Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)C.[CH2:20]=[CH:21][CH:22]=[CH2:23]>C(OCC)(=O)C>[C:16]([C:7]1[C:8](=[O:15])[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]2([CH2:23][CH2:22][CH:21]=[CH:20][CH2:4]2)[CH:6]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: C=CC=C
Reactant: CN(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCOC(C)=O
Product: CC(C)(C)C1=CC2(C=C(C(C)(C)C)C1=O)CC=CCC2
Yield: 100 %

Procedure:
Following the same general procedure as in Example I, 20 mmols of N,N-dimethyl-4-aminomethyl-2,6-di-t-butylphenol were reacted with approximately 222 mmols of 1,3-butadiene in 47 g of ethyl acetate at about 190° C. for 10 hours. As determined by GC analysis, the process resulted in a 100% yield of 2,4-di-t-butylspiro[5.5]undeca-1,4,8-trien-3-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][CH2:15][O:16][S:18]([CH3:17])(=[O:20])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CCOS(C)(=O)=O

Procedure:
To a solution of (S)-2-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (0.300 g, 1.30 mmol) in dichloromethane (5 mL) was added methane sulfonylchloride 0.304 mL, 3.9 mmol) and triethylamine (0.547 mL, 3.9 mmol) at rt for 1-16 h. The reaction mixture was diluted with dichloromethane and washed with NaHCO3 (10%, W/V), followed by water. The dichloromethane layer was dried (Na2SO4), filtered and the solvent was evaporated to dryness. The product was sufficiently pure for the next step and was used without any further purification. LC-MS [M+Na] 329.9.
Reaction SMILES: [CH:1]1([CH:6]([C:8]2[C:9]([Cl:17])=[N:10][C:11]([S:15][CH3:16])=[N:12][C:13]=2[Cl:14])[OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1>CC(C)=O>[CH:1]1([C:6]([C:8]2[C:9]([Cl:17])=[N:10][C:11]([S:15][CH3:16])=[N:12][C:13]=2[Cl:14])=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1nc(Cl)c(C(O)C2CCCC2)c(Cl)n1
Solvent: CC(C)=O
Product: CSc1nc(Cl)c(C(=O)C2CCCC2)c(Cl)n1
Temperature: 0 °C
Yield: 38.5 %

Procedure:
Cyclopentyl-(4,6-dichloro-2-methylsulfanyl-pyrimidin-5-yl)-methanol (8.1 g, 27.62 mmol) was dissolved in 100 mL dry acetone and stirred under nitrogen at 0° C. CrO3 (11.05 g, 110.497 mmol) was added in portions over three minutes. The reaction mixture was stirred for 20 minutes. The reaction was quenched by addition of 15 mL isopropanol, followed by basificaction with saturated aqueous sodium bicarbonate. The resulting solution was filtered through Celite, and the Celite was washed with acetone. The resulting solution was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 3.1 g of Cyclopentyl-(4,6-dichloro-2-methylsulfanyl-pyrimidin-5-yl)-methanone. Mass Spec. M+H=292.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:37]([O:39]CC)=[O:38])[CH2:5][C:6]1[CH:36]=[CH:35][C:9]([O:10][CH2:11]/[CH:12]=[C:13](/[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](/[C:27](/[CH3:34])=[CH:28]/[C:29]([O:31]CC)=[O:30])[CH:22]=3)=[CH:17][CH:16]=2)\[CH3:14])=[CH:8][CH:7]=1)[CH3:2].[OH-].[Na+]>>[C:37]([C@@H:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]1[CH:36]=[CH:35][C:9]([O:10][CH2:11]/[CH:12]=[C:13](/[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](/[C:27](/[CH3:34])=[CH:28]/[C:29]([OH:31])=[O:30])[CH:22]=3)=[CH:17][CH:16]=2)\[CH3:14])=[CH:8][CH:7]=1)([OH:39])=[O:38]
Reactant: CCOC(=O)/C=C(\C)c1cccc(-c2ccc(/C(C)=C/COc3ccc(C[C@H](OCC)C(=O)OCC)cc3)cc2)c1
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cccc(/C(C)=C/C(=O)O)c3)cc2)cc1)C(=O)O
Yield: 79.3 %

