Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=O.[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[Br:9][C:10]1[C:11]([O:25]C)=[CH:12][C:13]2[S:17][C:16]([NH:18][C:19]([NH:21][CH2:22][CH3:23])=[O:20])=[N:15][C:14]=2[CH:24]=1.[CH3:27]COC(C)=O>CN(C=O)C.O>[Br:9][C:10]1[C:11]([OH:25])=[C:12]([CH2:27][N:3]2[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[C:13]2[S:17][C:16]([NH:18][C:19]([NH:21][CH2:22][CH3:23])=[O:20])=[N:15][C:14]=2[CH:24]=1
Reactant: CCOC(C)=O
Reactant: CCNC(=O)Nc1nc2cc(Br)c(OC)cc2s1
Reactant: C1COCCN1
Agent: C=O
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)Nc1nc2cc(Br)c(O)c(CN3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 11 %

Procedure:
Paraformaldehyde (29 mg, 0.05 mmol) was suspended in anhydrous DMF (2 mL) under argon and morpholine (0.08 mL, 0.95 mmol) added. The mixture was stirred at RT for 10 min then Intermediate 6 (200 mg, 0.63 mmol) added. The mixture was stirred at RT overnight, heated to 90° C. for 2 h then cooled to RT. The mixture was diluted with H2O and a precipitate formed. EtOAc was added but the precipitate remained insoluble. The suspension was filtered through a PTFE filter and the solid rinsed with H2O and EtOAc. The biphasic filtrate was extracted into EtOAc (4×20 mL). The combined organic layers were washed with H2O (3×50 mL), dried (Na2SO4) and concentrated in vacuo. The material was purified by chromatography, on silica eluting with 0-10% MeOH in DCM to give Intermediate 12 (28 mg, 11%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[F-:13].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:13]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Reactant: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(F)c(Cl)c1
Reaction time: 15 h

Procedure:
A mixture of 3,4,5-trichloronitrobenzene (13.55 g, 59 mmol), potassium fluoride (4.65 g, 80 mmol) and dimethylformamide (DMF; 66 ml) is heated at 140° for 15 hours. An additional 2.5 g of potassium fluoride is added and the mixture is stirred an additional 15 hours at 140°. The reaction mixture is poured into water and extracted with ether. The combined organic layers are washed with water and with brine and filtered, and the solvent is removed to give a dark solid, which is purified by column chromatography to give 3,5-dichloro-4-fluoronitrobenzene, a yellow powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[N:13]=[C:12]([CH3:14])[C:11](Br)=[C:10]([CH3:16])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[OH-:17].[K+].O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][C:2]1[N:3]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([OH:17])=[C:10]([CH3:16])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: Cc1nc(-n2c(C)ccc2C)nc(C)c1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc(-n2c(C)ccc2C)nc(C)c1O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a stirred solution containing 2.00 g (7.14 mmol) of 2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-bromo-4,6-dimethylpyrimidine (4) in 16 mL of dioxane-degassed water 1:1 were added 132 mg (0.14 mmol) of Pd2dba3 followed by 242 mg (0.58 mmol) of 2-Di-tert-butylphosphino-2′,4′,6′-triisopropylbyphenyl (L1) and 1.2 g (21.42 mmol) of potassium hydroxide. The reaction mixture was stirred at 100° C. under argon atmosphere during 3 h. The reaction mixture was poured into 100 mL of water and extracted with two portions of 75 mL of ethyl acetate. The aqueous layer was acidified with HCl (pH 2-3) and then extracted with two portions of 100 mL of ethyl acetate. The combined organic solution was washed with a portion of 100 mL of brine, dried (MgSO4) and the concentrated under diminished pressure to afford the expected product as a light yellow crystals: yield 1.62 g (100%). 1H-NMR (CDCl3) δ 5.76 (s, 2H), 2.47 (s, 6H), 2.20 (s, 6H); 13C-NMR (CDCL3) δ 154.15, 149.87, 145.13, 128.74, 107.32, 18.40, 13.50.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1([CH3:24])[CH2:22][NH:21][C:20](=[O:23])[CH2:19]1>>[CH3:17][C:18]1([CH3:24])[CH2:22][N:21]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][N:13]=2)[C:20](=[O:23])[CH2:19]1
Reactant: OCc1ccc(C#Cc2ccccc2)cn1
Reactant: CC1(C)CNC(=O)C1
Product: CC1(C)CC(=O)N(Cc2ccc(C#Cc3ccccc3)cn2)C1

