Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(OC)cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The above ester (3.45 g, 16 mM) was dissolved in THF (100 ml), treated with 1M NaOH (25 ml), and stirred at ambient temperature for 5 hours. After removal of the solvent, the residue was treated with water (50 ml), acidified with 2M sulfuric acid, and extracted with ethyl acetate (3×60 ml). The combined organic extracts were washed with aqueous NaH2PO4, brine, and dried over MgSO4. Evaporation gave 3-methoxy-5-nitrobenzoic acid, which was allylated essentially as in Example 1, except that the chromatographic purification used a mixture of petrol/ethyl acetate (6:1), to give allyl 3-methoxy-5-nitrobenzoate. Nmr (CDCl3): δ 3.95 (s, 3H); 4.87 (dt, 2H); 5.31-5.48 (m, 2H); 5.95-6.15 (m, 1H); 7.89 (t, 1H); 7.92 (t, 1H); 8.46 (t, 1H).
Reaction SMILES: C([NH:4][N:5]1[CH2:10][C:9]([CH3:11])=[N:8][NH:7][C:6]1=[O:12])(=O)C.Cl.O.[OH-].[Na+]>CO>[NH2:4][N:5]1[CH2:10][C:9]([CH3:11])=[N:8][NH:7][C:6]1=[O:12]
Reactant: CC(=O)NN1CC(C)=NNC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1=NNC(=O)N(N)C1
Temperature: 5 °C

Procedure:
85 g of 4-acetylamino-6-methyl-3-oxo-2,3,4,5-tetrahydro-l,2,4-triazine in 250 ml of methanol are stirred together with 63 ml of hydrochloric acid (37%) for 4 hours at 50° C. After cooling to 5° C., 250 ml of icecold water and 125 ml of sodium hydroxide solution (50%) are added. The solvent is removed by evaporation in vacuo. The residue is taken up in 100 ml of ethanol, and the solvent is removed again in vacuo. The residue is taken up in 1200 ml of acetonitrile, undissolved salt precipitates are removed by filtration, the filtrate is concentrated to a small volume, the residue is caused to crystallise by adding 100 ml of acetic acid ethyl ester at 0° C., and the colourless crystals are filtered off and dried yielding 60.4 g (92% of the theoretical amount) of the title compound having a melting point of 118°-120° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.[Br:9]Br.O>C(O)(=O)C>[Br:9][C:5]1[S:1][CH:2]=[C:3]([C:6]([OH:8])=[O:7])[CH:4]=1
Reactant: O=C(O)c1ccsc1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1csc(Br)c1
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
To a solution of thiophene-3-carboxylic acid (5.00 g, 39.0 mmol) in acetic acid (140 mL), was added dropwise, a solution of bromine (6.60 g, 40.0 mmol) in acetic acid (40 mL). The reaction mixture was stirred for 30 minutes and then poured into water. The resultant solid was collected by filtration to afford the title compound as a grey solid (2.07 g, 26%). LCMS (Method B): RT=2.9 min, M+H+=208.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].O.Cl>CO>[CH:8]1[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15](=[O:16])[N:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[CH:13]2
Reactant: CCOC(=O)c1ccc2ccccn2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2ccccn2c1=O
Reaction time: 0.33 h
Yield: 92.6 %