Procedure:
The title compound was prepared from (E,E)-(S)-ethyl 3-(4′-{3-[4-(2-ethoxy-2-ethoxycarbonyl-ethyl)-phenoxy]-1-methyl-propenyl}-biphenyl-3-yl)-but-2-enoate (example 111) (190 mg, 0.34 mmol) and sodium hydroxide (1M, 1.4 ml, 1.4 mmol) by a procedure analogous to that described in example 51, yielding (E,E)-(S)-3-(4′-{3-[4-(2-carboxy-2-ethoxy-ethyl)-phenoxy]-1-methyl-propenyl}-biphenyl-3-yl)-but-2-enoic acid (135 mg, 79%) as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12](=[O:14])[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][CH:8]=2)[N:3]=1.C(=O)=O.C(#N)C>C1COCC1>[Cl:1][C:2]1[C:11]([C@H:12]([OH:14])[CH3:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(=O)c1cc2ccc(F)cc2nc1Cl
Agent: O=C=O
Solvent: CC#N
Solvent: C1CCOC1
Product: C[C@@H](O)c1cc2ccc(F)cc2nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
A solution of 1-(2-chloro-7-fluoroquinolin-3-yl)ethanone (164 g, 733 mmol) in THF (1.34 L) was added to a solution of (+)-DIP-Cl (517.5 g, 2.2 eq) in THF (3.5 L) at −45° C. (dry ice and acetonitrile) dropwise. The reaction was slowly warmed up to rt overnight. The reaction was then quenched with acetone (750 mL) and 10% Na2CO3 (750 mL) at 0° C. and stirred at rt for 1 h before the addition of EtOAc (3.5 L). The mixture was warmed up to rt and washed with 10% Na2CO3 and water. The organic layer was dried with brine, concentrated and treated with hexane (1.0 L) and water (1.8 L). The mixture was stirred at rt for 40 min and filtered. The white solid was washed with water and hexane, dried in the air over night (143 g). This material was dried on the roto-evaporator at 60° C. for 4 h under high vacuum (2 mm Hg) to give a white powder of (R)-1-(2-chloro-7-fluoroquinolin-3-yl)ethanol (122 g, 73.7%). Chiral HPLC on AD column (isopropanol in hexane, 10%) showed ee >99%. Mass Spectrum (ESI) m/e=226 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[C:8]1[C:13]([O:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[CH:12][CH:11]=[C:10]([CH3:29])[N:9]=1.CC1(C)C(C)(C)OC(B[C:39]2[CH:40]=[N:41][NH:42][CH:43]=2)O1>CN(C)C=O>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:14][C:13]1[C:8]([C:39]2[CH:40]=[N:41][NH:42][CH:43]=2)=[N:9][C:10]([CH3:29])=[CH:11][CH:12]=1
Reactant: CC1(C)OC(Bc2cn[nH]c2)OC1(C)C
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cn[nH]c3)c2cc1OC
Temperature: 70 °C
Reaction time: 4 h
Yield: 44.3 %