Procedure:
The title compound, light brown oil, MS: m/e=305.2 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from (5-phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) and 4,4-dimethyl-pyrrolidin-2-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]3[N:16]=[C:17]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18](I)=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:28]B(O)O>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]3[N:16]=[C:17]([CH2:20][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]([CH3:28])=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)c(I)c2C1
Reactant: CB(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1c(COc2ccccc2)nn2c1CN(C(=O)c1ccc(F)cc1)CC2
Temperature: 100 °C
Reaction time: 21 h
Yield: 41.6 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (15.7 mg, 0.014 mmol) was added to a stirred solution of (4-fluoro-phenyl)-(3-iodo-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone (0.13 g, 0.27 mmol), methylboronic acid (0.122 g, 2.04 mmol) and saturated solution of Na2CO3 (2 mL) in 1,4-dioxane (4 mL) under N2. The mixture was stirred at 100° C. for 21 hours and then the mixture was diluted with a saturated solution of Na2CO3 and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in heptane 0/100 to 70/30). The desired fractions were collected and the solvents evaporated in vacuo. The product was repurified by reverse phase HPLC (gradient from 80% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 20% MeOH to 0% of 0.1% solution of ammonium formate/ammonium hydroxide buffer pH 9 solution in water and 100% MeOH) to yield (4-fluoro-phenyl)-(3-methyl-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone (41 mg, 39% yield). C21H20FN3O2. 1H NMR (400 MHz, CDCl3) δ ppm 2.00 (br. s., 3H), 3.98 (br. s., 2H), 4.22 (br. s., 2H), 4.73 (br. s., 2H), 5.02 (s, 2H), 6.96 (t, J=7.4 Hz, 1H), 7.02 (d, J=7.9 Hz, 2H), 7.16 (t, J=8.7 Hz, 2H), 7.29 (dd, J=8.7, 7.3 Hz, 2H), 7.49 (dd, J=8.8, 5.3 Hz, 2H).
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:41]=[CH:40][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:42][CH3:43])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[Cl-].[CH:45]([C:48]1[S:49][CH:50]=[C:51]([CH2:53][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:52]=1)([CH3:47])[CH3:46].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:45]([C:48]1[S:49][CH:50]=[C:51](/[CH:53]=[CH:1]\[C:3]2[C:4]([O:14][CH2:15][C:16]3[CH:41]=[CH:40][C:19]([O:20][CH2:21][C:22]4[N:23]=[C:24]([C:28]5[CH:33]=[CH:32][C:31]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:30][CH:29]=5)[O:25][C:26]=4[CH3:27])=[C:18]([O:42][CH3:43])[CH:17]=3)=[N:5][N:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:7]=2)[N:52]=1)([CH3:47])[CH3:46]
Reactant: CC(C)c1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4C=O)cc3OC)c(C)o2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C\c4csc(C(C)C)n4)cc3OC)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 11.3 %

Procedure:
A mixture of ethyl (4-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (1.60 g), [(2-isopropyl-1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (1.7 g), potassium carbonate (0.57 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 17 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1:4, v/v) to give ethyl {4-[4-({4-[({4-[(Z)-2-(2-isopropyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate as colorless crystals (0.22 g, yield 11%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 126-127° C.
Reaction SMILES: [OH-].[K+].[Br:3][C:4](=[C:7]1[NH:11][C:10](=[O:12])[NH:9][C:8]1=[O:13])[CH2:5][CH3:6].[C:14]([CH:20](Cl)[C:21]([NH:23][C:24]1[CH:29]=[C:28]([NH:30][C:31](=[O:52])[CH:32]([O:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]([CH2:45][CH3:46])([CH3:44])[CH3:43])=[CH:38][C:37]=2[C:47]([CH2:50][CH3:51])([CH3:49])[CH3:48])[CH2:33][CH3:34])[CH:27]=[CH:26][C:25]=1[Cl:53])=[O:22])(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16].O>CO.CN(C)C=O>[C:14]([CH:20]([N:9]1[C:8](=[O:13])[C:7](=[C:4]([Br:3])[CH2:5][CH3:6])[NH:11][C:10]1=[O:12])[C:21]([NH:23][C:24]1[CH:29]=[C:28]([NH:30][C:31](=[O:52])[CH:32]([O:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]([CH2:45][CH3:46])([CH3:43])[CH3:44])=[CH:38][C:37]=2[C:47]([CH2:50][CH3:51])([CH3:49])[CH3:48])[CH2:33][CH3:34])[CH:27]=[CH:26][C:25]=1[Cl:53])=[O:22])(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CCC(Br)=C1NC(=O)NC1=O
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1ccc(Cl)c(NC(=O)C(Cl)C(=O)C(C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CCC(Br)=C1NC(=O)N(C(C(=O)Nc2cc(NC(=O)C(CC)Oc3ccc(C(C)(C)CC)cc3C(C)(C)CC)ccc2Cl)C(=O)C(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution containing 4 g of potassium hydroxide dissolved in 15 ml of methanol, was added a solution containing 17 g of 5-α-bromo-n-propylidenehydantoin dissolved in 50 ml of dimethylformamide, and further was added dropwise a solution containing 25 g of α-pivaloyl-α-chloro-2'-chloro-5'-[α-(2,4-di-tert-amylphenoxy)butyramido]acetanilide dissolved in 250 ml of dimethylformamide. After being stirred for 2 hours at room temperature, the reaction mixture was poured into 2 liters of water, and extracted with 1 liter of ethyl acetate. The ethyl acetate layer was separated, washed with a dilute hydrochloric acid solution, washed with water and dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure, and the residue was recrystallized from a solvent mixture of n-hexane and ethyl acetate, yielding 18 g of the coupler. The melting point was 129° to 131° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[S:9][C:10]3[N:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[N:13]=2)=[CH:5][CH:4]=1.[H-].[Li+].[CH2:25](I)[CH2:26][CH3:27]>>[CH2:25]([N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:7][C:6]1[CH:19]=[CH:20][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:4][CH:5]=1)[CH2:26][CH3:27]
Reactant: CCCI
Reactant: O=c1nc(Nc2ccc(C(F)(F)F)cc2)sc2ncccc12
Agent: [H-]
Agent: [Li+]
Product: CCCn1c(=Nc2ccc(C(F)(F)F)cc2)sc2ncccc2c1=O

