aqueous hydrochloric acid. The chloroform extract was concentrated and recrystallized from a mixture of ethanol and water to give 0.97 g of N,N-diethyl-3-methyl-4-(trifluoromethanesulfonamido)benzenesulfonamide (Compound No. 6). M.P., 128°-128.5° C.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:9][CH2:8][C:7](OC)=[N:6][CH2:5][CH2:4]1)[CH3:2].[Cl-:12].[NH4+:13]>CO>[ClH:12].[CH2:1]([CH:3]1[CH2:4][CH2:5][NH:6][C:7](=[NH:13])[CH2:8][CH2:9]1)[CH3:2]
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: CCC1CCN=C(OC)CC1
Solvent: CO
Product: CCC1CCNC(=N)CC1
Product: Cl
Yield: 84.9 %

Procedure:
The title product of EXAMPLE 26 (0.28 g, 1.80 mmol) and 0.11 g (2.0 mmol) of ammonium chloride (NH4Cl) were refluxed in 20 mL of methanol (MeOH) under a nitrogen atmosphere for 3.5 h. After cooling the reaction to room temperature, it was filtered, stripped of all solvent under reduced pressure, and partitioned between 20 mL of water and 25 mL of EtOAc. The organic and aqueous phases were separated and the aqueous phase was washed with another 25 mL portion of EtOAc before it was lyophilized to provide 0.27 g (80%) of the white solid title material.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:19]4[O:18][CH2:17]3)[C:9]2=[O:28])C=CC=CC=1.[H][H]>CCOC(C)=O.C(O)(=O)C.[Pd]>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:19]3[O:18][CH2:17]2)[C:9]1=[O:28]
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Yield: 65.8 %

Procedure:
To a solution of 1′-(diphenylmethyl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (2.10 g, 4.70 mmol) in EtOAc (100 mL) and acetic acid (0.10 mL) was added palladium on carbon (1.00 g). The reaction mixture was hydrogenated under 60 psi of hydrogen at ambient temperature for 5 days and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography to yield the title compound (0.87 g, 66%) as a white powder: mp 252° C. (dec.); 1H NMR (300 MHz, CDCl3) δ 10.55 (s, 1H), 7.25-6.84 (m, 4H), 6.64 (s, 1H), 6.22 (s, 1H), 5.88 (s, 2H), 4.76-4.57 (dd, 2H); MS (ES+) m/z 282.2 (M+1).
Reaction SMILES: Cl.[F:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.[CH3:12][C:13]([O-])([CH3:15])[CH3:14].[K+].C([OH:20])C>>[F:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[N:9]=[CH:14][C:13]([CH:15]=[O:20])=[CH:12][N:8]=2)=[CH:5][CH:4]=1
Reactant: N=C(N)c1ccc(F)cc1
Reactant: CCO
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: O=Cc1cnc(-c2ccc(F)cc2)nc1

Procedure:
2 g (11.45 mmol) of 4-fluorobenzamidine hydrochloride, 4.09 g (11.45 mmol) of 2-dimethylaminomethylene-1,3-bis(dimethylimmonio)propane-bis(tetrafluoroborate) and 3.86 g (34.36 mmol) of potassium tert-butylate in 70 ml of ethanol were heated under reflux for 8 h. After concentration, water and ethyl acetate were added. The organic phase was washed with a potassium hydrogensulfate solution and water, dried and evaporated. Yield: 1.87 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:20][C:21]4[NH:22][S:23](=[O:29])(=[O:28])[CH2:24][O:25][C:26]=4[N:27]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:37](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.C(=O)(O)[O-].[Na+]>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:20][C:21]4[N:22]([CH3:37])[S:23](=[O:28])(=[O:29])[CH2:24][O:25][C:26]=4[N:27]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NS(=O)(=O)CO4)cc2)CCC1
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1c2cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2OCS1(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.8 %

