Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.C(=O)([O-])[O-].[Ca+2].Cl[C:19]([O:21][CH2:22][CH2:23][Cl:24])=[O:20]>COCCOCCOC.O>[Cl:24][CH2:23][CH2:22][O:21][C:19](=[O:20])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: COc1ccc(N)cc1[N+](=O)[O-]
Reactant: O=C(Cl)OCCCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: COCCOCCOC
Solvent: O
Product: COc1ccc(NC(=O)OCCCl)cc1[N+](=O)[O-]
Temperature: 78 °C
Reaction time: 1.5 h

Procedure:
420.5 g of 4-amino-2-nitroanisole are dissolved in 1275 ml of diethylene glycol dimethyl ether and 150 ml of water, 135 g of calcium carbonate are added and the mixture is heated to 78° C. 375 g of 2-chloroethyl chloroformate are allowed to run into this mixture in the course of 3 hours such that the reaction temperature remains at 78°-80° C. The mixture is subsequently stirred for 1.5 hours to bring the reaction to completion and is cooled to 35° C. and water and ice are added. The product which has precipitated is filtered off, washed with water and dried.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:22]([C@H:24]([C@@H:26]([OH:42])[C@@H:27]([CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([OH:38])[C:32]=1[C:39]([OH:41])=[O:40])[CH3:28])[CH3:25])=[O:23])[C@H:4]1[O:8][C@@:7]([C@@H:11]2[O:16][C@@H:15]([CH3:17])[C@@:14]([OH:20])([CH2:18][CH3:19])[CH2:13][CH2:12]2)([CH2:9][CH3:10])[CH2:6][C@@H:5]1[CH3:21].[CH2:43](Cl)Cl.CI>[Ag]=O.CO>[CH3:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][CH:27]([CH3:28])[CH:26]([OH:42])[CH:24]([CH3:25])[C:22](=[O:23])[CH:3]([CH2:2][CH3:1])[CH:4]2[CH:5]([CH3:21])[CH2:6][C:7]([CH2:9][CH3:10])([CH:11]3[CH2:12][CH2:13][C:14]([CH2:18][CH3:19])([OH:20])[CH:15]([CH3:17])[O:16]3)[O:8]2)=[C:32]([C:39]([O:41][CH3:43])=[O:40])[C:33]=1[OH:38]
Reactant: ClCCl
Reactant: CC[C@@H](C(=O)[C@@H](C)[C@@H](O)[C@H](C)CCc1ccc(C)c(O)c1C(=O)O)[C@H]1O[C@](CC)([C@H]2CC[C@](O)(CC)[C@H](C)O2)C[C@@H]1C
Agent: O=[Ag]
Solvent: CI
Solvent: CO
Product: CCC(C(=O)C(C)C(O)C(C)CCc1ccc(C)c(O)c1C(=O)OC)C1OC(CC)(C2CCC(O)(CC)C(C)O2)CC1C
Reaction time: 18 h

