Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:13]([C:16]1[CH:17]=[C:18]([S:22]([NH2:25])(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14].C1CCN2C(=NCCC2)CC1.Cl>CO.C(#N)C>[Cl:12][C:11]1[C:2]([NH:25][S:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)(=[O:24])=[O:23])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)c1
Temperature: 5 °C

Procedure:
1 kg of 2,3 dichloroquinoxaline and 1 kg of 3-nitrobenzenesulfonamide are mixed in 5 volumes of acetonitrile. The reaction mixture is heated to reflux. 2.3 kg of DBU and 1 volume of acetonitrile are added. After completion of the reaction, cool down at 5° C. Add 12 volumes of methanol and 1.53 kg of HCl, filter the reaction mixture. Wash the cake with 6 volumes of methanol and dry under vacuum.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C([NH:32][CH:33]2[C:46](=[O:47])[N:35]3[CH:36]([C:41]4[NH:45][N:44]=[N:43][N:42]=4)[C:37]([CH3:40])([CH3:39])[S:38][C@H:34]23)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+].[C:50]1([CH2:56][C:57](Cl)=[O:58])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>O.CC(C)=O>[C:50]1([CH2:56][C:57]([NH:32][CH:33]2[C:46](=[O:47])[N:35]3[CH:36]([C:41]4[NH:42][N:43]=[N:44][N:45]=4)[C:37]([CH3:39])([CH3:40])[S:38][C@H:34]23)=[O:58])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CC1(C)S[C@@H]2C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC1(C)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1c1nnn[nH]1
Temperature: 25 °C