Procedure:
In a 15 mL reaction tube was added tert-butyl(1-(4-(2,2-dioxido-7-phenyl-1H-pyrido[3,2-e][1,3,4]oxathiazin-6-yl)phenyl)cyclobutyl)carbamate (50 mg, 0.099 mmol), potassium carbonate (41 mg, 0.296 mmol) and iodomethane (7.5 μL, 0.118 mmol) in anhydrous N,N-dimethylformamide (1 mL) to give an orange suspension. The reaction mixture was stirred at room temperature for 2 hours, then diluted with saturated sodium bicarbonate solution (5 mL) and extracted into dichloromethane (3×3 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give a yellow oil. This was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 90:10 to 20:80) to give the desired product as a colourless oil (50 mg, 97% yield). 1H-NMR (500 MHz, CDCl3) δ 7.24-7.47 (8H, m), 7.16-7.23 (2H, m), 5.23 (2H, s), 5.05 (1H, br s), 3.36 (3H, s), 2.20-2.65 (4H, m), 2.01-2.15 (1H, m), 1.77-1.90 (1H, m), 1.10-1.50 (9H, br m). LCMS (Method A) RT=7.16 min, M+H+=522.01.
Reaction SMILES: CC(OC([NH:8][C@@H:9]([CH2:14][CH2:15][C:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[C:10]([O:12][CH3:13])=[O:11])=O)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:25]1([CH2:24][O:23][C:20]2[CH:21]=[CH:22][C:17]([C:16]3[CH2:15][CH2:14][C@@H:9]([C:10]([O:12][CH3:13])=[O:11])[N:8]=3)=[CH:18][CH:19]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)[C@H](CCC(=O)c1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCC(c2ccc(OCc3ccccc3)cc2)=N1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
To a solution of methyl (2S)-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-oxo-5-{4-[(phenylmethyl)oxy]phenyl}pentanoate (D2, 323 mg, 0.75 mmol) in dry DCM (4 ml) at 0° C., under nitrogen atmosphere was added trifluoroacetic acid (1 ml) dropwise. The resulting pale pink solution was allowed to warm to room temperature over 1 hour, then it was evaporated under reduced pressure, affording the title compound (D7, 291 mg, 0.68 mmol, 91%) as a greenish oil which may be used in the next step without any further purification; Rt (HPLC): 3.69 min; MS: (ES/+) m/z: 310 [MH+], C19H19NO3 requires 309.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[S:8][C:7]2=[CH:18][CH:19]=[CH:20][C:21]3=[CH:22][CH:23]=[CH:24][C:5](=[C:6]23)[NH:4][C:3]1=[O:25].C(=O)([O-])[O-].[K+].[K+].[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]Cl>C(OCC)(=O)C>[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35][N:4]1[C:3](=[O:25])[C@H:2]([OH:1])[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[S:8][C:7]2=[CH:18][CH:19]=[CH:20][C:21]3=[CH:22][CH:23]=[CH:24][C:5]1=[C:6]23
Reactant: COc1ccc([C@@H]2Sc3cccc4cccc(c34)NC(=O)[C@@H]2O)cc1
Reactant: CN(C)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H]2Sc3cccc4cccc(c34)N(CCN(C)C)C(=O)[C@@H]2O)cc1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A mixture of 1.1 g of (±)-cis-2,3-dihydro-3-hydroxy2-(4-methoxyphenyl)naphtho[1,8-bc]-1,5-thiazocin-4(5H)-one, 0.48 g of powdered potassium carbonate and 0.425 g of 2-dimethylaminoethyl chloride in 25 mL of ethyl acetate was stirred and heated at reflux for 3 hours, then twice an additional 0.10 g of 2-dimethylaminoethyl chloride was added at 3 hour intervals. The mixture was heated at reflux for a total of 17 hours then was cooled to room temperature and filtered. The filtrate was diluted with 40 mL of ethyl acetate and washed with brine (40 mL) and dried (magnesium sulfate). Removal of the solvent gave 1.2 g (92%) of (±)-cis-2,3-dihydro-5-[2-(dimethylamino)ethyl]-3-hydroxy-2-(4-methoxyphenyl)naphtho[1,8-bc]-1,5-thiazocin-4(5H)- one. A sample of this compound was crystallized from ethyl acetate, mp. 121°-122°.
Reaction SMILES: Cl[S:2]([C:5]1[C:9]2[C:10]([N:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)=[N:11][CH:12]=[CH:13][C:8]=2[S:7][CH:6]=1)(=[O:4])=[O:3].[CH:27]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)([CH3:29])[CH3:28]>>[C:23]([O:22][C:20]([N:17]1[CH2:18][CH2:19][N:14]([C:10]2[C:9]3[C:5]([S:2]([NH:34][C:33]4[CH:35]=[CH:36][C:30]([CH:27]([CH3:29])[CH3:28])=[CH:31][CH:32]=4)(=[O:4])=[O:3])=[CH:6][S:7][C:8]=3[CH:13]=[CH:12][N:11]=2)[CH2:15][CH2:16]1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3scc(S(=O)(=O)Cl)c23)CC1
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(NS(=O)(=O)c2csc3ccnc(N4CCN(C(=O)OC(C)(C)C)CC4)c23)cc1
Yield: 52.5 %

