Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].CO.O.O.[OH-].[Li+]>C1COCC1>[C:21]([O:20][C:18]([N:11]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=[CH:8][N:9]=1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)c1nccnc1N(C(=O)OC(C)(C)C)c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(c1cccnc1)c1nccnc1C(=O)O
Temperature: 25 °C

Procedure:
3-(tert-Butoxycarbonyl-pyridin-3-yl-amino)-pyrazine-2-carboxylic acid methyl ester (364 mg, 1.1 mmol) was dissolved in 10 ml THF. 5 ml methanol, 5 ml water and lithium hydroxide hydrate (139 mg, 3.30 mmol) were added and stirred over night at room temperature. The organic solvent was evaporated and the residue was neutralized with 2N HCl-solution. The mixture was evaporated to dryness and used without further purification for the next step [(405 mg, >100%), MS: m/e=315.2 (M+H−)].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](=[O:25])[N:6]([C:8]([CH3:24])([CH3:23])[CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH:7]=1.CCN(C(C)C)C(C)C.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl.CC(O)(C)C>[CH3:22][O:21][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][CH2:9][C:8]([N:6]3[C:5](=[O:25])[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:42])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:7]3)([CH3:23])[CH3:24])=[CH:12][CH:13]=[N:14]2)=[CH:19][CH:18]=1
Reactant: COc1ccc2c(OCC(C)(C)n3cc(N)ccc3=O)ccnc2c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: COc1ccc2c(OCC(C)(C)n3cc(NC(=O)c4ccccc4)ccc3=O)ccnc2c1
Temperature: 23 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 5-amino-1-(1-(7-methoxyquinolin-4-yloxy)-2-methylpropan-2-yl)pyridin-2(1 H)-one (33 mg, 97 μmol) in CH2Cl2 (3 mL) and tBuOH (1 mL) at 0° C. under nitrogen was added DIEA (17 μl, 97 μmol) followed by a solution of benzoyl chloride (11 μl, 97 μmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred for 24 h at 23° C. and partitioned between CH2Cl2 (10 mL) and 5% NaHCO3 (5 mL). The organic was dried over MgSO4, concentrated onto dry silica, and purified on silica (12 g) eluting with 0-5% MeOH/CH2Cl2. MS (ESI pos. ion) m/z (MH+): 444. Calc'd exact mass for C26H25N3O4: 443. 1H NMR (400 MHz, Chloroform-d) 8 ppm 1.77 (s, 6 H) 3.89 (s, 3 H) 4.97 (s, 2 H) 6.15 (d, J=5.67 Hz, 1 H) 6.60 (d, J=9.59 Hz, 1H) 7.08 (dd, J=9.19, 2.54 Hz, 1 H) 7.29-7.58 (m, 8H) 7.66 (d, J=2.74 Hz, 1 H) 7.85-7.92 (m, 3 H) 8.02-8.18 (m, 2 H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[CH:10]=[CH:11][C:12](O)=[O:13]>C1C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[CH:10]=[CH:11][C:12]([Cl:3])=[O:13]
Reactant: COc1cccc(C=CC(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1cccc(C=CC(=O)Cl)c1

Procedure:
Thionyl chloride (38 g.) was added dropwise to a mixture of 3-methoxycinnamic acid (50 g.) and benzene (500 ml.), and the resulting mixture was heated under reflux for 1.5 hours, then evaporated under reduced pressure on a rotary evaporator to give an oil. The oil solidified on standing at room temperature, giving 59 g. of the product. Analytical sample (m.p. 43°-45°) was obtained by recrystallization from petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](OC2C=CC([N+]([O-])=O)=CC=2)=[O:9])=[C:6]([NH:20][C:21]2[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=2)[CH:5]=[CH:4][CH:3]=1.[CH3:31][S:32]([NH2:35])(=[O:34])=[O:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:7]([C:8]([NH:35][S:32]([CH3:31])(=[O:34])=[O:33])=[O:9])=[C:6]([NH:20][C:21]2[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CS(N)(=O)=O
Reactant: COc1cc(OC)nc(Nc2cccc(Cl)c2C(=O)Oc2ccc([N+](=O)[O-])cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OC)nc(Nc2cccc(Cl)c2C(=O)NS(C)(=O)=O)n1