Procedure:
To a solution of 3-ethoxycarbonyl-4H-quinolizin-4-one (2.17 g) in methanol (65.2 ml) was added dropwise 6N aqueous sodium hydroxide (6.5 ml) at room temperature. After stirring for 20 minutes, water (10 ml) was added. After stirring for 20 minutes, water (30 ml) was also added. After stirring for an hour, the reaction mixture was acidified to pH 3 with 4N aqueous hydrochloric acid. The precipitate was filtered and washed with water to give 4H-quinolizin-4-one-3-carboxylic acid (1.75 g) as pale yellow crystal. mp 233° C.
Reaction SMILES: [OH-].[K+].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C.[SH:19][CH2:20][CH2:21][OH:22].[CH:23]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1)=[CH2:24]>C(O)C>[OH:22][CH2:21][CH2:20][S:19][CH2:29][C:28]1[CH:31]=[CH:32][C:25]([CH:23]=[CH2:24])=[CH:26][CH:27]=1
Reactant: C=Cc1ccc(CCl)cc1
Reactant: OCCS
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=Cc1ccc(CSCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of potassium hydroxide (86 g, 1.3 moles) and 2,6-di-tert-butyl-p-cresol (1 g) in ethanol (1 liter) at room temperature was added under nitrogen atmosphere 2-mercaptoethanol (100 g, 1.3 moles), over fifteen minutes. Following addition the solution was stirred an additional hour at room temperature and then p-vinylbenzyl chloride (198 g, 1.3 moles) was added at room temperature over one hour. After addition, the mixture was allowed to reach ambient temperature overnight. The mixture was filtered and the solvent removed on a rotary evaporator. To the residue was added dichloromethane (1.2 liter) and the solvent was washed with water (3×200 ml), then with saturated NaCl solution (200 ml), dried over anhydrous magnesium sulfate, filtered and the solvent removed on a rotary evaporator. To the residue was added diethyl ether (200 ml) and petroleum ether (800 ml). The product crystallized and was then filtered to give a white solid: m.p. of 44°-45.5° C. Yield of 85%. Analysis calculated for C11H14OS: C. 68.0, H, 7.26, S, 16.50. Found: C, 67.7, H, 6.98, S, 15.37.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+].[CH2:14](Br)[C:15]#[CH:16]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.ClCCl.C1(C)C=CC=CC=1>[CH2:16]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])[C:15]#[CH:14]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: C#CCBr
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C#CCOCCNC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
The preparation of tert-butyl 2-hydroxyethylcarbamate is described in Example 80, Part A. Benzyltrimethylammonium chloride (18 g, 97 mmol) and 50% aqueous sodium hydroxide (1.5 L) were added to a solution of tert-butyl 2-hydroxyethylcarbamate (156.4 g, 970.0 mmol) in dichloromethane (2.4 L), and the mixture was stirred rapidly. Propargyl bromide (109 mL, 979 mmol), available as an 80% solution in toluene, was then added, and the reaction was stirred for three hours. The layers were separated, and the aqueous layer was cooled to ˜0° C. in an ice bath. Water was slowly added (1.2 L), and the aqueous solution was extracted with chloroform (2×300 mL). The combined organic solutions were washed with water (3×500 mL) and brine (2×500 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 173 g of tert-butyl 2-(prop-2-ynyloxy)ethylcarbamate as an orange oil, which was used without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH3:10].[Br:11]Br>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[Br:11][C:6]1[C:5]([CH3:8])=[CH:4][C:3]([O:9][CH3:10])=[C:2]([CH3:1])[CH:7]=1
Reactant: BrBr
Reactant: COc1cc(C)ccc1C
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(C)c(Br)cc1C
Temperature: 0 °C
Reaction time: 7 h
Yield: 89 %

Procedure:
In a three-neck flask, 60 g (4.4×10−1 mol) of 2,5-dimethylanisole was dissolved in 600 ml of CHCl3, and then cooled to 0° C. using ice bath. To the solution, 70.32 g (4.4×10−1 mol) of Br2 in 200 ml of CCl4 was added dropwise over 1 hour. While maintaining the reaction solution at 0° C., the reaction was left to stand for 7 hours. The reaction solution was washed 3 times with NaOH saturated solution and distilled under reduced pressure, to remove the solvent. The remaining liquid was vacuum-distilled, to produce the title compound in a liquid state. Yield: 89% (83.14 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: OB(O)c1ccccc1
Product: c1ccc(-c2ccccc2)cc1

Procedure:
Table 2 summarizes the coupling experiments of bromobenzene and benzeneboronic acid to give biphenyl under bis(N-pivaloyl-N′-butylbenzamidine)palladium(II) chloride catalysis.
Reaction SMILES: C[Li].[Cl-].[Cl-].[CH-:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1.[CH-:10]1[CH:14]=[CH:13][CH:12]=[CH:11]1.[Zr+2:15]>C(OCC)C>[CH3:10][C-:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1.[C-:10]1([CH3:5])[CH:14]=[CH:13][CH:12]=[CH:11]1.[Zr+2:15]
Reactant: c1cc[cH-]c1
Agent: [Zr+2]
Agent: [Cl-]
Agent: [Li]C
Solvent: CCOCC
Product: C[c-]1cccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 211 %

Procedure:
Following the literature procedure [b], 3.30 ml (5.33 mmol, 1.60M) of an ethereal solution of methyllithium are slowly added dropwise at -78° C. to a suspension of 1.03 g (2.66 mmol) of zirconocene dichloride (Example 10) in 50 ml of diethyl ether. The mixture is allowed to warm slowly to room temperature in a cold bath and is then stirred at room temperature for a further 5 hours. The solvent is removed in vacuo, and the colorless residue is extracted with 3×50 ml of pentane. The combined pentane solutions are evaporated and kept at -25° C. to crystallize. Removal of the solvent and drying in an oil-pump vacuum gives 700 mg (76%) of dimethylzirconocene as a colorless, crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7]([CH2:13][O:14]C)=[C:6]2[C:16]([O:18][CH3:19])=[O:17].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl.O>[CH:13]([C:7]1[N:8]([CH3:12])[C:9]2[C:5]([C:6]=1[C:16]([O:18][CH3:19])=[O:17])=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)=[O:14]
Reactant: COCc1c(C(=O)OC)c2cc(OC)ccc2n1C
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1c(C=O)n(C)c2ccc(OC)cc12
Temperature: 30 °C
Yield: 47.7 %