Procedure:
Prepared from tert-butyl 4-[3-(chlorosulfonyl)thieno[3,2-c]pyridin-4-yl]piperazine-1-carboxylate (90.0 mg, 0.215 mmol) and 4-isopropylaniline (37.9 mg, 0.28 mmol) to give the title compound as an off-white solid (58.3 mg, 52%). 1H NMR (400 MHz, CDCl3) δ 1.12 (d, J=7.0 Hz, 6H), 1.47 (s, 9H), 2.76 (sept., J=6.9 Hz, 2H), 3.01-3.53 (m, 6H), 4.04-4.41 (m, 2H), 6.79 (d, J=8.5 Hz, 2H), 6.66 (d, J=8.5 Hz, 2H), 7.69 (d, J=5.5 Hz, 1H), 8.23 (s, 1H), 8.40 (d, J=5.5 Hz, 1H), 9.90 (s, 1H). MS (ESI+) m/z 517.2 (M+H)+. HPLC 97%, RT: 4.01 min (5-99% MeCN over 3 min).
Reaction SMILES: [C:1]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(Cl)(Cl)=[NH2+].[Cl-].[C:24]([O:28][C:29](=[O:46])[CH2:30][N:31]1[CH2:36][CH2:35][NH:34][C@@H:33]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:32]1=[O:45])([CH3:27])([CH3:26])[CH3:25].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[C:24]([O:28][C:29](=[O:46])[CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:13](=[O:15])[C@@H:12]2[CH2:16][CH2:17][CH2:18][N:11]2[C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])[CH:33]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C:32]1=[O:45])([CH3:25])([CH3:27])[CH3:26]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)C[C@@H]1NCCN(CC(=O)OC(C)(C)C)C1=O
Agent: [Cl-]
Agent: [NH2+]=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC1C(=O)N(CC(=O)OC(C)(C)C)CCN1C(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
In 20 ml of dimethylformamide was dissolved 1.25 g of carbobenzyloxy-L-proline. The solution was cooled to -10° C., then there was added 810 mg of phosgene iminium chloride, and the mixture was stirred for 2 hours. To the mixture were added dropwise 5 ml of dimethylformamide containing 1.8 g of (S)-2-oxopiperazine-1,3-diacetic acid di-t-butyl ester synthesized in Working Example 3, then 2 ml of triethylamine. The mixture was stirred for one hour. The reaction mixture was diluted with ethyl acetate and was poured into ice-water. The organic layer was washed with a 5% potassium hydrogensulfate and a saturated aqueous solution of sodium hydrogenphosphate. The extract solution was dried over anhydrous magnesium sulfate and was concentrated under reduced pressure to give a crude product. The crude product was purified by s silica gel chromatography (ethyl acetate) to afford 1.0 g of the title compound as amorphous powder.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8][CH2:9][CH2:10][CH:11]([OH:22])[CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:30][S:31]([O:22][CH:11]([CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:9][CH2:8]/[CH:7]=[CH:6]\[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])(=[O:33])=[O:32]
Reactant: CCCCC/C=C\CCCC(O)CCC/C=C\CCCCC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC/C=C\CCCC(CCC/C=C\CCCCC)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution (0° C.) of 6Z,15Z)-henicosa-6,15-dien-11-ol 4 (5.6 g, 18.2 mmol) and triethylamine (3.8 mL, 27.2 mmol) in anhydrous dichloromethane (50 mL) was slowly added methanesulfonyl chloride (2.1 mL, 27.2 mmol). The reaction mixture was stirred for 2 hours at room temperature then diluted with dichloromethane (50 mL). The solution was washed with saturated sodium bicarbonate (3×25 mL) then the combined aqueous washes were extracted with dichloromethane (50 mL). The combined dichloromethane extracts were dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The pale yellow oil was filtered through a pad of silica (100% DCM) to afford (6Z,15Z)-henicosa-6,15-dien-11-yl methanesulfonate 5 as a crude colorless oil (7.6 g). Rf 0.8 (100% CH2Cl2).
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[C:25]([O:29][C:30]([NH:32][C@H:33]([C:49](O)=[O:50])[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:37][CH:36]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:5]([C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:49]([C@@H:33]([NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)=[CH:39][CH:40]=2)=[O:50])[CH2:1][CH:2]([CH3:3])[CH3:4])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccc(OCc3ccccc3)cc2)NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine (100 mg, 0.29 mmol, example 1, step E) as described in general procedure Bc using commercially available Nα-tert-butoxycarbonyl-O-benzyl-L-tyrosine (111 mg, 0.3 mmol). The final product was triturated with ether to yield 145 mg (68%) of the desired material.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:26]=[CH:25][C:14]([CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([C:22](O)=[O:23])[CH2:18][CH2:17]3)=[CH:13][CH:12]=2)[CH2:2]1.[NH:27]1[CH2:30][CH:29]([OH:31])[CH2:28]1>>[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:12]=[CH:13][C:14]([CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([C:22]([N:27]4[CH2:30][CH:29]([OH:31])[CH2:28]4)=[O:23])[CH2:18][CH2:17]3)=[CH:25][CH:26]=2)[CH2:2]1
Reactant: OC1CNC1
Reactant: O=C(O)C1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Product: O=C(C1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1)N1CC(O)C1