Procedure:
N,N-Dimethylformamide (1.2 ml) and a 2 M aqueous potassium carbonate solution (1 ml) were added to 4-[(2-iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (70 mg), and 4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-ylboranyl)-1H-pyrazole (34 mg) under an argon atmosphere, and the mixture was stirred at 70° C. for 4 hr. The reaction solution was cooled to room temperature and was then filtered through Celite. The solvent was removed from the filtrate by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water. The ethyl acetate layer was extracted with 1 N hydrochloric acid. The aqueous layer was then made alkaline by the addition of a 1 N aqueous sodium hydroxide solution and was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (19 mg, yield 44%).
Reaction SMILES: [OH:1][C@@:2]12[C:11](=O)[CH2:10][CH2:9][CH2:8][C@H:7]1[CH2:6][CH2:5][CH2:4][CH2:3]2.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O>[C:14]1([NH:13][C@H:11]2[C@:2]3([OH:1])[C@H:7]([CH2:6][CH2:5][CH2:4][CH2:3]3)[CH2:8][CH2:9][CH2:10]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1
Reactant: O=C1CCC[C@H]2CCCC[C@]12O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: O[C@]12CCCC[C@@H]1CCC[C@H]2Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (4aR,8aR)-8a-hydroxyoctahydronaphthalen-1(2H)-one (0.339 g, 2.015 mmol) and aniline (0.552 mL, 6.05 mmol) in 2% CH3COOH in ACE (20 mL) was stirred for 1 hr at rt. Sodium triacetoxyborohydride (1.37 g, 6.45 mmol) was then added and the mixture was stirred for several hours. The mixture was then quenched with sat'd. aq. NaHCO3 and extracted 3× with CH2Cl2. The combined organics were dried, filtered, and concentrated. The residue was purified by column chromatography on silica gel to give the title compound. 1H NMR (500 MHz, CDCl3) δ 7.12-7.18 (m, 2H), 6.60-6.69 (m, 3H), 1.96-2.04 (m, 1H), 1.73-1.81 (m, 1H), 1.64-1.70 (m, 2H), 1.18-1.60 (m, 12H). HRMS (ES) m/z M+H calc'd: 246.1852. found: 246.1850.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[CH:14][CH:13]=1)([O-])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.C(NC1C=CC(C(O)=O)=CC=1)(=O)C.N1C=CC=CC=1.[N+](C1C=CC=CC=1N)([O-])=O.[OH-].[Na+]>C(OCC)(=O)C>[NH:18]([C:15]1[CH:14]=[CH:13][C:12]([C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH2:1])=[O:22])=[CH:17][CH:16]=1)[C:19]([CH3:20])=[O:21]
Reactant: CC(=O)Nc1ccc(C(=O)Nc2ccccc2[N+](=O)[O-])cc1
Agent: CC(=O)Nc1ccc(C(=O)O)cc1
Agent: Nc1ccccc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(C(=O)Nc2ccccc2N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The N-(2'-nitrophenyl)-4-acetylaminobenzamide used as starting material is prepared as follows: 41.3 g (0.33 mole) oxalyl chloride are added dropwise at 0°-5° C., with the exclusion of moisture, to a solution of 60.3 g (0.83 mole) dimethylformamide in 1.5 L dry ethyl acetate. After stirring for 30 minutes at this temperature, 44.8 g (0.25 mole) 4-acetamidobenzoic acid, together with 27.7 g (0.35 mole) pyridine, are added thereto and the ice bath is removed. After stirring for 3 hours at ambient temperature, the reaction mixture is mixed with a solution of 38 g (0.28 mole) o-nitroaniline and 27.7 g (0.35 mole) pyridine in 30 mL dry ethyl acetate. After stirring for 15 hours at ambient temperature, the reaction mixture is mixed with 500 mL 1N aqueous sodium hydroxide solution, the phases are separated and the aqueous phase is shaken out three times with 150 mL amounts of ethyl acetate. The combined organic phases are washed neutral with water, dried over anhydrous sodium sulfate, and concentrated to about one-third. The precipitate obtained is filtered off with suction and purified either by recrystallization or by column chromatography. Yield 15 g (20% of theory); m.p. 205.8° C.
Reaction SMILES: [CH:1]([P:4]1(=[O:12])[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[CH2:6][O:5]1)=[C:2]=[CH2:3].[OH2:13].NN.Cl>C(#N)C>[CH2:1]([P:4]1(=[O:12])[O:5][CH2:6][C:7]([CH3:10])([CH3:11])[CH2:8][O:9]1)[C:2]([CH3:3])=[O:13]
Reactant: C=C=CP1(=O)OCC(C)(C)CO1
Reactant: O
Agent: Cl
Agent: NN
Solvent: CC#N
Product: CC(=O)CP1(=O)OCC(C)(C)CO1
Reaction time: 0.5 h