Procedure:
The reaction procedure of Example 11 was followed except that 646 mg of 2-(4-trifluoromethylanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 18 mg of lithium hydride and 0.19 ml of propyl iodide were used. As a result, 546 mg of 3-propyl-2-[(4-trifluoromethylphenyl)imino]-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=1.[NH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1.N1C2C(=CC=CC=2)C=C1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](OC)=[O:35])=[CH:26]1>>[S:12]1[CH:13]=[CH:14][N:15]=[C:11]1[NH:10][C:34]([C:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:25]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[CH:4]=2)[CH:26]=1)=[O:35]
Reactant: COC(=O)c1c[nH]c2ccccc12
Reactant: Fc1cccc(CBr)c1
Reactant: Nc1nccs1
Agent: c1ccc2[nH]ccc2c1
Product: O=C(Nc1nccs1)c1cn(Cc2cccc(F)c2)c2ccccc12

Procedure:
R5X=1-Bromomethyl-3-fluoro-benzene; NH2A=2-aminothiazole; Indole starting material=methyl indole 3-carboxylate
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12](I)=[C:13]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1B1OC(C)(C)C(C)(C)O1>>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:28]2[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]=2[F:26])=[C:13]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1F)CCCC3

Procedure:
The title compound was prepared from Methyl (2S)-tert-butoxy(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)acetate (Preparation 16, 100 mg, 212 μmol) and 2-(2-fluoro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 19, 99 mg, 424 μmol) using the same method as described in Example 44, Step 1 to yield 100 mg, 96%. Material obtained was a mixture of atropisomers, in a 2:1 ratio.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14]N(CCN(C)C)C.[Li]C(CC)C.S(OC)(OC)(=O)=O>CCOCC.O>[C:1]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH3:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1
Reactant: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CC1CCCCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
A solution of N-Boc-Piperidine (15.0 g, 80.95 mmol) in ether (160 mL) was cooled to −78° C. and treated with TMEDA (15.9 mL, 105.2 mmol) followed by sec-BuLi (85 mL, 105.2 mmol) dropwise. The mixture was stirred for 3 h at −78° C. and then treated with a solution of dimethyl sulfate (15.3 mL, 161.9 mmol) in 65 mL of ether. The mixture was warmed to room temperature and then was diluted with water and extracted with ether. The combined extracts were dried over K2CO3 and then concentrated to give a crude product as a colorless oil. The product was purified by column chromatography on silca gel with 5% EtOAc/hexane to afford 16.0 g (81%) of product as a clear oil which was homogeneous by TLC analysis. 1H NMR (300 MHz) δ 4.33 (m, 1H), 3.92-3.81 (pair of br. d, 1H), 2.81-2.72 (dt, 1H), 1.60-1.36 (m, 15H), 1.09-1.07 (d, 3H); 13C NMR (75 MHz) 154.9 (s), 78.6 (s), 45.9 (s), 38.6 (s), 29.9 (s), 28.4 (s), 25.6 (s), 18.6 (s), 15.6 (s) ppm.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].[F-:11].[K+].[F:13][C:14](=[CH2:18])[C:15](Cl)=[O:16]>COCCOCCOC>[F:13][C:14](=[CH2:18])[C:15]([O:4][C:3]([F:11])([C:5]([F:8])([F:7])[F:6])[C:2]([F:10])([F:9])[F:1])=[O:16]
Reactant: [F-]
Reactant: C=C(F)C(=O)Cl
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: COCCOCCOC
Product: C=C(F)C(=O)OC(F)(C(F)(F)F)C(F)(F)F
Reaction time: 2 h
Yield: 74.1 %