Procedure:
Compound 286 is synthesized from Intermediate K and azetidin-3-ol according to the procedure used to synthesize Example 255. (LC/MS method 16: ES+ m/z 410.4 [M+H]+, Rt=0.35 min)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[C:4]([F:13])[CH:3]=1.S(=O)(=O)(O)O.[CH3:19]O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([O:12][CH3:19])=[O:11])=[C:4]([F:13])[CH:3]=1
Reactant: O=C(O)C=Cc1ccc(Br)cc1F
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C=Cc1ccc(Br)cc1F

Procedure:
The 3-(4-bromo-2-fluorophenyl)-2-propenoic acid obtained (17.1 g, 0.0698 mol) is taken up in 250 ml of methanol and 0.5 ml of concentrated sulphuric acid and heated for 12 h at reflux. Evaporation is carried out under vacuum and the residue purified by chromatography on silica (eluent: 1/1 hexane/ethyl acetate). Yd.: 14.7 g (81%) M.p. : 63°-65° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[N:8][C:6]=2[N:7]=1.C(N(CC)CC)C.Cl.[CH3:26][S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28].[O:36]1CCC[CH2:37]1>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>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:37]([N:33]3[CH2:34][CH2:35][N:30]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:31][CH2:32]3)=[O:36])=[N:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: C1CCOC1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)nc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(C(=O)c2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 55 °C
Reaction time: 8 h

Procedure:
4-(5-Chloro-2-iodothiazolo[4,5-d]pyrimidin-7-yl)morpholine 27 was dissolved in tetrahydrofuran and combined with triethylamine, 1-methylsulfonylpiperazine hydrochloride (2 eq), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq). The solution was flushed with carbon monoxide stirred under a carbon monoxide balloon at 55° C. overnight. The solution was cooled to room temperature. Water was added and the solution was filtered to yield the tan product of (5-chloro-7-morpholinothiazolo[4,5-d]pyrimidin-2-yl)(4-methylsulfonylpiperazin-1-yl)methanone.
Reaction SMILES: S(C)C.[NH2:4][C:5]1[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:7][CH:8]=[C:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.[CH3:23][S:24]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1)(=[O:26])=[O:25]>C(Cl)Cl.CC(O)=O>[CH2:11]([C:9]1[CH:10]=[C:5]([NH:4][CH2:31][C:30]2[CH:29]=[CH:28][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:34][CH:33]=2)[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:7][CH:8]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: CCOC(=O)c1ncc(Cc2ccccc2)cc1N
Solvent: CSC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1ncc(Cc2ccccc2)cc1NCc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1M BH3.SMe2 in CH2Cl2 (7 mL, 7 mmol) was added dropwise to a solution of ethyl 3-amino-5-benzylpyridine-2-carboxylate (600 mg, 2.34 mmol) and 4-methylsulfonyl benzaldehyde (647 mg, 3.51 mmol) in CH2Cl2 (8 mL) and HOAc (4 mL). The mixture was stirred at rt for 30 min and additional amounts of 1M BH3.SMe2 (2 mL, 2 mmol) and 4-methylsulfonyl benzaldehyde (160 mg, 3.51 mmol) were added. After stirring overnight at rt, the solution was concentrated in vacuo, dissolved in CH2Cl2 and washed with NaHCO3 solution. The organic layer was dried, concentrated and chromatographed on silica gel eluting with 0-5% MeOH/CH2Cl2. This afforded the product as an amber foam: 1H NMR (CDCl3) δ 8.31 (1H, br m), 7.97 (1H, s), 7.86 (2H, d, J=8 Hz), 7.42 (2H, d, J=8 Hz), 7.22 (3H, m), 7.02 (2H, dd, J=8, 2 Hz), 6.58 (1H, s), 4.46 (2H, br), 4.46 (2H, q, J=7 Hz), 3.87 (2H, s), 3.04 (3H, s), 1.45 (3H, t, J=7 Hz); HRMS calcd for C23H24N2O4S+H+: 425.1535. Found: 425.1524.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=1[OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Br)=[CH:32][CH:31]=1>>[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][O:26][C:20]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=2[C:9]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:12]3[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=3[N:10]=2)=[CH:32][CH:31]=1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1ccccc1
Reactant: COC(=O)c1ccc(CBr)cc1
Product: COC(=O)c1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2Cc2ccccc2)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 2-(1-benzyl-5,6-difluoro-1H-benzoimidazol-2-yl)-5-chloro-phenol (Example 48, intermediate a) and 4-bromomethyl-benzoic acid methyl ester (CAS Reg. No. 2417-72-3). Brown sticky solid (86%). MS (Turbo Spray): m/z=518.0 (M+H).