Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([C@H:13]([NH2:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:21]([OH:23])=[O:22].O.O.O.[OH-].[Na+].Cl.CC([OH:34])C>O>[CH3:1][C:2]1([CH3:24])[S:6][C@H:5]([C@H:7]([NH:10][C:11]([C@H:13]([NH2:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])[C:8]([OH:9])=[O:34])[NH:4][C@H:3]1[C:21]([OH:23])=[O:22]
Reactant: CC(C)O
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)S[C@H]([C@H](NC(=O)[C@H](N)c2ccccc2)C(=O)O)N[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
Ampicilloic acid was prepared in the following manner. Ampicillin trihydrate (10 gm, Sigma) was suspended in 50 ml of water and dissolved by the addition of 10N NaOH. The pH was maintained at 12 by the addition of 10N NaOH. After 1 hour, the pH was adjusted to 7.0 with 6N HCl. 2-Propanol (140 ml) was then added, and the solution allowed to stand for 4 hours at 4° C., after which time crystals had formed. The crystals were filtered and washed several times with cold 2-propanol:water (3:1) and allowed to dry at room temperature. Thin layer chromatography confirmed that this material was essentially all ampicilloic acid. Yield was 1.97 gm.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])=[O:2].[O-:26][Mn](=O)(=O)=O.[K+]>C1COCC1.O>[C:18]([C:17]1[CH:16]=[CH:15][C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([C:5]3[CH:22]=[CH:23][C:24]([CH3:25])=[C:3]([CH:4]=3)[C:1]([OH:26])=[O:2])=[O:7])[CH2:9][CH2:10]2)=[CH:21][CH:20]=1)#[N:19]
Reactant: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1C=O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1C(=O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
To a stirred mixture of 4-(1-(3-formyl-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 39.2, 600 mg, 1.81 mmol, 1.00 equiv) in THF (5 mL) was added dropwise a solution of KMnO4 (1 g) in water (10 mL). The resulting mixture was stirred overnight at 60° C. in an oil bath. After cooling to ambient temperature, the solids were removed by filtration and the pH of the filtrate was adjusted to ≧10 with sodium hydroxide (aqueous, 1 M). The resulting mixture was washed with 20 mL of ethyl acetate. Aqueous 1 M HCl was then employed to adjust the pH of the aqueous layer to ˜4. The resulting aqueous phase was extracted with 2×100 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 500 mg (80%) of the title compound as light yellow oil.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4]([OH:6])=[O:5].[CH:13]1([NH2:16])[CH2:15][CH2:14]1>N1C=CC=CC=1>[CH:13]1([NH:16][C:2]2[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=2[C:4]([OH:6])=[O:5])[CH2:15][CH2:14]1
Reactant: O=C(O)c1c(F)cc(F)cc1F
Reactant: NC1CC1
Solvent: c1ccncc1
Product: O=C(O)c1c(F)cc(F)cc1NC1CC1
Yield: 70.2 %

Procedure:
2,4,6-Trifluorobenzoic acid (9.0 g, 34.1 mmol) and cyclopropylamine (14.65 g, 256 mmol) were stirred in pyridine (300 mL) at 120° C. in a sealed tube for 22 h. The solution was concentrated in vacuo. The residue was taken up in water (30 mL) and the solution was acidified to pH 2-3 with 1N HCl. The resulting precipitate was collected by filtration to yield 5.1 g (47%) of clean desired product as a beige solid. 1H NMR (400 MHz, DMSO-d6): δ 8.05 (s, 1H), 6.65 (d, 1H, J=8.0 Hz), 6.42 (t, 1H, J=10.8 Hz), 2.42-2.48 (m, 1H), 0.76-0.83 (m, 2H), 0.45-0.51 (m, 2H). MS (ES) [m+H] calc'd for C10H9F2NO2, 213; found 213.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)=[CH:3]1.[H][H]>C(O)C.[Pd]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:19])=[CH:3]1
Reactant: [H][H]
Reactant: Cn1cc(CNc2ccccc2[N+](=O)[O-])c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: Cn1cc(CNc2ccccc2N)c2ccccc21
Yield: 89.8 %

