Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]2([C:16]([F:19])([F:18])[F:17])[CH2:15][CH2:14]2)(=O)=O)=CC=1.[C-:20]#[N:21].[K+].O>CN(C=O)C>[F:19][C:16]([F:17])([F:18])[C:13]1([CH2:12][C:20]#[N:21])[CH2:14][CH2:15]1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OCC2(C(F)(F)F)CC2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCC1(C(F)(F)F)CC1
Temperature: 60 °C
Yield: 39.4 %

Procedure:
Treat a solution of (1-(trifluoromethyl)cyclopropyl)methyl 4-methylbenzenesulfonate (12 g, 40.8 mmol) in DMF (150 mL) with potassium cyanide (3.5 g, 53 mmol) and heat at 50-70° C. for 3 days. Treat the mixture with water, extract with EtOAc (3×), wash the combined organics with water, then brine, dry and concentrate under reduced pressure to give the title compound (2.4 g, 39% yield). 1H NMR (400 MHz, CDCl3): δ 2.81 (s, 2H), 1.24-1.18 (m, 2H), 0.95-0.92 (m, 2H).
Reaction SMILES: Cl.[C:2]([O:6][C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])([CH3:5])([CH3:4])[CH3:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:45][C:46]1[CH:68]=[CH:67][C:49]2[NH:50][C:51](=[C:53]([C:57]3[N:62]=[C:61]([C:63]([F:66])([F:65])[F:64])[CH:60]=[CH:59][N:58]=3)[C:54]([NH2:56])=[O:55])[S:52][C:48]=2[CH:47]=1>CN(C=O)C.CC(=O)OCC>[C:2]([O:6][C:7]([NH:9][CH2:10][C:11]([NH:45][C:46]1[CH:68]=[CH:67][C:49]2[NH:50][C:51](=[C:53]([C:57]3[N:62]=[C:61]([C:63]([F:66])([F:65])[F:64])[CH:60]=[CH:59][N:58]=3)[C:54]([NH2:56])=[O:55])[S:52][C:48]=2[CH:47]=1)=[O:13])=[O:8])([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: NC(=O)C(=C1Nc2ccc(N)cc2S1)c1nccc(C(F)(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2c(c1)SC(=C(C(N)=O)c1nccc(C(F)(F)F)n1)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 76A was prepared from compound 32A as follows. To a solution of N-(tert-butoxycarbonyl)glycine hydrochloride (20 mg) in DMF (5 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (190 mg), triethylamine (388 μL, 3.88 mmol), and 2-[6-aminobenzothiazol-2(3H)-ylidene]-2-(4-trifluoromethylpyrimidin-2-yl)acetamide (141 mg). The mixture was stirred at room temperature for 1 hr, then poured into EA (50 mL). The EA layer was washed three times with 10% aqueous sodium bicarbonate (30 mL each), and three times with water (15 mL each), then dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 2-{6-[(tert-butyloxycarbonylamino)acetylamino]benzothiazol-2(3H)-ylidene}-2-(4-trifluoromethylpyrimidin-2-yl)acetamide as a brown foam. 2-{6-[(Tert-butyloxycarbonylamino)-acetylamino]benzothiazol-2(3H)-ylidene}-2-(4-trifluoromethylpyrimidin-2-yl)acetamide (80 mg, 156 mmol) was dissolved in 4N hydrogen chloride in dioxane (5.0 mL, 20 mmol), and the mixture stirred at room temperature for 2 hr. The mixture was concentrated to give 2-{6-[(2-aminoacetyl)-amino]benzothiazol-2(3H)-ylidene}-2-(4-trifluoromethylpyrimidin-2-yl)acetamide (50 mg) as a beige solid. Other compounds with an amide side-chain may be similarly prepared from compound 32A.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])=[CH:8][C:7]=1[Cl:19].[Br:20][C:21]1[O:25][C:24]([C:26](O)=[O:27])=[CH:23][CH:22]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(OCC)(=O)C.C(Cl)(Cl)Cl>[Cl:19][C:7]1[CH:8]=[C:9]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:11]([Cl:12])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][NH:1][C:26]([C:24]1[O:25][C:21]([Br:20])=[CH:22][CH:23]=1)=[O:27]