Procedure:
A mixture of p-toluenesulfonic acid monohydrate (788 mg., 4.14 mmoles), acetone (35 ml.) and 6-triphenylmethylamino-2,2-dimethyl-3-(5-tetrazoly)penam (2.0g., 4.14 mmole) is stirred for twenty minutes at room temperature and is then diluted with water (100 ml.) and ispropylether (100 ml.). The biphasic mixture is stirred vigorously and adjusted to pH 7 with 2N sodium hydroxide. Phenylacetyl chloride (700 mg., 4.55 mmole freshly distilled) is added and the reaction mixture maintained at pH 5.5-6.5 by addition of 2N sodium hydroxide as necessary. Reaction is continued until the pH levels off at 6.5. The two phases are separated and the aqueous phase is washed with ether (2 × 50 ml.). Chloroform (100 ml.) is added and the pH is adjusted to 2 by addition of 6N HCl. The mixture is stirred, the phases separated and the aqueous phase extracted with chloroform (2 × 50 ml.). The chloroform phases are combined, dried (Na2SO 4), and then concentrated under reduced pressure to about 50 ml. volume. A 1:1 solution of ether-hexane is added dropwise with vigorous stirring until precipitation of the product is complete. The white precipitate is filtered and air-dried. The yield is 850 mg. (57.4%), m.p. 168°-170°. NMR (DMSO-d6): 7.30 (s, 5H), 5.80-5.42 (m, 2H), 5.28 (s, 1H), 3.60 (s, 2H), 1.68 (s, 3H) and 1.10 ppm (s, 3H).
Reaction SMILES: BrCCBr.[C:5]([O:8][CH2:9]Br)(=[O:7])[CH3:6].[Br-].C(OC[Zn+])(=O)C.Cl[C:19]1[N:24]=[C:23]([O:25][C:26]2[C:27]([F:36])=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30]([CH3:35])=[CH:29]3)[CH:22]=[CH:21][N:20]=1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[NH4+].[Cl-]>CN(C=O)C.[Zn].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:5]([O:8][CH2:9][C:19]1[N:24]=[C:23]([O:25][C:26]2[C:27]([F:36])=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][C:30]([CH3:35])=[CH:29]3)[CH:22]=[CH:21][N:20]=1)(=[O:7])[CH3:6]
Reactant: Cc1cc2c(F)c(Oc3ccnc(Cl)n3)ccc2[nH]1
Reactant: CC(=O)OCBr
Agent: [Pd+2]
Agent: CC(=O)OC[Zn+]
Agent: CC(=O)[O-]
Solvent: BrCCBr
Solvent: CN(C)C=O
Product: CC(=O)OCc1nccc(Oc2ccc3[nH]c(C)cc3c2F)n1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
1,2-Dibromoethane (425 μl, 5.0 mmol) is added to a suspension of zinc powder (2.83 g, 43.2 mmol) in dry DMF (8 mL). The reaction mixture is heated at 60° C. for 10 min, then cooled to room temperature. TMSCI (500 μl, 4.0 mmol) is added (caution: exothermic!) and the resulting mixture is sonicated for 30 min. Zinc powder is allowed to settle and the supernatant is removed by syringe. DMF (8 mL) is added, followed by bromomethyl acetate (2.12 mL, 21. 61 mmol). The mixture is stirred at 23° C. for 2.5 h. Zinc is allowed to settle and the solution of acetoxymethylzinc bromide is then transferred to a solution of 5-(2-chloropyrimidin-4-yloxy)-4-fluoro-2-methyl-1H-indole (2.00 g, 7.20 mmol), palladium acetate (0.081 g, 0.360 mmol), and S-phos (0.355 g, 0.864 mmol) in DMF (10 mL) at 23° C. The resulting mixture is stirred at 23° C. for 15 h. Saturated aqueous NH4Cl (100 mL) is added and the mixture is then partitioned between EtOAc (150 mL) and water (150 mL). The aqueous layer is extracted with EtOAc (2×100 mL). The combined organic layers are washed with brine (60 mL), dried (Na2SO4), and concentrated. The residue is purified by silica gel chromatography (0-100% EtOAc/heptane) to give (4-(4-fluoro-2-methyl-1H-indol-5-yloxy)pyrimidin-2-yl)methyl acetate.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[C:19]([CH:22]=1)[CH2:20][OH:21].O>CN(C=O)C>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH3:24])=[C:19]([CH:22]=1)[CH2:20][O:21][Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(Br)cc1CO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1CO[Si](C)(C)C(C)(C)C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
Imidazole (3.45 g) and t-butyldimethylchlorosilane (17.6 g) were added to a solution of 5-bromo-2-methoxybenzyl alcohol (10.0 g) in DMF (100 ml) under cooling with ice and the mixture was stirred for two hours. The reaction mixture was added to ice-cooled water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain [(5-bromo-2-methoxybenzyl)oxy](t-butyl)dimethylsilane (15.2 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[C:24]#[N:25])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[BH4-].[Na+].Cl>CO.C1COCC1.O.O.O.O.O.O.[Co](Cl)Cl>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][NH2:25])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C#N)c1
Agent: Cl[Co]Cl
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2′-cyano-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.545 g, 1.5 mmol) and cobalt(II) chloride hexahydrate (0.71 g, 3.0 mmol) in MeOH (60 mL) and THF (24 mL) was added sodium borohydride (0.58 g, 15.3 mmol), and the reaction was stirred at room temperature for 2 hours. 2N Aqueous HCl (67 mL) was added, and the mixture was concentrated. 2N Aqueous NH4OH was added until the solution was basic, and the mixture was extracted twice with CH2Cl2. The combined organic layers were washed three times with H2O, dried over Na2SO4, filtered, and concentrated to give the title compound.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[CH2:3]1.C[O:20][C:21]([CH:23]1[CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[S:32](Cl)(=[O:34])=[O:33])[CH2:24]1)=[O:22]>>[CH3:1][C@H:2]1[CH2:3][N:4]([C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]([F:18])([F:16])[F:17])=[CH:12][CH:13]=2)[CH2:5][CH2:6][N:7]1[S:32]([C:29]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:30]=1[CH2:31][CH:23]([C:21]([OH:22])=[O:20])[CH2:24]2)(=[O:34])=[O:33]
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)Cl)c2C1
Reactant: C[C@H]1CN(c2ccc(OC(F)(F)F)cc2)CCN1
Product: C[C@H]1CN(c2ccc(OC(F)(F)F)cc2)CCN1S(=O)(=O)c1cccc2c1CC(C(=O)O)C2