Procedure:
829 mg (6 mmol) of 2-nitroaniline and 1242 mg (7.8 mmol) of 1-methylindole carboxyaldehyde were dissolved in 20 ml of tetrahydrofuran followed by the sequential addition of 200 μl of acetic acid and 5087 mg (24 mmol) of NaBH(OAc)3 and stirring overnight at room temperature. After adding saturated aqueous sodium bicarbonate solution, extracting with ethyl acetate and drying with anhydrous magnesium sulfate, the solvent was distilled off and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5) to obtain 264 mg of ((1-methylindole-3-yl)methyl)(2-nitrophenyl)amine (yield: 18%). 264 mg (0.939 mmol) of ((1-methylindole-3-yl)methyl)(2-nitrophenyl)amine were then dissolved in 10 ml of ethanol followed by the addition of 50 mg (0.047 mmol) of 10% Pd—C and stirring for 6 hours at room temperature in a hydrogen atmosphere. After completion of the reaction, the Pd—C was filtered out and the solvent was distilled off under reduced pressure to obtain 212 mg of ((1-methylindole-3-yl)methyl)(2-aminophenyl)amine (yield: 90%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH:7]([NH:17][C:18](N1C=CN=C1)=[O:19])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28](=[O:39])[CH2:29][CH:30]([NH2:38])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([I:37])[CH:32]=1>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[C@@H:7]([NH:17][C:18]([NH:38][C@H:30]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([I:37])[CH:32]=1)[CH2:29][C:28]([O:27][CH3:26])=[O:39])=[O:19])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)n1ccnc1)C(=O)OC(C)(C)C
Reactant: COC(=O)CC(N)c1cccc(I)c1
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)C[C@H](NC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1cccc(I)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 48.8 %

Procedure:
2-[(Imidazole-1-carbonyl)-amino]-pentanedioic acid di-tert-butyl ester (370 mg, 1.05 mmol) was dissolved in DCE (10 mL) and cooled to 0° C. MeoTf (142 μL, 1.25 mmol) was added and the reaction was allowed to proceed for 20 min. (±)-3-Amino-3-(3-iodo-phenyl)-propionic acid methyl ester (356 mg, 1.045 mmol) was added and the reaction was allowed to warm to room temperature and then warmed to 55° C. and stirred overnight. The reaction was diluted with DCM (50 mL) and washed with water (30 mL), 5% aq. Citric acid (30 mL), sat. sodium bicarbonate (30 mL), water (30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate and concentrated to afford the crude product. The product was purified by column chromatography to afford the desired product (303 mg, 0.51 mmol, 49%) as a white foam. 1H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.29 (s, 1H), 7.07-7.02 (m, 1H), 5.74 (br, 1H), 5.17 (br, 2H), 4.30 (m, 1H), 3.63 (s, 1.5H), 3.62 (s, 1.5H), 2.88-2.76 (m, 2H), 2.38-2.24 (m, 2H), 2.10-2.00 (m, 1H), 1.90-1.80 (m, 1H), 1.46 (s, 9H), 1.44 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([CH3:33])[C:23]=1[O:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[CH:19]=O.II.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:33][C:22]1[CH:21]=[C:18]([C:19]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:17]=[C:16]([CH3:15])[C:23]=1[O:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: Cc1cc(C=O)cc(C)c1OCCN1CCOCC1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN4CCOCC4)c(C)c3)nc2c1
Temperature: 70 °C
Reaction time: 48 h

Procedure:
To a solution of 2-amino-4,6-dimethoxybenzamide (451 mg, 2.3 mmol) and 3,5-dimethyl-4-(2-morpholin-4yl-ethoxy)-benzaldehyde (550 mg, 2.09 mmol) in N,N-dimethyl formamide (20 mL), iodine (636 mg, 2.5 mmol) and potassium carbonate (288 mg, 2.09 mmol) were added and the reaction mixture was stirred at 70° C. for 48 h. The reaction mixture was poured into ice. The mixture was extracted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous Na2SO4. Removal of the solvent gave the crude product was purified by column chromatography and converted to the hydrochloride salt of 2-(3,5-dimethyl-4-(2-morpholinoethoxy)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (40 mg, 4%) as an off-white solid. Selected data: MS (ES) m/z: 440.1; MP 185-187° C. (HCl salt).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]([NH2:24])=O)=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][C:22]([NH2:24])=[S:39])=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C1=C(COCC(N)=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: CC#N
Product: CCOC(=O)C1=C(COCC(N)=S)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85 %