Procedure:
This compound is prepared in a manner analogous to that of Example 1, Step I, using equimolar amounts of 4-nitrophenyl 6-chloro-2-(4,6-dimethoxypyrimidin-2-ylamino)benzoate, methanesulfonamide, and potassium carbonate in acetonitrile, yielding 2-[3-chloro-2-(methylsulfonylaminocarbonyl)phenylamino]-4,6-dimethoxypyrimidine, Compound 39 of Table 1.
Reaction SMILES: [C:1]([CH:5]([OH:28])[C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[C:14]([C:15]([N:17]=[CH:18][N:19]=3)=[NH:16])=[N:13][C:12]2=[SiH2:21])[C@H:8]([OH:22])[C@@H:7]1[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:4])([CH3:3])[CH3:2].[CH3:29]OS(OC)(=O)=O.[H-].[Na+]>CN1CCCC1=O.CN(C=O)C.C1(C)C=CC=CC=1>[C:1]([CH:5]([OH:28])[C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[C:14]([C:15]([N:17]=[CH:18][N:19]=3)=[NH:16])=[N:13][C:12]2=[SiH2:21])[C@H:8]([O:22][CH3:29])[C@@H:7]1[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)O[C@H]1[C@@H](O)[C@H](n2c(=[SiH2])nc3c2=NC=NC3=N)O[C@@H]1C(O)C(C)(C)C
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CO[C@@H]1[C@H](OC(C)(C)C)[C@@H](C(O)C(C)(C)C)O[C@H]1n1c(=[SiH2])nc2c1=NC=NC2=N
Temperature: -35 °C
Yield: 60 %

Procedure:
Compound (72) (35.9 g, 88.1 mmol) was dissolved in mixture of 1-methyl-2-pyrrolidinone (60 ml) and DMF (240 ml) at 80° C. The resulting solution was cooled to −35° C. and dimethylsulfate (20.9 ml, 220.4 mmol) was added. Sodium hydride (5.99 g as 60% suspension in mineral oil, 149.8 mmol) was washed with ca. 75 ml of toluene and then suspended in toluene (approximately 15 ml). The resulting suspension was added to the reaction mixture dropwise via syringe while stirring. The reaction was allowed to proceed at −35° C. until nearly all starting material was consumed (about 4 h). The reaction was quenched by careful addition of methanol (200 ml) followed by water (100 ml). The resulting suspension was stirred 30 min at −20-−30° C. The precipitate of (73) was filtered out and washed with methanol twice on filter bed and then dried in vacuo to give 28.1 g of crude (73) having about 85% of purity. Yield 60-65%.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2CCNCC2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].BrCC[OH:28].[CH3:29][CH2:30][N:31]([CH:35]([CH3:37])C)[CH:32]([CH3:34])C>CN(C=O)C.CS(C)=O>[NH2:24][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:34][CH2:32][N:31]([CH2:30][CH2:29][OH:28])[CH2:35][CH2:37]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCNCC3)c2n1
Reactant: OCCBr
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCN(CCO)CC3)c2n1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
2-(Butyloxy)-8-(methyloxy)-9-(4-piperidinylmethyl)-9H-purin-6-amine (for example, as prepared for Intermediate 28) (0.0335 g, 0.10 mmol) in DMF (0.4 mL) was added to 2-bromoethanol (commercially available, for example, from Aldrich) (0.0085 mL, 0.12 mmol). DIPEA (0.040 mL, 0.23 mmol) was added and the reaction mixture heated at 50° C. for 18 hours. Additional DIPEA (0.040 mL, 0.23 mmol) was added and heating continued for a further 18 hours. The reaction mixture was diluted with DMSO:MeOH (0.25 mL) and the resultant solution purified by MDAP (Method A). Appropriate fractions were combined and evaporated in vacuo. The residue was dissolved in 4M HCl in dioxane (0.2 mL) and allowed to stand at room temperature for 4 hours. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus. The residue was redissolved in methanol (0.5 mL) and applied to top of 0.1 g aminopropyl SPE (preconditioned with methanol, 1.5 mL). The cartridge was washed with methanol (1.5 mL). The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound (0.0053 g).
Reaction SMILES: [Br:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8]1([P:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1>[Br-:1].[C:3]([CH2:2][P+:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 38 °C
Reaction time: 12 h
Yield: 86 %