Procedure:
15.3 g (0.092 mol) of hexafluoroacetone were passed with stirring in the course of 30 minutes at a temperature of 25° C. into a suspension of 5.34 g (0.092 mol) of dried potassium fluoride in 25 ml of dry diethylene glycol dimethyl ether, and the potassium fluoride dissolved. After a further 2 hours of stirring, unreacted hexafluoroacetone was distilled off under reduced pressure (water jet pump). 10 g (0.092 mol) of α-fluoroacryloyl chloride were added at a temperature of 25° C. with stirring to the remaining solution in the course of 5 minutes, and a colorless solid precipitated. The reaction mixture was stirred at a temperature of 25° C. for a further 80 minutes, and 0.005 g of hydroquinone monomethyl ether were then added, which has followed by distillation under a pressure of 40 mbar. 17.6 g (74 percent of theory) of perfluoroisopropyl α-fluoroacrylate having a boiling point of 40° C. (under 165 mbar) were obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)O)([CH3:4])([CH3:3])[CH3:2].[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[N:23]1[C:19](=[O:29])[C:20]2[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:22]1=[O:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NCC(O)c1cccc(Cl)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(c1cccc(Cl)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of [2-(3-chloro-phenyl)-2-hydroxy-ethyl]carbamic acid tert-butyl ester (20 g, 73.5 mmol), phthalimide (11.1 g, 73.5 mmol) and PPh3 (25.1 g, 95.5 mmol) in THF (500 mL) was added DEAD (11.4 mL, 95.5 mmol) dropwise at −5 to 0° C. The reaction mixture was stirred at room temperature for 3 hours. Then the mixture was concentrated to dryness. The residue was purified by column chromatography (ethyl acetate:petroleum ether, 1:10) to afford [2-(3-chloro-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-carbamic acid tert-butyl ester. (Yield 20 g, 69%). LC-MS: [M+H]+ 401.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:9])=[C:4](C)[CH:5]=[CH:6][CH:7]=1.[CH:10]([CH:12]=O)=O.S(=O)(O)[O-].[Na+].[C:19](=O)([O-])[O-].[K+].[K+]>O>[CH3:19][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][CH2:12][CH2:10][NH:9]2
Reactant: O=CC=O
Reactant: Cc1cccc(N)c1N
Reactant: O=C([O-])[O-]
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: Cc1ccc2c(c1)NCCN2
Temperature: 60 °C

Procedure:
3,4-diaminotoluene was purified by sublimation. 12.2 g (0.1 mol) diaminotoluene was dissolved in 100 cm3 water at 70° C. To this was added 15.0 g 40% aqueous glyoxal solution (0.104 mol) in a solution of 21.5 g sodium bisulfite in 100 cm3 water. After 15 minutes at 60° C. the reaction mixture was cooled and 15 g potassium carbonate added. The product, 6-methylquinoxaline, was extracted with dichloromethane and purified by distillation. 6-methylquinoxaline was hydrogenated at 60 psi, 50° C. with PtO2 catalyst in ethanol, to produce 1,2,3,4-tetrahydro-6-methylquinoxaline. 1.48 g (0.01 mol) 1,2,3,4-tetrahydro-6-methylquinoxaline, 3.7 g (0.04 mol) epichlorohydrin, 3 cm3 benzene and 0.027 cm3 (0.00045 mol) acetic acid were reacted under nitrogen at 60° C. until reaction was shown to be complete by reverse phase HPLC (approximately 3 hours). Solvent and excess reactants were removed by distillation. 3.0 cm3 of water and 1.5 g of concentrated HCl were added under nitrogen and stirred to dissolve at 60° C., then 0.49 g (approximately 0.006 mol) of 37% aqueous formaldehyde was added and the mixture stirred for 2 hours at 60° C. After cooling, the solution was neutralised with 10% aqueous NaOH, upon which it separated into an organic and an aqueous layer. The aqueous layer was decanted off and the organic layer dried thoroughly under vacuum. The resulting friable foamed solid was powdered finely, 1.0 g (0.025 mol) powdered NaOH and 12 cm3 butanone were added under nitrogen, and the resulting slurry was stirred vigorously for 2 hours at 60° C. The reaction mixture was allowed to cool and settle, was filtered, and the solvent removed from the filtrate to give an amber coloured resinous product.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:16][CH2:15][CH2:14][C@H:2]1[C:3]([NH:5][C@H:6]([C:11]([OH:13])=[O:12])[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].ON1C2C=CC=CC=2N=N1.S1CCNC1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.C(OCC)(=O)C>[NH:1]1[CH2:16][CH2:15][CH2:14][C@H:2]1[C:3]([NH:5][C@H:6]([C:11]([OH:13])=[O:12])[C@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1CSCN1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1)C(=O)O
Reaction time: 8 h
Yield: 80 %