Procedure:
24.7 g (100 mmol) of 5-methoxy-3-methoxycarbonyl-2-methoxymethyl -1-methylindole obtained in Example 2 or 4 was dissolved in 494 ml of methylene chloride and 27.4 ml of water, followed by the addition of 25.0 g (110 mmol) of DDQ and subsequent 8 hours of stirring at 30° C. The reaction mixture was filtered and the thus collected insoluble materials were washed with 120 ml of methylene chloride. The filtrate and the washings were combined and applied to a column packed with 123.5 g of alumina. The eluate was combined with another eluate obtained by further elution of the alumina column with 2,260 ml of methylene chloride, and the thus combined eluates were concentrated under reduced pressure. The thus obtained residue was recrystallized from 111 ml of ethyl acetate, and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain 11.8 g of the title compound with a yield of 80.1%. The compound thus obtained showed the same properties as those of the compound obtained in Example 5 in terms of NMR, IR and TLC data.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1(=O)C2C(C=C3C(C=2)=CC=CC3=O)=CC(S(O)(=O)=O)=C1S(O)(=O)=O.[Na][Na]>>[CH:10]1[CH:11]=[C:12]2[C:13]([OH:15])=[C:14]3[C:5](=[C:6]([OH:16])[C:7]2=[CH:8][CH:9]=1)[CH:4]=[CH:3][CH:2]=[CH:1]3
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Agent: O=C1C=CC=c2cc3c(cc21)=CC(S(=O)(=O)O)=C(S(=O)(=O)O)C3=O
Agent: [Na][Na]
Product: Oc1c2ccccc2c(O)c2ccccc12

Procedure:
The anthraquinone model compound (1,5-anthraquinonedisulfonic acid, disodium salt) and two polymers were subjected to the hydrogenation conditions. The reaction mixtures were analyzed with UV/visible spectroscopy following removal of the catalyst under an inert atmosphere (argon or nitrogen). Where anthrahydroquinone is formed, a bright yellow solution results. The results of some of the hydrogenation experiments are determined from the absorption spectra both before and after hydrogenation, and are summarized in Table 4.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([OH:14])=[O:13].S(Cl)(Cl)=O.[CH3:19]O>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([O:14][CH3:19])=[O:13]
Reactant: O=C(O)c1cccc2c(Br)cccc12
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc2c(Br)cccc12
Yield: 98 %