Procedure:
Ethyl bromoacetate (14.4 g, 0.094 mol) was added dropwise over 30 min to a stirred solution of 26.2 g (0.1 mol) of triphenylphosphine in 120 ml of benzene maintained at 35 38° C. After stirring for additional 12 h at room temperature the precipitate was filtered and washed twice with hexane to give 34.7 g (86%) of (carboethoxymethyl)-triphenylphosphonium bromide, m.p. 159 160° C. 115 ml of 10% aqueous sodium hydroxide was added dropwise with cooling at 5° C. to a stirred suspension of 118.4 g (0.276 mol) of the bromide in 500 ml of water and 200 ml of chloroform containing a small amount of phenolphthalein. Stirring was continued over 30 min. period without external cooling followed by adding 500 ml of chloroform to give clear layers. The aqueous layer was extracted three times with 100 ml of chloroform and the combined chloroform fractions were dried over sodium sulfate and concentrated in vacuo. Crystallization of the residue from 180 ml of 1:1 mixture of benzene and hexane gave 86.2 g (90%) of pure (carboethoxymethylene)triphenylphosphorane, m.p. 119 120° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[S:11]([CH3:14])(=[O:13])=[O:12].[Cl:15][C:16]1[CH:33]=[CH:32][C:19]2[N:20]([CH2:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:21]([CH2:23]Cl)=[N:22][C:18]=2[CH:17]=1>>[Cl:15][C:16]1[CH:33]=[CH:32][C:19]2[N:20]([CH2:25][CH2:26][CH2:27][S:28]([CH3:31])(=[O:29])=[O:30])[C:21]([CH2:23][N:7]3[C:8]4[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[C:5]([S:11]([CH3:14])(=[O:12])=[O:13])=[CH:6]3)=[N:22][C:18]=2[CH:17]=1
Reactant: CS(=O)(=O)c1c[nH]c2ccc(F)cc12
Reactant: CS(=O)(=O)CCCn1c(CCl)nc2cc(Cl)ccc21
Product: CS(=O)(=O)CCCn1c(Cn2cc(S(C)(=O)=O)c3cc(F)ccc32)nc2cc(Cl)ccc21

Procedure:
The title compound was prepared in analogy to Example 1-2 by using 5-fluoro-3-(methylsulfonyl)-1H-indole and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole instead of 3-(methylsulfonyl)-1H-indole and 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH3:7])[C:3](O)=[O:4].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:41]([C@H:43]1[C@H:48]([NH:49][C:50]2[C:51]3[N:52]([CH:59]=[C:60]([C:62]4[CH:63]=[N:64][N:65]([CH3:67])[CH:66]=4)[CH:61]=3)[N:53]=[CH:54][C:55]=2[C:56]([NH2:58])=[O:57])[CH2:47][CH2:46][NH:45][CH2:44]1)[CH3:42]>CN(C=O)C>[CH2:41]([C@H:43]1[C@H:48]([NH:49][C:50]2[C:51]3[N:52]([CH:59]=[C:60]([C:62]4[CH:63]=[N:64][N:65]([CH3:67])[CH:66]=4)[CH:61]=3)[N:53]=[CH:54][C:55]=2[C:56]([NH2:58])=[O:57])[CH2:47][CH2:46][N:45]([C:3](=[O:4])[C@@H:2]([OH:1])[CH2:6][CH3:7])[CH2:44]1)[CH3:42]
Reactant: CC[C@@H]1CNCC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(C)c3)cc12
Reactant: CC[C@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1CN(C(=O)[C@@H](O)CC)CC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(C)c3)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
To a solution of (S)-2-hydroxybutanoic acid (3.54 mg, 0.034 mmol) in DMF (181 μl) were added DIEA (28.5 μl, 0.163 mmol) and HATU (25.9 mg, 0.068 mmol). After 15 minutes, 4-(((3R,4R)-3-ethylpiperidin-4-yl)amino)-6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (10 mg, 0.027 mmol) was added. The reaction was stirred at room temperature for 3 hrs. The product mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified via preparative HPLC (Column: Waters XBridge C18, 19×200 mm, 5-μm). The collected fractions were combined and dried via centrifugal evaporation to yield the title compound (7.9 mg, 0.017 mmol, 64.0% yield) as a white solid. 1H NMR (500 MHz, 1:1 Chloroform-d/Methanol-d4) δ 8.12-8.09 (m, 1H), 7.77 (d, J=2.5 Hz, 1H), 7.72 (d, J=3.5 Hz, 2H), 6.92-6.88 (m, 1H), 4.42-4.34 (m, 2H), 4.24-4.13 (m, 1H), 3.95 (s, 3H), 3.12-3.03 (m, 1H), 2.41-2.34 (m, 1H), 1.84-1.73 (m, 2H), 1.70-1.58 (m, 3H), 1.43-1.32 (m, 1H), 1.06-0.97 (m, 7H). LCMS (Method K) m/z 454.249 ([M+H]+). HPLC (Method F) Rt: 1.12 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].C([O-])(=O)C.[NH4+:24]>>[Cl:1][C:2]1[C:3]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH2:24])=[O:6]
Reactant: [NH4+]
Reactant: O=C(O)c1ccnc(Cl)c1Nc1ccc(I)cc1F
Agent: CC(=O)[O-]
Product: NC(=O)c1ccnc(Cl)c1Nc1ccc(I)cc1F