Procedure:
The compound 4-[2-(S)-Methyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid was prepared from 3-(S)-methyl-1-(4-trifluoromethoxy-phenyl)-piperazine and 4-chlorosulfonyl-indan-2-carboxylic acid methyl ester following the procedure outlined in Example 79. 1H NMR (400 MHz, DMSO-d6): δ 7.65 (d, 1H), 7.53 (d, 1H), 7.38 (t, 1H), 7.18 (d, 2H), 6.98-6.92 (m, 2H), 4.15-4.00 (m, 1H), 3.60-3.12 (m, 9H), 2.83-2.75 (m, 1H), 2.64-2.50 (m, 1H), 1.18 (d, 3H); MS (ESI): 485.3 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:14][C:11]3([CH2:13][CH2:12]3)[CH2:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.ClC1C=C(C=CC=1)C(O)=O.C([O-])(=O)C.[Na+]>ClCCl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:15]3[CH:16]=[CH:17][C:18]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:19][CH:20]=3)=[CH:10][C:11]3([CH:14]=2)[CH2:12][CH2:13]3)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(C2=C(c3ccc(F)cc3)CC3(CC3)C2)cc1
Agent: CC(=O)[O-]
Agent: O=C(O)c1cccc(Cl)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(C2=CC3(C=C2c2ccc(F)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 39.6 %

Procedure:
A solution of 300 mg (0.88. mmol) of 4-[6-(4-fluorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide (from Step 1) in 5 mL of dichloromethane was treated with 300 mg (55% peroxyacid, 0.96 mmol) of m-chloroperoxybenzoic acid (MCPBA). The reaction was stirred at ambient temperature for 2.5 hours, washed with aqueous saturated sodium bisulfite, dried (MgSO4), and concentrated in vacuo to give a mixture of desired expoxide intermediate and m-chlorobenzoic acid; this crude mixture in 6 mL of acenic acid and 0.6 mL of water was subsequently treated with 300 mg (3.7 mmol) of sodium acetate and stirred at 80° C. for 10 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was partitioned between water and ethyl acetate; the organic phase was washed with aqueous saturated sodium bicarbonate, water, brine, dried (MgSO4), and reconcentrated in vacuo. Purification by silica gel chromatography gave 118 mg (39%) of 4-[6-(4-fluorophenyl)spiro[2.4]hepta-4,6-dien-5-yl]benzenesulfonamide as a colorless solid: mp 110°-116° C. (dec); NMR (CDCl3) δ 1.80 (s, 4H), 4.81 (br s, 2H), 6.21 (d, J=2 Hz, 1H), 6.33 (d, J=2 Hz, 1H), 6.94 (t, J=9 HZ, 2H), 7.06-7.15 (m, 2H), 7.29 d, J=8 Hz, 2H), 7.78 (d, J=8 Hz, 2H),
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>CN(C=O)C>[Cl:17][C:18]1[N:23]=[C:22]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:21]=[CH:20][N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)n2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 26 %

Procedure:
To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (1.0 g, 5.0 mmol, Aldrich) in DMF (15.0 mL) at 0° C. was added sodium hydride (0.55 g, 15.0 mmol, 65% dispersion in mineral oil, commercially available from Sigma-Aldrich Corporation). in several portions. After stirring at 0° C. for 10 min, 2,4-dichloropyrimidine (745 mg, 5 0 mmol, commercially available from Sigma-Aldrich Corporation) in DMF (10.0 mL) was added. The resulting mixture was stirred at 0° C. for 10 min and at room temperature for 2 h and then quenched with saturated NH4Cl aqueous solution (1.5 mL). The reaction mixture was diluted with EtOAc and H2O and the aqueous solution was extracted further with EtOAc (2×). The combined organic extracts were washed with H2O (3×) and brine, dried (Na2SO4) and evaporated. The residual was purified by flash chromatography (0 to 50% EtOAc/hexanes) to yield 409.3 mg (26%) of the product as an off-white semi-solid. MS (ESI) 314 (M+H).
Reaction SMILES: C(N(CC)CC)C.C(O)=O.ClC1C=CC=CC=1.[C:18]([NH:37][CH:38]([C:44](=[O:60])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:39]([O:41][CH2:42][CH3:43])=[O:40])(=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>O>[C:18]([NH:37][C@H:38]([C@H:44]([OH:60])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[C:39]([O:41][CH2:42][CH3:43])=[O:40])(=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCCCCCCCCC(=O)NC(C(=O)CCCCCCCCCCCCCCC)C(=O)OCC
Solvent: Clc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: CCCCCCCCCCCCCCCCCC(=O)N[C@@H](C(=O)OCC)[C@H](O)CCCCCCCCCCCCCCC
Temperature: 40 °C
Reaction time: 72 h
Yield: 73 %