Procedure:
To a solution of 6.2 g. of crystalline antibiotic X-537A in 125 ml. of methylene chloride was added 4.6 g. of silver oxide and 14 g. of methyl iodide. After stirring for 18 hours, the reaction mixture was filtered and the filtrate concentrated to 7.07 g. of a light yellow oil, which was decolorized with Darco, giving 6.09 g. of a colorless foam. A portion (4 g.) of the foam was chromatographed on a florisil column (150 g.) eluting with a gradient between methylene chloride (1 l.) to ether (1 l.) and then ether (500 ml.) to acetone (500 ml.). Rechromatography of the slightly yellow oil, recovered from the florisil column, on a 75 g. silica gel column and eluting with a gradient between methylene chloride (1 l.) and 15 percent ether/-methylene chloride gave 200 mg. of a clear viscous oil, Bp. 170°d/005 mm. [α] D25 -7.19° , (1.1 percent CH3OH).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[N+:12]([O-])=O)([CH3:3])[CH3:2].Cl[Sn]Cl.Cl>O>[CH:1]([NH:4][C:5]1[C:6]([NH2:12])=[CH:7][CH:8]=[C:9]([CH3:11])[CH:10]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc([N+](=O)[O-])c(NC(C)C)c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Product: Cc1ccc(N)c(NC(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
A mixture of N-isopropyl-5-methyl-2-nitroaniline (150 mg, 0.77 mmol), SnCl2 (0.5 g, 2.6 mmol), 0.5M HCl (10 mL), and water (20 mL) was stirred at room temperature for 16 hours. The crude product was partitioned in a mixture of aqueous NaHCO3 and CH2Cl2. The organic layer was separated and concentrated to obtain the desired product (120 mg, 95%).
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[OH:19][CH2:20][CH2:21][NH2:22]>O>[OH:19][CH2:20][CH2:21][NH:22][C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3
Reactant: NCCO
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Solvent: O
Product: COc1ccc2c(c1)CCn1c-2cc(NCCO)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 2-hydroxy-ethylamine as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 7.62 (d 1H), 7.54 (t, 1H), 7.00-6.93 (2H), 6.17 (s, 1H), 4.85 (t, 1H), 3.91 (t, 2H), 3.82 (s, 3H) 3.50 (q, 2H), 2.91 (t, 2H) and 2H were overlapped with H2O; MS (ESI) (M+H)+ 288.
Reaction SMILES: CS(O[C@@H:6]1[C@@H:11]([CH3:12])[CH2:10][N:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:19]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])C(OC(C)(C)C)=O)[CH2:8][C@H:7]1[NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])(=O)=O.[C-:42]#[N:43].[Na+]>CN(C=O)C>[C:30]([O:29][C:27]([NH:19][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[N:9]1[CH2:10][C@H:11]([CH3:12])[C@H:6]([C:42]#[N:43])[C@H:7]([NH:34][C:35](=[O:36])[O:37][C:38]([CH3:39])([CH3:41])[CH3:40])[CH2:8]1)=[O:28])([CH3:31])([CH3:33])[CH3:32]
Reactant: C[C@H]1CN(c2ccncc2N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OS(C)(=O)=O
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2ccncc2NC(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1C#N
Temperature: 80 °C
Reaction time: 6 h
Yield: 5 %

Procedure:
To a solution of (3R,4R,5S)-1-(3-(bis(tert-butoxycarbonyl)amino)pyridin-4-yl)-3-(tert-butoxycarbonylamino)-5-methylpiperidin-4-yl methanesulfonate (1.0 equiv.) in DMF (0.10 M) was added NaCN (5.0 equiv.). The mixture was stirred at 80° C. for 6 hrs and partitioned between EtOAc and H2O. The organic layer was washed NaCl(sat), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield tert-butyl ((3S,4S,5R)-1-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-4-cyano-5-methylpiperidin-3-yl)carbamate in 5% yield. LC/MS (m/z)=432.2 (MH+), Rt=0.73 min.
Reaction SMILES: C(=O)([O-])[O-].[K+:5].[K+].[O:7]=[C:8]1[O:14][C@H:13]([C@H:15]([CH2:17][OH:18])[OH:16])[C:11]([OH:12])=[C:9]1[OH:10]>O>[O:7]=[C:8]1[O:14][C@H:13]([C@H:15]([CH2:17][OH:18])[OH:16])[C:11]([O-:12])=[C:9]1[OH:10].[K+:5]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Yield: 5.2 %

Procedure:
Bramley apples were preserved as in Example 12a, except that the preservative solution contained 13.74 grams of potassium carbonate, 35 grams ascorbic acid, 765 grams water, having a pH of 6.8 to provide a 5.2% potassium ascorbate solution.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[C:14]([CH3:17])([CH3:16])[CH3:15])(=O)C.[OH-].[Na+]>CO.O>[C:14]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:5]=1[OH:4])[C:9]([OH:11])=[O:10])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(C(=O)O)ccc1O
Yield: 98.8 %

Procedure:
50.0 g of 4-acetoxy-3-tert-butylbenzoic acid are dissolved in 200 g of methanol. A solution of 10.2 g of sodium hydroxide in 180 ml of water is added. The mixture is refluxed for 3 hours. The methanol is removed, and the mixture is acidified with hydrochloric acid (10%) at 10° C. The precipitate is filtered off and washed, giving 40.6 g of product in the form of colourless crystals having a melting point of from 158° to 159° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:37](O)=[O:38])=[C:9]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH2:27][CH2:26]3)[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[N:11]2)=[CH:6][C:5]=1[S:40]([CH3:43])(=[O:42])=[O:41])[CH3:2].[F:44][C:45]([F:55])([F:54])[C@@H:46]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[NH2:47].C(N(CC)C(C)C)(C)C.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>C(OCC)(=O)C.ClCCl.C([O-])(O)=O.[Na+]>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:37]([NH:47][C@H:46]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:45]([F:54])([F:55])[F:44])=[O:38])=[C:9]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([N:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)[CH2:27][CH2:26]3)[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=3)=[N:11]2)=[CH:6][C:5]=1[S:40]([CH3:43])(=[O:42])=[O:41])[CH3:2]
Reactant: N[C@H](c1ccccc1)C(F)(F)F
Reactant: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)O)c2cc1S(C)(=O)=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)N[C@H](c3ccccc3)C(F)(F)F)c2cc1S(C)(=O)=O
Temperature: 25 °C
Yield: 36.4 %