Procedure:
2-Chloro-3-(2-fluoro-4-iodo-phenylamino)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.2 mmol of 2-Chloro-3-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid and 0.5 mmol of ammonium acetate. LC/MS [8.61 min; 392 (M+1)].
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]2[C:13]3[C:18]([O:19][CH2:20][C:3]=12)=[CH:17][C:16]([OH:21])=[CH:15][CH:14]=3.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[OH:21][C:16]1[CH:17]=[C:18]2[O:19][CH2:20][C:3]3[C:4](=[N:5][C:6]4[C:11]([C:2]=3[C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=4)[C:13]2=[CH:14][CH:15]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Oc1ccc2c(c1)OCc1c-2nc2ccc(O)cc2c1Br
Product: COc1ccc(-c2c3c(nc4ccc(O)cc24)-c2ccc(O)cc2OC3)cc1
Yield: 84 %

Procedure:
This compound was prepared from 7-bromo-3,9-dihydroxy-6H-chromeno[4,3-b]quinoline (7) using 4-methoxyphenylboronic acid according to method M. Yellow powder; Yield: 84%; mp 195° C. (dec.); 1H-NMR (400 MHz, DMSOd-6) δ 3.87 (s, 3H), 5.03 (s, 2H), 6.36 (d, J=2.2 Hz, 1H), 6.60 (dd, J=8.5, 2.5 Hz, 1H), 6.73 (d, J=8.6 2.6 Hz, 1H), 7.16 (d, J=8.6 Hz, 2H), 7.24 (dd, J=9.0, 2.6 Hz, 1H), 7.30 (d, J=8.6 Hz, 2H), 7.89 (d, J=9.0 Hz, 1H), 8.15 (d, J=8.6 Hz, 1H), 9.80 (s, 1H), 9.98 (s, 1H); MS (ESI) m/z 370 ([M−H]−), 372 ([M+H]+); HRMS (ESI+) calcd for C23H17NO4 372.1230 ([M+H]+). Found: 372.1226.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:20]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:17]2[O:16][C:15]([CH3:19])([CH3:18])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.[H][H]>C1(C)C=CC=CC=1.[Pt]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:17]2[O:16][C:15]([CH3:19])([CH3:18])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)[NH2:20]
Reactant: CC1(C)Cc2cccc(Oc3ccc([N+](=O)[O-])cc3Cl)c2O1
Reactant: [H][H]
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CC1(C)Cc2cccc(Oc3ccc(N)cc3Cl)c2O1
Yield: 90.6 %