Procedure:
Triethylamine (830 mg, 8.20 mmol) and formic acid (227 mg, 4.93 mmol) were added to a chlorobenzene solution (15.0 ml) of RuCl[(R,R)-TsDPEN](p-cymene) complex (11.0 mg, 0.03 mmol) and ethyl 2-octadecanoylamino-3-oxooctadecanoate (1.00 g, 1.64 mmol) synthesized in the same method as Example 10. After the reaction mixture was stirred for 3 days at 40° C., water (10 mL) was added thereto and separation operation was carried out at 40° C. to obtain the organic layer. After the organic layer was concentrated until the total amount became 3.11 g, 10 mL of AcOEt was added thereto and recrystallization was carried out to obtain 0.73 g of the title compound (yield: 74%). Anti-form:syn-form was 100:0 and the optical purity of the anti-form was 100% ee.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[F:16][C:17]1[CH:18]=[C:19]([N+:25]([O-:27])=[O:26])[CH:20]=[C:21]([F:24])[C:22]=1F>CN1CCCC1=O.O.Cl>[F:16][C:17]1[CH:18]=[C:19]([N+:25]([O-:27])=[O:26])[CH:20]=[C:21]([F:24])[C:22]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: C1COCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1cc(F)c(N2CCOCC2)c(F)c1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
5.10 mL morpholine are dissolved in 1 mL 1-methyl-2-pyrrolidon and combined with 14.99 mL N,N-diisopropylethylamine and 1.85 mL 3,4,5-trifluoronitrobenzene. The reaction mixture is stirred for 1 h at 110° C. After cooling the reaction mixture is diluted with 70 mL water and 15 mL concentrated aqueous HCl solution are added. The precipitate formed is filtered off, with water washed and dissolved with ethyl acetate. Then the solvent is eliminated in vacuo.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[NH:11](CCO)[CH2:12][CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][N:11]1[CH2:10][CH2:9][O:8][C:1](=[O:7])[C:2]1=[O:4]
Reactant: CCOC(=O)C(=O)OCC
Reactant: OCCNCCO
Product: O=C1OCCN(CCO)C1=O
Reaction time: 2 h

Procedure:
In a flask similar to that used for example 9 was placed 146 g (1.0 mole) of diethyl oxalate, and to this flask was added dropwise 26 g (0.25 moles) of diethanolamine maintaining reaction temperature at 30° C. during 1 hour. After the dropping finished, the stirring was continued at 25° C. for further 2 hours and then crystals separated were taken by filtration to obtain N-hydroxyethylmorpholine-2,3-dione.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.CO.[NH:13](CCO)[CH2:14][CH2:15][OH:16]>C(O)(C)C>[OH:16][CH2:15][CH2:14][N:13]1[CH2:10][CH2:9][O:8][C:1](=[O:7])[C:2]1=[O:4]
Reactant: OCCNCCO
Reactant: CCOC(=O)C(=O)OCC
Solvent: CO
Solvent: CC(C)O
Product: O=C1OCCN(CCO)C1=O
Temperature: 2.5 °C
Reaction time: 8 h