Procedure:
7-(ethyloxy)-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.200 g, 0.303 mmol), (1R)-2,2,2-trifluoro-1-phenylethanamine (0.069 g, 0.393 mmol), N,N-diisopropylethylamine (10.57 μL, 0.061 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (0.252 mL of a 50% solution in ethyl acetate, 0.424 mmol) in dichloromethane (2 mL) was stirred at 0° C. for 2 h. The solution was warmed to room temperature overnight. The solution was diluted with saturated aqueous NaHCO3 and extracted with methylene chloride (3 times). The combined organic extracts were washed with brine (two times), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in DMSO and purified via HPLC (Waters, Sunfire, 30×75 mm column, 50 mL/min, 20-60% MeCN/H2O with 0.1% TFA). The fractions containing the product were neutralized with saturated aqueous NaHCO3 and extracted with CH2Cl2 (3 times). The combined organic extracts were washed with brine (2 times), dried over Na2SO4, filtered, and concentrated in vacuo to afford 7-(ethyloxy)-6-(methylsulfonyl)-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.086 g, 35% yield). 1H NMR (400 MHz, CDCl3) δ9.88 (br. s., 1H), 8.79 (s, 1H), 7.81 (s, 1H), 7.78 (d, J=6.02 Hz, 1H), 7.64-7.69 (m, 2H), 7.53-7.60 (m, 3H), 7.43-7.48 (m, 3H), 6.25 (quin, J=7.65 Hz, 1H), 4.36 (q, J=6.94 Hz, 2H), 3.66-3.71 (m, 4H), 3.53-3.65 (m, 2H), 3.33 (s, 3H), 2.64 (br. s., 1H), 2.38-2.46 (m, 4H), 2.20 (br. s., 1H), 2.04 (t, J=10.92 Hz, 1H), 1.56-1.66 (m, 9H); MS (m/z) 779.3 (M+H+).
Reaction SMILES: C(OC(C1CC[N:9](C2C=CC(NC(C3N=C(C4C=CC=CC=4)OC=3C(F)(F)F)=O)=CC=2)CC1)=O)C.[CH2:36]([O:38][C:39]([CH:41]1[CH2:46][CH2:45][N:44]([CH:47]2C[CH2:51][CH:50]([NH:53][C:54]([C:56]3[N:57]=[C:58]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[O:59][C:60]=3[C:61]([F:64])([F:63])[F:62])=[O:55])[CH2:49][NH:48]2)[CH2:43][CH2:42]1)=[O:40])[CH3:37].C1(C2OC(C(F)(F)F)=C(C(O)=O)N=2)C=CC=CC=1.C(OC(C1CCN(C2CCC(N)CN2)CC1)=O)C>>[CH2:36]([O:38][C:39]([CH:41]1[CH2:46][CH2:45][N:44]([C:47]2[N:9]=[CH:51][C:50]([NH:53][C:54]([C:56]3[N:57]=[C:58]([C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[O:59][C:60]=3[C:61]([F:62])([F:64])[F:63])=[O:55])=[CH:49][N:48]=2)[CH2:43][CH2:42]1)=[O:40])[CH3:37]
Reactant: CCOC(=O)C1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Reactant: CCOC(=O)C1CCN(C2CCC(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)CN2)CC1
Agent: CCOC(=O)C1CCN(C2CCC(N)CN2)CC1
Agent: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: CCOC(=O)C1CCN(c2ncc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1