Procedure:
To a solution containing 42.5 g of 3-chloro-4-(2,3-dihydro-2,2-dimethyl-7-benzofuranyloxy)-1-nitrobenzene in 600 ml of toluene was added 1.5 g of 5% Pt on carbon. This mixture was then placed in a 1 L rocking hydrogenator. An atmosphere of hydrogen at 100 psi was introduced into the bomb. The pressure was maintained between 100 psi and 80 psi until the hydrogen uptake ceased. The contents were removed from the bomb and filtered through celite. Removal of the solvents from the filtrates afforded 34.91 g of white solid, mp 102°-104° C. NMR (CDCl3) δ1.45 (s, 6H), 3.0 (s, 2H), 3.55 (broad s, 2H), 6.2-6.9 (m, 6H).
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([C:7](=O)C=CC1C=CC(Cl)=CC=1)=[O:6])[CH3:3].Cl[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27]O)=O)[CH:20]=1.S(C1C(C)=CC(O)=C(C(C)(C)C)C=1)C1C(C)=CC(O)=C(C(C)(C)C)C=1.C(Cl)C[Cl:56]>>[CH3:1][CH:2]([NH:4][C:5]([CH:7]1[CH:25]([C:21]2[CH:20]=[CH:19][C:24]([Cl:56])=[CH:23][CH:22]=2)[O:27]1)=[O:6])[CH3:3]
Reactant: CC(C)NC(=O)C(=O)C=Cc1ccc(Cl)cc1
Reactant: ClCCCl
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cc1cc(O)c(C(C)(C)C)cc1Sc1cc(C(C)(C)C)c(O)cc1C
Product: CC(C)NC(=O)C1OC1c1ccc(Cl)cc1

Procedure:
This compound was prepared from N-(1-methylethyl)-4-chlorocinnamoylcarboxamide (18.3 g.), m-chloroperbenzoic acid (19.4 g.), 4,4'-thiobis(6-tert-butyl-m-cresol) (0.3 g.), and ethylene dichloride (250 ml.) as described in Example 7, and purified by recrystallization from ether. The compound melted at 139°-141°, and weighed 11.7 g. The analytical sample which was obtained by another recrystallization from ether melted at 143°-145°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH:15]([CH3:17])[CH3:16])[C:11]([Cl:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:40][N:39]=[C:38]([CH3:41])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH:15]([CH3:16])[CH3:17])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[O:40][N:39]=[C:38]([CH3:41])[CH:37]=2)[CH:31]=1)=[O:29])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)Nc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(NC(C)C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-isopropylamino-phenyl)-carbamic acid tert-butyl ester (Example J40) (300 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (169 mg, 32%).
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:17])([CH3:16])[CH2:10][C:11](=[O:15])[NH:12]2)=[CH:7][CH:6]=1)(=O)C.Cl.N>C(O)C>[NH2:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([CH3:17])([CH3:16])[CH2:10][C:11](=[O:15])[NH:12]2)=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)CC2(C)C
Agent: Cl
Agent: N
Solvent: CCO
Product: CC1(C)CC(=O)Nc2cc(N)ccc21

Procedure:
A suspension of 23.2 g. (0.1 mole) 7-acetamido-1,2,3,4-tetrahydro-4,4-dimethylquinolin-2-one, 200 ml. ethanol and 20 ml. concentrated hydrochloric acid is boiled under reflux until dissolving is complete. The pH value is then adjusted with ammonia to 8, the reaction mixture is extracted three times with dichloromethane and the organic phase is dried over anhydrous sodium sulphate and freed from solvent. Yield 13.1 g. (69% of theory); m.p. 161°-163° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2OC(=O)[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].[F:15][C:16]([F:28])([C:24]([F:27])([F:26])[F:25])[C:17]#[C:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].ClC1C=CC=C(Cl)C=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:17]([C:16]([F:28])([F:15])[C:24]([F:25])([F:26])[F:27])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCOC(=O)C#CC(F)(F)C(F)(F)F
Reactant: CCc1ccc(-c2nsc(=O)o2)cc1
Solvent: Clc1cccc(Cl)c1
Product: CCOC(=O)c1c(-c2ccc(CC)cc2)nsc1C(F)(F)C(F)(F)F
Temperature: 150 °C
Reaction time: 16 h
Yield: 67.5 %