Reactant: NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=C(O)c1ccc(Br)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)c1ccc(Br)o1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To a mixture of 0.35 g of 4-(3-aminopropyloxy)-3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)benzene, 0.19 g of 5-bromo-2-furancarboxylic acid, 0.18 ml of triethylamine and 10 ml of chloroform was added 0.23 g of WSC hydrochloride, while stirring at room temperature. After stirring at room temperature for 6 hours, the reaction mixture was concentrated to give a residue. The residue was dissolved in 50 ml of ethyl acetate, and the ethyl acetate layer was successively washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.35 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(5-bromo-2-furancarboxamido)propyloxy)-benzene (64% yield), nD24.0 1.5918.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:43][NH2:44]>>[NH:43]([C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)=[O:36])[NH2:44]
Reactant: NN
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: COc1cc(C(=O)NN)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with hydrazine to give (2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-hydrazinocarbonyl-2-methoxy-phenyl)-amide. MS (ES+) m/z calcd. for C31H32Cl2F2N5O3: [(M+H)+]: 630. found: 630.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][C:9]=2[C:17]([F:20])([F:19])[F:18])=[CH:3][CH:2]=1.[OH:21]OS([O-])=O.[K+].[OH2:27]>CO.O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([S:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][C:9]=2[C:17]([F:18])([F:20])[F:19])(=[O:21])=[O:27])=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc(Sc2ccncc2)c(C(F)(F)F)c1
Reactant: O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1ccc(S(=O)(=O)c2ccncc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 53 %

Procedure:
To a solution of the product obtained from step 2 (4.80 g, 16.15 mmol) in methanol (80 ml) and tetrahydrofurane (80 ml) was added drop wise to a solution of oxone, monopersulfate compound (17.87 g, 29.07 mmol) in water (80 ml) at 0° C. The suspension was stirred 4 days at RT. Water (100 ml) was added and the reaction mixture was extracted with DCM. The combined organic phases were washed with brine and dried over magnesium sulphate. Evaporation and purification of the crude product by silica gel chromatography using DCM/methanol=20:1 gave the desired product (2.80 g, 53%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[S:6][CH:7]=[CH:8][C:2]1=2.C([Li])CCC.[Cl:14]C(Cl)(Cl)C(Cl)(Cl)Cl.[Cl-].[NH4+]>O1CCCC1>[Cl:14][C:5]1[S:1][C:2]2[CH:8]=[CH:7][S:6][C:3]=2[CH:4]=1
Reactant: c1cc2sccc2s1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1cc2sccc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
A solution of thieno[3,2-b]thiophene (see Fuller, L.; Iddon, B.; Smith, K. A. J. Chem. Soc. Perkin Trans 1 1997, 3465-3470) (1.27 g) in tetrahydrofuran (30 ml) was cooled to −78° C. under argon atmosphere, and thereto was added dropwise n-butyl lithium (1.59 M hexane solution, 5.70 ml). The mixture was stirred at 0° C. for 30 minutes, and cooled again to −78° C. Added thereto was a solution of hexachloroethane (2.14 g) in tetrahydrofuran (5 ml). The mixture was stirred at the same temperature for one hour, and warmed to 0° C. Added thereto was a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to give 2-Chlorothieno[3,2-b]thiophene (1.19 g) as a solid.