Procedure:
With a method similar to that used for the preparation of 1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4-carboxylic acid ethyl ester above, 1-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-piperidin-2-yl}-piperidine-4-carboxylic acid ethyl ester was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (1.2 equivalents) and 1-(5-amino-piperidin-2-yl)-piperidine-4-carboxylic acid ethyl ester. HRMS calcd for C23H22F3N5O4 (M+H) 490.1697, obsd 490.1695.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13](I)=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[Cl:21][C:22]1[N:23]=[C:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[S:25][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.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]>[Cl:21][C:22]1[N:23]=[C:24]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[S:25][C:26]=1[C:13]1[N:8]2[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]2=[N:15][C:14]=1[C:16]([F:19])([F:18])[F:17]
Reactant: Clc1csc(N2CCOCC2)n1
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C(F)(F)F)nc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N4CCOCC4)nc3Cl)c(C(F)(F)F)nc12
Temperature: 130 °C
Yield: 3.7 %

Procedure:
In a dry 25 mL round bottom flask, 8-(1-ethyl-propyl)-3-iodo-6-methyl-2-trifluoromethyl-imidazo[1,2-b]pyridazine (250 mg, 0.630 mmol), 4-(4-chloro-thiazol-2-yl)-morpholine (194 mg, 0.945 mmol), and Cs2CO3 (410 mg, 1.26 mmol) are dissolved in DMF. The mixture is degassed with bubbling nitrogen for 15 minutes. Then, Pd2(dba)3 (18 mg, 0.032 mmol) and PPh3 (33 mg, 0.126 mmol) are added. The reaction mixture is heated to 130° C. overnight. The reaction is cooled to room temp., quenched with a solution of NH4Cl sat? (20 mL), and extracted with Et2O (3×50 mL). The combined organic extracts are washed with brine (30 mL), dried with Na2SO4, filtered and concentrated. The residue is purified via reverse phase HPLC with a 30-80% gradient of CH3CN in 10 mM NH4HCO3/H2O/5% CH3CN (pH 10.0) to give the title compound (11 mg, 0.023 mmol, 4%). 1H-NMR (CDCl3), δ 0.86 (t, J=7.3 Hz, 6H), 1.84 (m, 4H), 2.55 (s, 3H), 3.31 (m, 1H), 3.54 (dd, J=5.2, 4H), 3.84 (dd, J=5.2 Hz, 4H), 6.82 (s, 1H) ppm. ES-MS (m/z): calcd for C20H23ClF3N5OS (M+H)+: 473.95; found: 474.2.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([C:15]([OH:17])=[O:16])[NH2:14])=[CH:8][CH:7]=2)=[CH:2]1.S(Cl)(Cl)=O.[CH3:22]O>>[CH3:22][O:16][C:15](=[O:17])[C@H:13]([CH2:12][C:9]1[CH:8]=[CH:7][C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[CH:11][CH:10]=1)[NH2:14]
Reactant: CO
Reactant: N[C@@H](Cc1ccc(-c2ccsc2)cc1)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)Cc1ccc(-c2ccsc2)cc1
Temperature: 25 °C

Procedure:
A solution of 3-[4-(3-thienyl)phenyl]alanine in methanol (2 ml) is slowly added to a solution of thionyl chloride (6.8 ml, 94 mmol) in methanol (5 ml) at -10° C. The mixture is slowly warmed to room temperature, then refluxed overnight. The reaction mixture is concentrated in vacuo, diluted with ethyl acetate (10 ml), and extracted with water (10 ml×3). The aqueous layer is made basic with sodium bicarbonate and extracted with ethyl acetate (10 ml×3). The organic layer is dried over magnesium sulfate and concentrated in vacuo to give a crude 3-[4-(3-thienyl)phenyl]-alanine methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=O.[F:11][C:12]([F:21])([F:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>Cl>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:3]=1[CH:4]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]([C:12]([F:11])([F:21])[F:20])[O:10]2
Reactant: O=Cc1c(O)cccc1F
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=Cc2c(F)cccc2OC1C(F)(F)F
Yield: 62.2 %