Procedure:
0.69 g (3.7 mmol) of 2-allenyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane (II) was dissolved in 3 ml of acetonitrile, and 0.22 g (4.4 mmol) of hydrazine monohydrate was added thereto. The mixture was left for 30 minutes at room temperature. Then, 4.8 g of 10% by weight hydrochloric acid was added thereto and stirred for one hour. The solvent was distilled off to about one-half its initial volume under reduced pressure and the reaction mixture diluted with 30 ml of 20% by weight sodium chloride aqueous solution, was extracted 2 times with 40 ml of chloroform. The chloroform layers were combined and dried over anhydrous sodium sulfate, followed by filtration. The solvent was distilled off to obtain 0.75 g (yield: about quantitative amount) of the desired product of 2-acetonyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane (IV) as colorless solid.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[O:14][CH2:15][CH3:16].CN(C)CCN(C)C.C1CCN([CH:31]=[O:32])CC1>CCCCCC.O1CCCC1>[CH2:15]([O:14][C:8]1[CH:9]=[CH:10][C:11]([CH:31]=[O:32])=[C:12]([F:13])[C:7]=1[F:6])[CH3:16]
Reactant: CCOc1cccc(F)c1F
Reactant: O=CN1CCCCC1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOc1ccc(C=O)c(F)c1F
Temperature: -60 °C
Reaction time: 2 h

Procedure:
125 ml of a solution of 0.2 mole of n-butyllithium in hexane is added, at -78° C., to a mixture of 0.2 mole of 2,3-difluorophenetole, 0.2 mole of tetramethylethylenediamine and 400 ml of tetrahydrofuran, and the mixture is stirred for 2 hours at -60° C. A mixture of 0.2 mole of n-formylpiperidine and 20 ml of tetrahydrofuran is added dropwise to this mixture. Warming to -20° C. and working up in the customary manner gives the aldehyde in the form of a colourless solid, melting point 70° C.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[C:17]([O-])(O)=O.[Na+]>CO.C1(C)C=CC=CC=1.O>[Br:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH3:17])=[O:11])=[CH:7][CH:8]=1
Reactant: O=C([O-])O
Reactant: O=C(O)Cc1ccc(CBr)cc1
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc(CBr)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a mixture of p-bromomethylphenylacetic acid (50.0 g, 218 mmol) in MeOH (125 g) and toluene (250 g), was added thionyl chloride (15.6 g) dropwise at 0° C. and stirred for 3 hr. Separately NaHCO3 (33 g, 393 mmol) was dissolved in water (540 g), mixed with toluene (200 g) and cooled to 0° C. The reaction solution described above was added dropwise to the mixture and stirred for 1 hr. The aqueous layer was removed and the organic layer washed with water. The solution was then concentrated under reduced pressure at a temperature below 40° C. to give the subtitle compound as a crude product (58.9 g) used directly in the following reaction. 1H NMR (DMSO-d6) δ 7.37 (d, 2H), 7.34 (d, 2H), 4.62 (s, 2H), 3.73 (s, 2H), 3.63 (s, 3H)
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][C:13]1[N:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:27])[CH3:26])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:25]([N:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:9](=[O:11])[CH2:8][C:5]3[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=3)=[N:18][CH:17]=2)[CH2:24][CH2:23]1)(=[O:27])[CH3:26]
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: O=C(O)Cc1ccc(I)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(I)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(4-iodophenyl)acetic acid 177-1 (524 mg, 2.0 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (440 mg, 2.0 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (798 mg, 2.1 mmol) in DMF (10 mL) was added DIEA (1.04 mL, 6.0 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted into ethyl acetate, washed with saturated NaHCO3 then brine, dried over Na2SO4. The solvent was removed by rotary evaporation to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-iodophenyl)acetamide 177-2 as tan solid. MS m/z 465.2 (M+1).
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[C@@H:3]([CH3:5])[OH:4].Cl.[NH2:17][C@@H:18]([C:31]([NH:33][C@H:34]([C:42]([N:44]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[CH3:45])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:32])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([CH:29]=[O:30])[CH:21]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([NH:17][C@@H:18]([C:31]([NH:33][C@H:34]([C:42]([N:44]([CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[CH3:45])=[O:43])[CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:32])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([CH:29]=[O:30])[CH:21]=1)=[O:8])[C@@H:3]([CH3:5])[OH:4]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN(Cc1ccccc1)C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](N)Cc1cn(C=O)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
Boc-Thr-OH (1.23 g), HCl.H-D-Trp(CHO)-Phe-NMeBzl (3.0 g) and HOBT (0.757 g) were dissolved in DMF (40 ml). To this solution was added WSC (887 mg) under ice cooling and the mixture was stirred for 1.5 hours at the same temperature and overnight at room temperature. After evaporation and extraction with ethyl acetate, the organic layer was washed successively with water, diluted sodium hydrogencarbonate solution, water, 0.5N hydrochloric acid, and sodium chloride solution and dried over magnesium sulfate. The evaporated residue was crystallized from a mixed solvent of ethyl acetate and diisopropyl ether (1:1) (10 ml) with seeding and the crystals were washed out by addition of diisopropyl ether (30 ml) and dried to give Boc-Thr-D-Trp(CHO)-Phe-NMeBzl (3.64 g).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:11]=2)=[O:8])=[CH:4][CH:3]=1.[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.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>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:5]2[S:6][C:2]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)=[CH:3][CH:4]=2)=[O:8])=[CH:11][C:12]=1[N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1
Reactant: OB(O)c1ccncc1
Reactant: COc1ccc(NC(=O)c2ccc(Br)s2)cc1N1CCN(C)CC1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(NC(=O)c2ccc(-c3ccncc3)s2)cc1N1CCN(C)CC1
Yield: 64.4 %