Reaction SMILES: ClC1C=CC=C(Cl)C=1C(Cl)=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1)[NH2:16].[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44]>C1(C)C=CC=CC=1.C(O)C>[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[C:37]=1[C:43]([N:45]=[C:46]=[S:47])=[O:44].[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:46]([NH:45][C:43](=[O:44])[C:37]2[C:38]([Cl:42])=[CH:39][CH:40]=[CH:41][C:36]=2[Cl:35])=[S:47])[CH:17]=[CH:18][C:19]=1[O:20][C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1c(Cl)cccc1Cl
Agent: O=C(N=C=S)c1c(Cl)cccc1Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4c(Cl)cccc4Cl)cc3Cl)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
2,6-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,6-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,6-dichloro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (40 mg, yield 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[CH3:43][C:44]1[S:48][C:47]([CH:49]([NH2:51])[CH3:50])=[N:46][CH:45]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:35]([NH:51][CH:49]([C:47]2[S:48][C:44]([CH3:43])=[CH:45][N:46]=2)[CH3:50])=[O:41])=[CH:18][C:17]=1[F:23]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: Cc1cnc(C(C)N)s1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4ncc(C)s4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(5-methyl-1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (16 mg, yield 35%).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:43][C:44]([CH3:64])=[CH:45][CH2:46][CH2:47]/[C:48](/[CH3:63])=[CH:49]/[CH2:50][CH2:51]/[C:52](/[CH3:62])=[CH:53]/[CH2:54][S:55][CH2:56][C@H:57]([NH2:61])[C:58]([OH:60])=[O:59]>C1COCC1.C(OCC)(=O)C>[CH3:9][O:8][C:1](=[O:7])[CH2:2][CH2:3][C:4]([NH:61][C@@H:57]([CH2:56][S:55][CH2:54]/[CH:53]=[C:52](\[CH3:62])/[CH2:51][CH2:50]/[CH:49]=[C:48](\[CH3:63])/[CH2:47][CH2:46][CH:45]=[C:44]([CH3:64])[CH3:43])[C:58]([OH:60])=[O:59])=[O:6]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Reactant: COC(=O)CCC(=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCC(=O)N[C@@H](CSC/C=C(\C)CC/C=C(\C)CCC=C(C)C)C(=O)O
Temperature: 25 °C

Procedure:
In a 100 mL round bottom flask, mono-methyl succinate (132 mg, 1 mmol), 2-(7-Aza-1H-benzotriazole-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.1 mg, 1.1 mmol) and N,N-diisopropyl-ethyl-amine (0.52 mL, 3 mmol) were mixed in THF (5 mL). The reaction solution was stirred at room temperature for ten minutes. S-trans, trans-Farnesyl-L-cysteine (325 mg, 1 mmol) was added to reaction mixture. The reaction solution was stirred at room temperature overnight. Ethyl acetate (50 mL) was added and then washed with saturated ammonium chloride aqueous solution (20 mL×2), DI water (20 mL×2) and brine (20 mL×2) sequentially. The ethyl acetate solution was dried by Na2SO4 and concentrated in vacuo to afford a crude Compound N-17. The crude Compound N-17 was purified by HPLC (110 mg, 25%) to yield Compound N-17. 1H-NMR (500 MHz, MeOH-d4): δ 1.50 (s, 6H), 1.57 (s, 3H), 1.58 (s, 3H), 1.85-1.88 (m, 2H), 1.91-1.96 (m, 4H), 1.99-2.03 (m, 2H), 2.46-2.54 (m, 4H), 2.68 (dd, J=7.5, 13.5 Hz, 1H), 2.90 (dd, J=4.5, 13.5 Hz, 1H), 3.09-3.12 (m, 2H), 3.21 (s, 3H), 4.35 (dd, J=4.5, 7.0 Hz, 1H), 4.98-5.02 (m, 2H), 5.14 (t, J=7.5 Hz, 1H). 