Procedure:
A mixture of 2-{[4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}-acetamide (6.8 g) and Lawesson's reagent (6.4 g) in acetonitrile (300 ml) was stirred at room temperature for 2.5 hours, filtered and evaporated. The residue was purified by chromatography on silica (80 g) using dichloromethane plus 0-10% v/v ethyl acetate as eluant. Appropriate fractions were combined and evaporated and the residual oil triturated with diethyl ether. The resulting solid was collected, washed with diethyl ether and dried to give the title compound (5.9 g), m.p. 149°-150° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19](Br)[C:18]=2[CH3:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH3:26][C:27]([CH3:32])=[CH:28]B(O)O>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:26]=[C:27]([CH3:32])[CH3:28])[C:18]=2[CH3:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2cccc(Br)c2C)Cc2ccccc2C1
Reactant: CC(C)=CB(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc(C=C(C)C)c2C)Cc2ccccc2C1
Temperature: 110 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
A suspension of 2-(3-bromo-2-methylbenzoylamino)indan-2-carboxylic acid ethyl ester (293) (402 mg-1 mmol) and 2-methyl-1-propenylboronic acid (200 mg, 2 mmol, 2 eq) in dry DMF (20 mL) and saturated NaHCO3 (5 mL) is degassed for 10 min and then treated with tetrakis(triphenylphosphine)palladium(0) (400 mg). The mixture is stirred at 110° C. for 5 h. The reaction is cooled and the DMF removed in vacuo and the residue diluted with water (80 mL). The aqueous is filtered through celite and extracted with EtOAc (3×50 mL). The organic extracts are washed with water (2×30 mL) and brine (2×30 mL), and dried over MgSO4. The organic phase is then concentrated in vacuo and purified by flash chromatography (120 g silica gel, 30% EtOAc in heptane) to give pale yellow oil (350 mg, 92%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.[F:49][C:50]1[CH:57]=[C:56]([F:58])[CH:55]=[CH:54][C:51]=1[CH2:52][NH2:53]>>[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:53][CH2:52][C:51]2[CH:54]=[CH:55][C:56]([F:58])=[CH:57][C:50]=2[F:49])=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: NCc1ccc(F)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(NCc1ccc(F)cc1F)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-bromo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 1, Step G) and 2,4-difluorobenzylamine and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C22H15BrF2N4O3S, 532.0; m/z found, 533/535 [M+H]+, 555/557 [M+Na]+. HPLC (reverse phase): RT=9.64 min. 1H NMR (500 MHz, CDCl3, rotameric broadening): 11.31 (s, 1H), 8.92-8.86 (m, 2H), 8.62-8.53 (m, 1H), 8.35-8.29 (m, 1H), 7.96-7.90 (m, 1H), 7.90-7.83 (m, 1H), 7.41-7.32 (m, 1H), 7.15-7.10 (m, 1H), 7.09-7.03 (m, 1H), 6.94-6.82 (m, 2H), 6.31-6.24 (m, 1H), 4.53 (br s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)=[C:20]([O:32][CH3:33])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.[CH:34](O)=[O:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([N:24]([CH2:25][CH2:26][N:27]5[CH2:28][CH2:29][CH2:30][CH2:31]5)[CH:34]=[O:35])=[C:20]([O:32][CH3:33])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1NCCN1CCCC1
Reactant: O=CO
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1N(C=O)CCN1CCCC1

Procedure:
A solution of 6-(4-Chlorophenyl)3-{3-methoxy-4-[(2-pyrrolidin-1-ylethyl)amino]phenyl}thieno[3,2-d]pyrimidin-4(3H)-one (0.050 g, 0.1 mmol) in formic acid (88%, 2 mL) was heated to reflux, concentrated, and then diluted with aqueous sodium hydroxide (0.1N, 2 mL) to precipitate the product as a white solid (0.051 g, 100%). LCMS m/z 509 (MH+). 1H NMR (300 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.95 (d, 2H), 7.60 (d, 2H), 7.43 (d, 1H), 7.42 (s, 1H), 7.20 (d, 1H), 3.82 (s, 3H), 3.78 (t, 2H), 3.30-3.50 (m, 2H), 2.40 (m, 4H), 1.70 (m, 4H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1.[ClH:20].[N:21](=[CH:29][CH2:30]Cl)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][Cl:28].C(N(CC)CC)C>C(O)C>[ClH:28].[ClH:20].[N:21]1([CH2:29][CH2:30][N:14]2[CH2:15][CH2:16][C:11]3[C:6]4[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=4[O:18][C:17](=[O:19])[C:12]=3[CH2:13]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCNC3
Reactant: ClCC=NCCCCCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2oc(=O)c3c(c2cc1OC)CCN(CCN1CCCCCC1)C3