Procedure:
5-bromo-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]thiophene-2-carboxamide (0.31 g;0.76 mmol) was stirred with 4-pyridylboronic acid (0.093 g;0.76 mmol), tetrakis(triphenylphosphine)palladium(0) (0.045 g;5 mol %) and anhydrous sodium carbonate (0.089 g;0.84 mmol) in water (14 ml) and DME (14 ml) and the whole heated at reflux under Ar (18 hours). The reaction mixture was poured into 10% Na2CO3 (aq) (30 ml) and extracted into CHCl3. The organic extracts were combined, dried over Na2 SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 4%MeOH/CHCl3 to yield a yellow, semi-solid residue which was triturated with acetone/Et2O. The solid that formed was collected by filtration and dried in vacuo to yield the tide compound as a yellow solid (0.2 g;65%), mp=191-194° C.
Reaction SMILES: [F:1][C:2]([F:20])([C:16]([F:19])([F:18])[F:17])[C:3]([F:15])([F:14])[C:4]([F:13])([F:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]O.[BrH:21].S(=O)(=O)(O)O>O>[Br:21][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([F:13])([F:12])[C:3]([F:15])([F:14])[C:2]([F:20])([F:1])[C:16]([F:19])([F:18])[F:17]
Reactant: Br
Reactant: OCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCCCCBr
Temperature: 100 °C

Procedure:
To a mixture of 18.00 g of 6-(nonafluorobutyl)-1-hexanol and 225 mL of 48 weight percent hydrobromic acid was slowly added 23 mL of concentrated sulfuric acid. The reaction mixture was heated at 100° C. for 12 hr and poured into 1 liter of water. The mixture was extracted with hexanes, and the combined organic phases were then washed with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The hexanes solution was concentrated to a light amber liquid, which was eluted through 2 inches (5 cm) of silica with hexanes. Concentration of the eluent yielded a light amber liquid, and bulb-to-bulb distillation gave 18.29 g of 1-bromo-6-(nonafluorobutyl)hexane as a clear, colorless liquid, b.p. 70-80° C. at 0.05 torr (7 Pa).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][C:24]1[N:25]=[CH:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:28]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][C:24]1[N:25]=[CH:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:28]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)n1cnc(CON)c1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1cnc(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (10.0 mL) was added tert-butyl 4-[(aminooxy)methyl]-1H-imidazole-1-carboxylate 122 (0.289 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 123 (0.40 g, 94%) as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-n3cncn3)nc3sc([N+](=O)[O-])cc23)c1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-nitro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-nitro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.