13C-NMR (125 MHz, MeOH-d4): δ 16.12, 16.25, 17.79, 25.94, 27.48, 27.79, 30.40, 30.69, 31.73, 35.49, 40.77, 40.89, 52.24, 55.45, 121.82, 125.22, 125.47, 132.08, 136.15, 139.97, 173.57, 174.80, 177.17; ES-MS: mass calcd for Chemical Formula: C23H37NO5S 439.2. Found (M+Na) m/z 462.2.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:31]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[N:42]([CH3:43])[CH:41]=[N:40][CH:39]=3)[CH2:33][CH2:32]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:30]=[CH:29][C:14]([CH2:15][N:16]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:31]2[CH2:32][CH2:33][N:34]([CH2:37][C:38]3[N:42]([CH3:43])[CH:41]=[N:40][CH:39]=3)[CH2:35][CH2:36]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:30]=[CH:29][C:14]([CH2:15][N:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cn1cncc1CN1CCN(c2c(Br)cnc3[nH]c(-c4ccc(CN5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cncc1CN1CCN(c2c(Br)cnc3[nH]c(-c4ccc(CN5CCNCC5)cc4)nc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
tert-Butyl 4-(4-(6-bromo-7-(4-((1-methyl-1H-imidazol-5-yl)methyl)piperazin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)benzyl)piperazine-1-carboxylate (0.028 g, 0.043 mmol) was suspended in DCM (2.3 mL) and the mixture cooled in an ice bath. TFA (0.56 mL) was added and the resulting solution was allowed to warm up to room temperature and stirred for 2 h. The mixture was passed through an SCX column (2 g), the filtrate collected and the solvent removed in vacuo to give the title compound as a off-white solid (0.021 g, 89%); 1H-NMR (500 Mz, DMSO-d6): 2.27-2.36 (m, 4H), 2.55-2.62 (m, 4H), 2.72 (t, J=4.8 Hz, 4H), 3.50 (s, 2H, NCH2), 3.54 (s, 2H, NCH2), 3.61-3.66 (m, 4H), 3.68 (s, 3H, imidazole Me), 6.80 (s, 1H, imidazole 4-H), 7.45 (d, J=8.0 Hz, 2H, ArH, C6H4), 7.57 (s, 1H, imidazole 2-H), 8.14 (d, J=8.5 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H); LC (Method B)-MS (ESI, m/z) 1.66 min—550/552 [(M+H)+], Br isotopic pattern]; ESI-HRMS: Found: 550.2044, calculated for C26H33BrN9 (M+H)+: 550.2042.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Cl:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:21])=[CH:18][CH:17]=1.[C:30]1([C:32](=[CH:34][CH:35]=[CH:36][CH:37]=1)O)[OH:31]>C1C=CC=CC=1>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C:20]1([C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:29][CH:28]=2)[O:31][C:30]2[CH:32]=[CH:34][CH:35]=[CH:36][C:37]=2[O:21]1)[CH3:27]
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)cc1
Reactant: Oc1ccccc1O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: c1ccccc1
Product: CCOC(=O)CC1(c2ccc(Cl)cc2)Oc2ccccc2O1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
98.9 g of P2O5 is added to a mixture of 64 g of ethyl p-chlorobenzoylacetate and 90.4 g of pyrocatechol, heated at 80°C in portions over about 1/2 hour. After 15 minutes the heating is interrupted and 1000 cc of benzene are added. The organic phase is decanted. The latter is repeatedly washed first with NaHCO3 and subsequently with H2O until same is rendered neutral and finally dried with Na2SO4. The solvent is removed in vacuum and the residual oil fractionated, b.p. 150°-155°C (0.4 mm.Hg).