Procedure:
A mixture of 0.02m of 1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one, 0.022m of 2-(hexamethyleneimino)-ethyl chloride HCl and 0.022m of triethylamine in 200ml of ethanol was refluxed for 6 hours. The mixture was filtered while hot and immediately treated with excess HCl gas. Crystallization of the crude product from methanol gave 2.5g of material, m.p. 233°-4° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:12][C:11](=[N:13][N+:14]([O-:16])=[O:15])[NH:10][C@H:9]2[CH3:17])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][N:22]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[O:12][C:11](=[N:13][N+:14]([O-:16])=[O:15])[N:10]([CH2:27][C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[N:22][CH:23]=3)[C@H:9]2[CH3:17])=[CH:6][CH:7]=1
Reactant: C[C@@H]1NC(=N[N+](=O)[O-])O[C@H]1c1ccc(Cl)cc1
Reactant: ClCc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1[C@H](c2ccc(Cl)cc2)OC(=N[N+](=O)[O-])N1Cc1ccc(Cl)nc1
Temperature: 0 °C
Yield: 33.5 %

Procedure:
1.0 g of trans-5-(4-chlorophenyl)-4-methyl-2-nitroiminooxazolidine obtained in Example 1 and 0.2 g of 60% sodium hydride were added into 20 ml of DMF. 0.7 g of 2-chloro-5-chloromethylpyridine was added gradually to the mixture with stirring on cooling. Then, the mixture was further stirred for 6 hours at 70° C., followed by pouring the reaction mixture into ice water. The solution was extracted with ethyl acetate, and the organic layer was dried and then condensed under reduced pressure. The oily product obtained was purified by column chromatography to give 0.5 g of the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:9]12[CH2:16][NH:15][CH2:14][CH:13]1[CH2:12][NH:11][CH2:10]2>>[Cl:8][C:6]1[CH:7]=[C:2]([N:11]2[CH2:12][CH:13]3[CH:9]([CH2:16][NH:15][CH2:14]3)[CH2:10]2)[CH:3]=[N:4][CH:5]=1
Reactant: Clc1cncc(Cl)c1
Reactant: C1NCC2CNCC12
Product: Clc1cncc(N2CC3CNCC3C2)c1

Procedure:
3,5-Dichloropyridine (1 eq.), 3.7-Diazabicyclo[3.3.0]octane (1 eq.) and palladacycle (0.2%) [Herrmann W A, Brossmer C, Öfele K, Reisinger, C-P, Priermeier, T, Beller M, and Fischer, H; Angew. Chem. Int. Ed. Enql. 1995 34 1844] is stirred at 160° C. for 24 hours. Workup-procedure A/B.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][CH2:6][OH:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[S:23](Cl)(=[O:25])=[O:24]>ClCCl>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[S:23]([N:4]([CH:1]1[CH2:3][CH2:2]1)[CH2:5][CH2:6][OH:7])(=[O:24])=[O:25]
Reactant: OCCNC1CC1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(Cl)c1S(=O)(=O)N(CCO)C1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To 2-(cyclopropylamino)ethanol (2 eq.) was added triethylamine (2.5 eq.) and the mixture was cooled to 0° C. To this cold reaction mixture was added 2-chloro-6-methylbenzene sulfonyl chloride (1 eq.) and the mixture was stirred at 25° C. for 2 h. It was diluted with dichloromethane and the organic layer was washed with water and brine and finally dried over sodium sulfate. Evaporation of the organic layer under reduced pressure gave the crude product which was purified by column chromatography (10% ethyl acetate in hexane). Yield: 50%
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.[N+:11]([C:14]1[CH:15]=[N:16][NH:17][CH:18]=1)([O-:13])=[O:12].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N+:11]([C:14]1[CH:15]=[N:16][N:17]([C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)[CH:18]=1)([O-:13])=[O:12]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(-n2cc([N+](=O)[O-])cn2)cc1
Reaction time: 5 h
Yield: 31 %