Procedure:
A mixture of 8.7 g (62 mmole) of 2-fluoro-6-hydroxybenzaldehyde, 18.6 mL (20.9 g, 124 mmole) of ethyl trifluorocrotonate and 17.3 mL (12.6 g, 124 mmole) of triethylamine was heated to reflux. After 3 hrs an additional 18.6 mL of ethyl trifluorocrotonate and 2 g of potassium carbonate was added and the mixture heated for 3 days. The mixture was allowed to cool, concd in vacuo, diluted with 1N HCl and extracted three times with diethyl ether. The combined extracts were washed with 1N HCl, brine, dried and concd to afford a dark oil. Kugelrohr distillation (0.2 torr, 50° C.) afforded 11.2 g (62%) of a white solid: mp 45.5-47.0° C.; 1H NMR (CDCl3/400 MHz) 1.33 (t, 3H, J=7.1 Hz), 4.30 (m, 2H), 5.68 (q, 1H, J=6.8 Hz), 6.70 (t, 1H, J=9.0 Hz), 6.76 (d, 1H, J=8.3 Hz), 7.24 (q, 1H, J=7.2 Hz), 7.92 (s, 1H); 19F NMR (CDCl3/ 400 MHz) −78.9 (d, 3F, J=7.7 Hz), −118.9 (m, 1F); 13C NMR (CDCl3/100 MHz) 14.2, 61.6, 70.7 (q, J=33.2 Hz), 108.7 (d, J=18.7 Hz), 109.2 (d, CH, J=20.6 Hz), 111.9 (d, CH, J=3.2 Hz), 117.0, 123.3 (q, J=287.5 Hz), 129.9 (d, CH, J=5.0 Hz), 133.2 (d, CH, J=10.3 Hz), 153.9, 158.5, 162.3 (d, J=253.5 Hz); MS(ES+) 291 (M+1, 100); MS(EI) 290 (M+, 13), 245 (18), 221 (100), 193 (99); HRMS (EI) m/z calcd for (C13H10O3F4) 290.0566, found 290.0589.
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([CH3:19])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:20])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Br[Mg][CH:23]1CCCC1>>[CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([CH3:19])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:20])[CH:6]=2)[CH2:2][CH2:3][CH2:23][CH2:4]1
Reactant: Br[Mg]C1CCCC1
Reactant: Cc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Product: Cc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCCC2)[nH]1

Procedure:
The title compound was synthesized using standard chemical manipulations and procedures similar to those used for the preparation of compound 152.8 and using bromo(cyclopentyl)magnesium in place of bromo(cyclobutyl)magnesium.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.O.[CH3:26][O:27][C:28]1[C:33](B(O)O)=[CH:32][CH:31]=[CH:30][N:29]=1>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:33]4[C:28]([O:27][CH3:26])=[N:29][CH:30]=[CH:31][CH:32]=4)=[C:4]([CH:9]=3)[C:3]([OH:2])=[O:24])[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COc1ncccc1B(O)O
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Solvent: O
Product: COc1ncccc1-c1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1C(=O)O
Yield: 12 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with and 2-methoxypyridine-3-boronic acid hydrate (available from Combi-Blocks Inc.; 68 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2-(2-methoxy-pyridin-3-yl)-benzoic acid (11 mg, 12%). 1H NMR (300 MHz, DMSO-d6) δ 12.94 (br s, 1H), 8.47 (s, 1H), 8.41 (d, J=1.9 Hz, 1H), 8.33 (d, J=2.1 Hz, 1H), 8.25 (dd, J=8.0, 2.0 Hz, 1H), 8.18 (dd, J=5.0, 1.8 Hz, 1H), 8.09 (dd, J=8.5, 2.1 Hz, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.70 (dd, J=7.3, 1.8 Hz, 1H), 7.52 (d, J=7.9 Hz, 1H), 7.10 (dd, J=7.2, 5.1 Hz, 1H), 3.78 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.C(N(CC)CC)C.[ClH:26].[C:27]([Cl:35])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1.Cl>C(Cl)Cl.O1CCOCC1>[ClH:35].[ClH:26].[CH2:13]([N:12]([CH2:16][CH:17]=[CH2:18])[C:4]1[N:3]=[C:2]([NH:1][C:27](=[O:34])[C:28]2[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=2)[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=1)[CH:14]=[CH2:15]
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)c1nc(NC(=O)c2cccnc2)n2oc(=O)nc2n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4.5 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are suspended in 100 ml. of methylene chloride and 15 ml. of triethylamine. A suspension of 4.5 g. of nicotinoyl chloride hydrochloride in 50 ml. of methylene chloride is slowly added dropwise at 0° C. The dark solution is stirred at 0° C. for 2 hours, then washed twice with water and dried over sodium sulfate. The solvent is distilled off under reduced pressure and the residue is chromatographed over silica gel. The thus-obtained crude product is treated in methylene chloride with hydrochloric acid in dioxan, there being obtained pure N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}nicotinamide dihydrochloride having a melting point of 135°-140° C.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][C:5]1[C:6]([CH2:11][CH3:12])=[N:7][NH:8][C:9]=1[NH2:10].O=[C:19]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[CH2:20][C:21](OCC)=[O:22]>C(O)(=O)C.O>[Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][C:5]1[C:6]([CH2:11][CH3:12])=[N:7][N:8]2[C:21]([OH:22])=[CH:20][C:19]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[N:10][C:9]=12
Reactant: CCc1n[nH]c(N)c1Cc1cccc(Cl)c1Cl
Reactant: CCOC(=O)CC(=O)c1ccncc1
Solvent: CC(=O)O
Solvent: O
Product: CCc1nn2c(O)cc(-c3ccncc3)nc2c1Cc1cccc(Cl)c1Cl
Temperature: 120 °C
Reaction time: 20 h
Yield: 25.6 %