Procedure:
Into a 10-mL sealed tube, was placed 5-(4-ethylphenyl)-2H-1,3,4-oxathiazol-2-one (155 mg, 0.75 mmol, 1.00 equiv), ethyl 4,4,5,5,5-pentafluoropent-2-ynoate (250 mg, 1.16 mmol, 1.55 equiv), 1,3-dichlorobenzene (3 mL). The resulting solution was stirred for 16 h at 150° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:19). The resulted in a mixture of the product 0.192 g as the yellow oil. Mass spectrum (ESI, m/z): Calcd. for C16H14F5NO2S, 380.3 (M+H). found 380.3.
Reaction SMILES: [F:1][S:2]([O:5][CH3:6])(=[O:4])=[O:3].[CH3:7][N:8]([CH3:28])[C:9]([C@@H:11]1[CH2:15][C@H:14]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:13][N:12]1[CH2:26][CH3:27])=[O:10]>C(Cl)Cl>[F:1][S:2]([O-:5])(=[O:4])=[O:3].[CH3:28][N:8]([CH3:7])[C:9]([C@@H:11]1[CH2:15][C@H:14]([S:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[CH2:13][N+:12]1([CH2:26][CH3:27])[CH3:6])=[O:10]
Reactant: CCN1C[C@@H](SCc2ccc(OC)cc2)C[C@H]1C(=O)N(C)C
Reactant: COS(=O)(=O)F
Solvent: ClCCl
Product: CC[N+]1(C)C[C@@H](SCc2ccc(OC)cc2)C[C@H]1C(=O)N(C)C
Product: O=S(=O)([O-])F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
128 μl of methyl fluorosulfonate were added to a solution of 438 mg of (2S, 4S)-2-(N,N-dimethyl-carbamoyl)-1-ethyl-4-(4-methoxybenzylthio)pyrrolidine dissolved in 10 ml of methylene chloride, and the mixture was stirred at room temperature for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was washed repeatedly by decantation with diethyl ether and dried under reduced pressure to afford the title compound as an oil.
Reaction SMILES: [C:1](=[O:18])([O:10][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17])ON1C(=O)CCC1=O.[C:19]([NH:29][CH:30]([CH2:34][CH2:35][CH2:36][CH3:37])C(O)=O)(=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.N1C=CC=CC=1.C(OCC)(=O)C>C(#N)C>[CH2:13]1[C:12](=[O:17])[N:11]([O:10][C:1]([CH2:37][CH2:36][CH2:35][CH2:34][CH2:30][NH:29][C:19]([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:28])=[O:18])[C:15](=[O:16])[CH2:14]1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: CCCCC(NC(=O)CCc1ccccc1)C(=O)O
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)NCCCCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71.7 %

Procedure:
Disuccinimidyl carbonate (155 mg, 604 μmoles) was added to a solution of 31 (159 mg, 604 μmoles) and pyridine (97.7 μL, 1.21 mmoles) in acetonitrile (1 mL). The reaction mixture was stirred at room temperature for 2.5 h, during which the solution became clear and evolved gas. The solution was added to ethyl acetate (5 mL), washed with 1 N HCl (2×1 mL) and saturated aqueous NaHCO3 (2×1 mL), dried over MgSO4, and concentrated in vacuo to yield a colorless oil (156 mg, 433 μmoles, 72%). LRMS: not performed. 1H NMR: spectrum is consistent with the predicted structure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C@H:11]([CH2:17][CH2:18][OH:19])[O:10][C:9]1([CH3:21])[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[C@H:11]([CH2:17][CH2:18][O:19][S:29]([C:32]2[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[O:10][C:9]1([CH3:20])[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)C[C@H]1[C@H](CCO)OC(C)(C)N1C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC[C@@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]2CC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
200 mg of the compound obtained in Example 10 was dissolved in 2 ml of dry methylene chloride, and 115 μl of triethylamine and 152 mg of tosyl chloride were added thereto. The mixture was stirred at room temperature overnight. Then, 115 μl of triethylamine was further added, and the mixture was reacted at room temperature and then evaporated to dryness under reduced pressure. A solution mixture of benzene/ethyl acetate (30/1) was added to the residue. After filtering insolubles off, the filtrate was purified by silica gel column chromatography to obtain 281 mg of (4S,5S)-3-tert-butyloxycarbonyl-2,2-dimethyl-5-(2-p-toluenesulfonyloxyethyl)-4-isobutyloxazolidine as a syrup.