Procedure:
To 4-tolylboronic acid (544 mg, 4.00 mmol), 4-nitropyrazole (226 mg, 2.00 mmol), copper (II) acetate (545 mg, 3.00 mmol), and 4 Å sieves (1.5 g) in DCM (15 mL), was added pyridine (0.32 mL, 4 mmol) at RT, and stirred for 5 h. The mixture was filtered through Celite, washing with DCM, then evaporated to dryness. The residue was purified by FCC, eluting with 0-30% ethyl acetate in cyclohexane, to give the title compound as a white solid (126 mg, 31%). LCMS (Method 3): Rt 3.93 min, m/z 204.1 [MH−].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([NH2:16])=[CH:11][CH:12]=[C:13]([CH3:15])[CH:14]=2)=[CH:4][CH:3]=1.[C:17](OCC)(=[O:21])[C:18]([CH3:20])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:15])[CH:14]=3)[N:16]=[C:18]([CH3:20])[C:17]2=[O:21])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)=O
Reactant: Cc1ccc(N)c(Nc2ccc(Cl)cc2)c1
Product: Cc1ccc2nc(C)c(=O)n(-c3ccc(Cl)cc3)c2c1

Procedure:
Preparation as in Example 1 but using N-(4-chlorophenyl)-5-methylbenzene-1,2-diamine and ethyl pyruvate gave the title compound mp 144°-145° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:20]([C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])(=[O:22])=[O:21])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[C:35]([O:41][CH2:42]Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].[I-].[K+]>C(COC)OC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([S:20]([C:23]([F:28])([F:27])[CH:24]([F:25])[F:26])(=[O:21])=[O:22])[N:11]([CH2:42][O:41][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])[C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: O=S(=O)(c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1)C(F)(F)C(F)F
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)(C)C(=O)OCn1c(S(=O)(=O)C(F)(F)C(F)F)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Yield: 63.9 %

Procedure:
To a solution of 5.0 g (0.012 mole) of 4,5-bis(4-fluorophenyl)-2-(1,1,2,2-tetrafluoroethylsulfonyl)imidazole in 50 ml glyme was added 1.7 g (0.015 mole) of potassium t-butoxide, followed by a solution of 4.6 g (0.031 mole) of chloromethyl pivalate in 25 ml of glyme dropwise and a catalytic amount of potassium iodide. The reaction mixture was heated at reflux overnight, then poured onto water. The aqueous mixture was extracted with ether. The combined ether extracts were washed, then dried and concentrated to give 13.4 g of crude oily product. The product was purified by chromatography on silica gel, eluting with toluene, to give 4.1 g of crystals, mp 121°-123.5° (from methyl cyclohexane).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([OH:31])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:45]([O:47][C:48](=[O:51])[CH2:49]Br)[CH3:46]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:49][C:48]([O:47][CH2:45][CH3:46])=[O:51])[N:28]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N2CCN(C(=O)OCC)CC2)nn1-c1ccccc1
Temperature: 100 °C

Procedure:
To a solution of 60 mg of 4-{(S)-4-tert-Butoxycarbonyl-2-[(5-hydroxy-1-phenyl-1H-pyrazole-3-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester in 20 ml of DMF, 73 mg of cesium carbonate and 38 mg of Bromo-acetic acid ethyl ester was added and heated to 100° C. for 4 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was used in the subsequent reaction.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[C:3]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9])=[O:4].S(Cl)([Cl:19])=O>ClCCl.N1C=CC=CC=1>[CH3:1][C:2]([CH3:16])([CH3:15])[C:3]([O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([Cl:19])=[O:9])=[O:4]
Reactant: CC(C)(C)C(=O)Oc1ccccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 104.6 %

Procedure:
6 g (27 mmol) of 2-(2,2-dimethylpropionyl-oxy)benzoic acid are dissolved in 60 ml of dichloromethane with a few drops of pyridine. 2.4 ml (32 mmol) of thionyl chloride are added dropwise and the mixture is stirred at ambient temperature for 18 h and then concentrated to dryness. 6.8 g of 2-(chlorocarbonyl)phenyl 2,2-dimethylpropanoate are obtained in a quantitative yield.