Reaction SMILES: [N+:1]([C:4]1[CH:40]=[CH:39][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:37][OH:38])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50].O>ClCCl>[CH3:48][S:49]([O:38][CH2:37][C@@H:13]1[CH2:14][C@H:15]([S:17][C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:16][N:12]1[C:10]([O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:40][CH:39]=1)=[O:11])(=[O:51])=[O:50]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H]1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
To a solution of (2S,4S)-1-p-nitrobenzyloxycarbonyl-4-tritylthiopyrrolidine-2-methanol (5.0 g: 9.01 mmole) in dichloromethane (50 ml) stirring at -15° C., triethylamine (1.63 ml: 1.3 eq.) and methanesulfonyl chloride (0.85 ml: 1.1 eq.) are added. The mixture is stirred at -15° to -10° C. for 30 minutes. The reaction mixture is poured into water and extracted with dichloromethane. The extract is successively washed with dilute hydrochloric acid, aqueous sodium hydrogen carbonate, and water, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene: ethyl acetate=9:1) to give (2S,4S)-1-p-nitrobenzyloxycarbonyl-4-tritylthiopyrrolidine-2-methanol methanesulfonate (4.86 g). Yield: 85.2%.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3](=[O:5])[CH3:4].[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][CH2:4][C:3](=[O:5])[C:2]([CH3:13])([CH3:1])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: BrBr
Reactant: CC(=O)C(C)(C)Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(Cc1ccccc1)C(=O)CBr
Temperature: 25 °C
Yield: 100 %

Procedure:
100 g (0.57 mol) of 3,3-dimethyl-4-phenylbutan-2-one (Example 5) are dissolved in 0.8 liter of chloroform, and 29 ml (91.9 g; 1.14 mols) of bromine are added slowly at room temperature. The mixture is stirred for a further hour at room temperature and is concentrated. 145.5 g (quantitative) of 1-bromo-3,3-dimethyl-4-phenylbutan-2-one are obtained, and this directly reacted further, without isolation. ##STR24##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2[CH:27]=[CH:28][CH:29]=[N:30]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:49][C:50]1[S:51][CH:52]=[C:53]([C:55]2[CH:63]=[CH:62][C:58]([C:59]([OH:61])=[O:60])=[CH:57][CH:56]=2)[N:54]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:15])[NH:49][C:50]1[S:51][CH:52]=[C:53]([C:55]2[CH:56]=[CH:57][C:58]([C:59](=[O:61])[NH:30][CH:29]3[CH2:27][CH2:28]3)=[CH:62][CH:63]=2)[N:54]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4].[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:14])[NH:49][C:50]1[S:51][CH:52]=[C:53]([C:55]2[CH:56]=[CH:57][C:58]([C:59]([OH:61])=[O:60])=[CH:62][CH:63]=2)[N:54]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1nc(-c2ccc(C(=O)O)cc2)cs1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1nc(-c2ccc(C(=O)NC3CC3)cc2)cs1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1nc(-c2ccc(C(=O)O)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-pyrrolidine-1,2-dicarboxylic acid 1-tertbutyl ester (1.30 g, 6.04 mmol), HATU (2.31 g, 6.07 mmol)), and DIEA (1.2 mL, 9.18 mmol) in DMF (32 mL) was stirred at room temperature for 1 h. Then 4-(2-amino-thiazol-4-yl)-benzoic acid (0.89 g, 4.04 mmol) was added and the reaction mixture was stirred at room temperature overnight. The resulting mixture was purified by reverse phase HPLC to furnish the desired product (S)-2-[4-(4-carboxy-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester; MS: 418.1 (M+H+).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH2:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[C:18](#[N:20])[CH3:19]>>[CH3:6][CH:7]([NH:20][C:18](=[O:2])[CH3:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=S(=O)(O)O
Reactant: CC#N
Reactant: C=CCCCCCCCCCC
Product: CCCCCCCCCCC(C)NC(C)=O
Temperature: 0 °C
Yield: 74 %

Procedure:
To 80 g (0.8 mole) 97% sulfuric acid was slowly added over a period of 1/2 hour with stirring, a mixture of 12 g acetonitrile and 34 g 1-dodecene, the temperature being maintained at 25°-30° C. with an ice-bath. The reaction mixture was stirred and cooled for an additional 2 hours, until no more heat evolved. The reaction mixture was stirred at room temperature for an additional 21/2 hours and then poured into 200 ml ice water and allowed to separate in a separatory funnel. The top layer was again poured into 200 ml ice water, neutralized with about 45 g sodium carbonate, extracted with ether, dried over Na2SO4 and evaporated in vacuum to 39.6 g of a yellow oil. Kugelrohr distillation gave 34 g of N-β-dodecylacetamide boiling at 120°-160° C. (50μ) and having a m.p. of 41°-49° C. Analysis of the end product showed that less than 2% of the product had hydrolyzed to amine.