Procedure:
6.5 mM Boc-Pro-Ile-OH (one equivalent=1 eq.) is suspended, together with N-hydroxybenzotriazole (1 eq.) and thiazolidine (1 eq.), in 30 ml of dichloromethane (DCM). The equivalent amount of IM dicyclohexylcarbodiimide solution is added dropwise, at −10° C., with stirring. Stirring is carried out at −10° C. and overnight at room temperature. For the purpose of working-up, the solution is thoroughly filtered off from the dicyclohexylurea that is precipitated out, DCM is drawn off in vacuo and the residue obtained is taken up in ethyl acetate. The ethyl acetate solution is washed at least three times with saturated bicarbonate solution, once with saturated NaC1 solution, three times with dilute KHSO4 solution and again with NaC1 solution. The ethyl acetate phase is dried over Na2SO4 and concentrated using a rotary evaporator, and the remaining crude product is recrystallised using ethyl acetate/pentane. Boc-Pro-Ile-Thia crystallises after 1–2 days at 4° C. (yield 80%). 1.1N HC1/glacial acetic acid solution is added to Boc-Pro-Ile-Thia (3 ml per mmol of peptide). Stirring is carried out for two hours at RT, absolute ether is added and excess removal solution is evaporated off using a rotary evaporator. The hydrochloride crystallises quantitatively under absolute ether overnight at 4° C. The crystals are quickly separated off by suction filtration, washed several times with absolute ether, and the product is stored in a desiccator over KOH or phosphorus pentoxide.
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].B(O)O.[C:18]([O-:21])([O-])=O.[Na+].[Na+].[CH2:24]1[CH2:28]O[CH2:26][CH2:25]1>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>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:2]=1[C:24]1[CH:28]=[CH:11][C:2]2[CH2:3][CH:8]([O:21][CH3:18])[CH2:9][CH2:10][C:26]=2[CH:25]=1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Reactant: C1CCOC1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OBO
Agent: [Na+]
Product: COC(=O)c1cccc([N+](=O)[O-])c1-c1ccc2c(c1)CCC(OC)C2
Yield: 43 %

Procedure:
A solution of 5.69 g (26.5 mmol) of methyl 2-chloro-3-nitrobenzoate and 6.00 g (29.1 mmol) of the boronic acid from Part A in 110 mL of THF was treated with 1.68 g of tetrakis(triphenylphosphine)palladium(0) followed by 29.1 mL (58.2 mmol) of 2.0 N Na2CO3. The mixture was flushed with a stream of N2 and heated to mild reflux for 48 hrs. The reaction was allowed to cool and was extracted with EtOAc (5×100 mL). The combined organic layers were washed sequentially with H2O, 1 N aq HCl, saturated aq NaHCO3, and H2O. The organic layers were dried over Na2SO4, filtered and concentrated in vacuo 12.4 g of crude material. The residue was purified by flash chromatography (SiO2; 30% hexanes in toluene to 100% toluene) to afford 3.88 g (43%) of the title compound. 1H NMR (DMSO-d6) δ 8.04 (dd, J=8.1 and 1.1 Hz, 1H), 7.94 (dd, J=7.7 and 1.1 Hz, 1H), 7.68-7.61 (m, 1H), 6.69-6.64 (m, 2H), 3.54 (m, 6H), 2.74-2.67 (m, 2H), 2.61-2.53 (m, 2H), 1.74-1.64 (m, 4H); IR (CHCl3) 2936, 1735, 1535, 1511, 1465, 1298, 1268, 1126 cm−1; FDMS 342 (M+1).