Procedure:
A mixture of 4-(2,3-dichlorobenzyl)-3-ethyl-1H-pyrazol-5-amine (250 mg, 0.93 mmol), ethyl 3-oxo-3-(pyridin-4-yl)propanoate (198 mg, 1.03 mmol) in acetic acid (10 mL) and water (0.5 mL) was stirred at 120° C. for 20 h, cooled and the pH was carefully adjusted to 8. The mixture was extracted with DCM (100 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column (PE:EA=10:1) to give the titled compound (95 mg, 26%); LC/MS: MS (ES+) m/e 399 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 1.12 (t, J=7.5 Hz, 3H), 2.56 (q, J=7.5 Hz, 2H), 4.07 (s, 2H), 5.97 (s, 1H), 7.16-7.21 (m, 2H), 7.42 (d, 2.1 Hz, 1H), 7.90 (dd, J=1.5, 4.5 Hz, 1H), 8.56 (dd, J=1.5, 4.5 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N+:29]([O-])=O)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.O.[C:33](O)(=[O:35])[CH3:34]>C(OC(=O)C)(=O)C.[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[NH:29][C:33](=[O:35])[CH3:34])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)O
Reactant: COc1ccc(-c2nc(Sc3ccccc3[N+](=O)[O-])[nH]c2-c2ccc(OC)cc2)cc1
Agent: [Fe]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COc1ccc(-c2nc(Sc3ccccc3NC(C)=O)[nH]c2-c2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
At room temperature, 2.5 g of iron filings is added to a solution of 4.34 g of 4,5-bis(4-methoxyphenyl)-2-(2-nitrophenylthio)imidazole in 50 ml of glacial acetic acid and 3 ml of acetic anhydride. The mixture is stirred overnight, poured into 500 ml of water, the precipitated product is vacuum-filtered, taken up in ethyl acetate, and the solution washed with sodium bicarbonate solution. The solution is then dried over sodium sulfate and concentrated to dryness under vacuum. The residue is crystallized from ethyl acetate/ether. Recrystallization from ethyl acetate yields 3.67 g of 4,5-bis(4-methoxyphenyl)-2-(2-acetamidophenylthio)imidazole, mp 183°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:13](Br)[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1)[CH3:14]
Reactant: CCBr
Reactant: COC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cccc(CC(=O)OC)c1
Reaction time: 24 h

Procedure:
Methyl 3-hydroxyphenylacetate (6.4 g, 38.5 mmol) was dissolved in acetone (50 mL). Ethyl bromide (3.5 mL, 46.9 mmol) was added, followed by potassium carbonate (6.37 g, 46 mmol). The reaction was heated to reflux. After 24 hours, more ethyl bromide (3.55 mL, 46.9 mmol) was added and the reaction refluxed for a further 24 hours. The mixture was cooled, filtered and rotary evaporated. The product was dissolved in ethyl acetate and the solution washed with saturated sodium bicarbonate (2×50 mL) and brine, and dried (MgSO4). Removal of solvent revealed methyl 3-ethoxyphenylacetate as an oil that crystallized upon standing. 1H NMR (500 MHz, CDCl3) δ 7.25 (1H, dd), 6.87 (3H, m), 4.08 (2H, q), 3.73 (3H, s), 3.65 (2H, s), 1.45 (3H, t).