Procedure:
5-Bromonapthoic acid (J Chem. Soc., 1950, 991) (5.13 g, 20 mmol) was added to a solution of thionyl chloride (10 ml) in methanol (200 ml). The mixture was stirred at reflux for 4 h, yielding a dark brown solution. On cooling, the title compound precipitated as a light brown solid, which was filtered off and dried, yielding 5.34 g material (98%).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:19])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[C:20]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:22])[CH3:21].CN(C)C=O.C([O-])(=O)C.[K+]>ClCCl>[C:20]([C:23]1[CH:28]=[CH:27][C:26]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:8]3[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[O:6][C:7]=3[CH3:19])=[CH:13][CH:14]=2)=[CH:25][CH:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(COc2ccc(I)cc2)c(C)o1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A stirred mixture of 4-(4-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (20) (0.26 g), 4-acetylphenylboronic acid (0.15° g), N,N-dimethylformamide (30 mL), potassium acetate (0.26 g) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(11), complex with dichloromethane (1:1) (40 mg) was heated at 90° C. over night. The reaction mixture was concentrated in vacuo, dissolved in ethyl acetate (30 mL) and washed successively with water (30 mL), brine (30 mL), dried and 3 concentrated in vacuo. The residue was dissolved in a mixture of tetrahydrofuran/methanol (2:1 by volume) (30 mL) and 1.0 M aqueous lithium hydroxide solution (6.78 mL) and stirred for 16 hours. The reaction mixture was acidified to pH 2 using 0.1 M hydrochloric acid and extracted with ethyl acetate (3×25 mL). The extract was dried, concentrated in vacuo and the residue purified by HPLC to give compound 21 as a white solid (50 mg). LC/MS System C: Rt=4.18 mins, m/z (ES−)=349 (M− for C21H18O5).
Reaction SMILES: CS(O[C@@H:6]1[C@@H:10]([CH2:11][O:12]S(C)(=O)=O)[O:9][C@@H:8]([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[CH2:7]1)(=O)=O.[OH-].[Na+]>O>[C@@H:8]1([N:17]2[CH:25]=[C:23]([CH3:24])[C:21](=[O:22])[NH:20][C:18]2=[O:19])[O:9][C@@H:10]2[CH2:11][O:12][C@@H:6]2[CH2:7]1
Reactant: Cc1cn([C@H]2C[C@H](OS(C)(=O)=O)[C@@H](COS(C)(=O)=O)O2)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cn([C@H]2C[C@H]3OC[C@H]3O2)c(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
3',5'-Di-O-(methanesulfonyl)thymidine (248 g, 0.62M) was added in portions to a stirred solution of sodium hydroxide (74.7 g, 1.87M) in water (1.6 L). On addition the reaction mixture became a yellow-orange solution. This stirred solution was then heated to reflux for 2 hr. Once the reaction mixture had cooled to room temperature, 6N hyddrochloric acid (100 mL) was added. The reaction mixture was concentrated in vacuo by removing 1.3 L of water. The resulting slurry was cooled in an ice bath for 2 hr. The solid was then filtered and washed sparingly with ice water, and then vacuum dried to constant weight (103.7 g, 74%). The product 3, mp 188°-190° C. (lit. 190°-193° C.) was used without further purification. 1H NMR (360 MHz, d6 -DMSO) 11.35 (s, 1H, NH), 8.01 (s, 1H, H-6), 6.49 (q, 1H, H-1'), 5.47 (m, 1H, H-3'), 4.88 and 4.67 (m, 2H, H-5'), 4.22 (d, 1H, H-4'), 2.47 (m, 2H, H-2'), 1.77 (S, 3H, CH3). 13C NMR (75 MHz, d6 -DMSO) 163.64 (C2), 151.10 (C4), 136.57 (C6), 109.62 (C5), 88.29 (C4'), 86.85 (C1'), 79.83 (C3'), 75.14 (C5'), 37.17 (C2'), 12.33 (CH3).
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[N:4][C:3]1=2.C1(N=C=NC2CCCCC2)CCCCC1.CN(C)C(=O)C.[CH3:37][N:38]([CH3:43])[CH2:39][CH:40](O)[CH3:41]>CCOCC.CC(C)=O>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15][CH:40]([CH3:41])[CH2:39][N:38]([CH3:43])[CH3:37])=[O:14])[CH:5]=[N:4][C:3]1=2
Reactant: CC(O)CN(C)C
Reactant: O=C(O)CCn1cnc2c(=O)[nH]cnc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: CC(CN(C)C)OC(=O)CCn1cnc2c(=O)[nH]cnc21
Yield: 96.5 %

Procedure:
0.300 g (1.441 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid (AIT-0080) and 0.305 g (1.478 mmol) of dicyclohexylcarbodiimide were placed into a 10 ml round bottom flask equipped with magnetic stirring bar and thermometer. 4 ml of N,N-dimethylacetamide and 0.168 g (1.628 mmol) of 1-dimethyamino-2-propanol were added and the solution was heated to 75° (closed flask) for two hours. The solution was allowed to come to room temperature and a large amount of precipitate formed. The contents were transferred to a larger flask with 20 ml of acetone. 20 ml of ether was added and the solution was allowed to cool down in the refrigerator. Crystals formed within a short period of time. A solid was obtained by filtration and washed with ether. 408 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 1-(dimethylamino)-2-propyl ester (AIT-0106) as a white crystalline solid was obtained. Yield: 97%. m.p.: 280° -284°.
Reaction SMILES: [F:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C(Cl)(=O)C(Cl)=O.[CH3:39][NH:40][CH3:41]>C(Cl)Cl.C1COCC1>[CH3:39][N:40]([CH3:41])[C:6]([CH:4]1[CH2:5][C:2]([F:1])([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:13][CH:14]=2)[CH2:3]1)=[O:8]
Reactant: CNC
Reactant: O=C(O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C(=O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reaction time: 1 h
Yield: 29 %

Procedure:
To a stirred solution of 3-fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid (Preparation 7, 0.085 g, 0.166 mmol) in DCM (4 mL) was added oxalyl chloride (0.025 g, 0.199 mmol) at 0° C. and stirred for 1 hour. After 1 hour, saturated solution of dimethyl amine in THF (4 mL) was added. Resulting reaction mixture was stirred at room temperature for 16 hours. After complete consumption of starting material, reaction mixture was concentrated in vacuo to afford crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 0.7% methanol in DCM to afford off white solid (0.026 g, 29%). 1H-NMR (400 MHz, CDCl3) δ: 2.72-2.78 (m, 2H), 2.87-2.92 (m, 1H), 2.94 (s, 3H), 2.98 (s, 3H), 2.99-3.09 (m, 2H), 3.68 (d, 1H, J=17.2 Hz), 4.08 (d, 1H, J=17.16 Hz), 7.54 (d, 2H, J=8.16 Hz), 7.64 (s, 2H), 7.70 (d, 2H, J=8.24 Hz); LC-MS (m/z): [M−H] 534.60.
Reaction SMILES: [CH3:1][C@@H:2]([OH:6])[CH2:3][C:4]#[CH:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>CN(C=O)C.CCN(CC)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:7][C:8]1[C:9]([C:5]#[C:4][CH2:3][C@H:2]([OH:6])[CH3:1])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]
Reactant: C#CC[C@@H](C)O
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC[C@@H](C)O)c21

Procedure:
Using Method C above, (R)-pent-4-yn-2-ol (68 mg, 0.82 mmol) (see Example 78 below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (100 mg, 0.27 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (31 mg, 0.03 mmol) and Cul (6 mg) in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 4 hrs. Upon completion, the reaction mixture was concentrated and the residue was chromatographed on a silica gel column with neat CH3CN then THF and finally MeOH as elution solvent. The resulting (R)-(Z)-1,3-Dihydro-5-fluoro-4-(4-hydroxy-1-pentynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one was triturated with Et2O and then recrystalized from superheated EtOH. (Yield 18mg, 20%).
Reaction SMILES: C[O-].[Na+].CO.[C:6]([O:13][CH3:14])(=[O:12])[CH2:7][C:8]([O:10][CH3:11])=[O:9].[C:15]([O:20][CH3:21])(=[O:19])/[CH:16]=[CH:17]/[CH3:18].C(O)(=O)C.[Na+].[Cl-]>CO.O>[CH3:18][CH:17]([CH2:16][C:15]([O:20][CH3:21])=[O:19])[CH:7]([C:6]([O:13][CH3:14])=[O:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CC(=O)OC
Reactant: C/C=C/C(=O)OC
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)CC(C)C(C(=O)OC)C(=O)OC
Reaction time: 2 h
Yield: 89.1 %

Procedure:
To a mixture of 28% NaOMe/methanol (0.25 eq) and dimethyl malonate (1.0 eq) in methanol (1.6 vol) was added methyl crotonate at 70° C. The reaction mixture was stirred at the same temperature for 2 hr. After neutralization with acetic acid (0.25 eq)/water (50/50) at 25° C., the mixture was concentrated under reduced pressure. To the mixture was added 5% aq NaCl (3.82 vol) and extracted with MTBE (2 vol X 2), washed two times with 10% NaCl (2 vol) and concentrated to give the product as an oil (89.1% yield, 95% pure as measured by GC-MS).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1
Reactant: COC1CCC(O)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COC1CCC(=O)CC1
Reaction time: 60 h

Procedure:
4-Methoxycyclohexanol (2.0 g, 15.0 mmol) was taken up in 150 mL of DCM. Pyridinium chlorochromate (5.0 g, 23.0 mmol) was added. After 60 hours, the mixture was filtered through a plug of Florisil and concentrated under reduced pressure. The residue was taken up in 50 mL of ether and filtered through a plug of silica gel. The solvent was removed under reduced pressure, affording 4-methoxycyclohexanone as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:5]2[O:6][CH2:7][C:8](=O)[NH:9][C:4]=2[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:12]=[N:11][C:5]2[O:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2ncc(Br)cc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1cnc2c(c1)NCCO2
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
7-bromo-1H-pyrido[2,3-b][1,4]oxazin-2-one (1.3 g, 5.68 mmol) was dissolved in 30 ml of anhydrous tetrahydrofuran under nitrogen atmosphere and the mixture was cooled to 0□. 1.0M Lithium aluminum hydride dissolved in tetrahydrofuran (6.90 ml, 6.82 mmol) was added thereto dropwise and then stirred for 30 minutes. To the reaction mixture, water (0.3 ml), 10% sodium hydroxide (0.6 ml) and water (0.9 ml) were added dropwise in this order and then stirred vigorously at room temperature for 1 hour. The resulting solid was filtered and washed with excess ethyl acetate. The filtrate was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure to obtain 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine as white solid (629 mg, 52%).