Procedure:
A 4(2-hydroxyethyl)morpholine-2,3-dione was prepared at low temperatures by the following procedure. Into a five-necked 22 liter round bottomed flask equipped with a reflux condenser, nitrogen bubbler, addition funnel, thermocouple well, and mechanical stirrer was charged 3000 g (20.53 mol) of diethyl oxalate and 2000 ml of isopropyl alcohol. The solution was cooled to 0 to 5° C. using a cold bath of ice and methanol. A solution of 2160 g (20.53 mol) of diethanolamine dissolved in 2000 ml of isopropyl alcohol was added through the addition funnel during a period of 5 to 6 hours. The reaction is exothermic. After addition was complete, the mixture was allowed to stand at room temperature overnight. The product is collected by filtration. After air drying, 2923 g (89.5% yield) of white crystals were obtained with identical spectral properties to the compound prepared in Example 1.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4][CH2:5][C:6](OC)=[O:7].O.[NH2:12][NH2:13]>CO>[CH3:2][N:3]([CH3:10])[CH2:4][CH2:5][C:6]([NH:12][NH2:13])=[O:7]
Reactant: COC(=O)CCN(C)C
Reactant: NN
Agent: Cl
Solvent: CO
Solvent: O
Product: CN(C)CCC(=O)NN
Temperature: 70 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To a solution of methyl 3-(dimethylamino)propanoate hydrochloride (compound 142.6, 2.00 g, 15.3 mmol, 1.00 equiv) in methanol (40 mL) was added hydrazine hydrate (6 mL, 6.00 equiv). The reaction mixture was stirred at 70° C. for 3 h. The mixture was concentrated in vacuo and then dissolved in 50 mL of H2O and washed with 2×10 mL of ethyl acetate. The aqueous layers were combined and concentrated in vacuo to afford 1.30 g (65%) of 3-(dimethylamino)propanehydrazide as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]([O:26][CH3:27])=[O:25])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:6]([N+:14]([O-])=O)[C:7]=1[C:8]#[C:9][Si:10]([CH3:13])([CH3:12])[CH3:11].CO.[Cl-].[NH4+].O>C(OCC)(=O)C.[Zn]>[NH2:14][C:6]1[C:7]([C:8]#[C:9][Si:10]([CH3:12])([CH3:11])[CH3:13])=[C:2]([Cl:1])[CH:3]=[C:4]([C:24]([O:26][CH3:27])=[O:25])[C:5]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1
Reactant: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)c([N+](=O)[O-])c1-c1cccc(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)c(N)c1-c1cccc(F)c1
Reaction time: 3 h
Yield: 102.3 %

Procedure:
A solution of methyl 4-chloro-3′-fluoro-6-nitro-5-[(trimethylsilyl)ethynyl]biphenyl-2-carboxylate (330 g, 780 mmol) in ethyl acetate (1 L) was treated with methanol (1 L) and saturated aqueous ammonium chloride solution (670 mL, 10 mol). The mixture was cooled with an ice-water bath and treated with <10 micron zinc dust (310 g, 4.7 mol) in portions with internal temperature at 15 to 45° C. After addition, the ice bath was removed and the reaction mixture was stirred for 3 hours. The reaction mixture was filtered over a pad of celite and rinsed with ethyl acetate (2×1 L). The combined filtrate was diluted with brine (500 mL) and stirred for 10 minutes. The brine layer was separated and extracted with ethyl acetate (300 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give a green oil which contained approximately 12% water. This material was dried with azeotropic drying with toluene to give the desired product (300 g, quantitative) as a green semi-solid. HPLC 90.5% pure @ 220 nm. LCMS for C19H20ClFNO2Si (M+H)+: m/z=376.1; Found: 376.0; 1H NMR (300 MHz, DMSO-d6): δ 7.56-7.42 (m, 1H), 7.28-7.16 (m, 7.28-7.16 (m, 1 H), 7.07 (s, 1 H), 7.06-6.94 (m, 2 H), 5.06 (s, 2 H), 3.47 (s, 3 H), 0.25 (s, 9 H).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].C[Si](OC(=O)C)(OC(=O)C)OC(=O)C.C([Si](C=C)(C)O[Si](C)(C)C)=C>C1(C)C=CC=CC=1>[CH2:1]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=Cc1ccccc1
Reactant: CCO[SiH](OCC)OCC
Agent: C=C[Si](C)(C=C)O[Si](C)(C)C
Agent: CC(=O)O[Si](C)(OC(C)=O)OC(C)=O
Solvent: Cc1ccccc1
Product: CCO[Si](CCc1ccccc1)(OCC)OCC
Temperature: 50 °C
Yield: 96 %

Procedure:
130 mg Of styrene and 217 mg of triethoxysilane were placed in a glass reaction tube and 0.0032 mg of methyltriacetoxysilane was added. Next, 0.0045 ml of a toluene solution of a 0-valent platinum complex of divinyltetramethyldisiloxane (platinum content: 0.04 Wt. %) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the tube contents were analyzed by GC-MS following cooling, the conversion rate of styrene was 98% and phenethyltriethoxysilane was produced at a yield of 96%. The yield of (α-methylbenzyl) triethoxysilane was 0.7%.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH2:8][C:9]([O:11]C)=[O:10].Cl.O.C(OCC)(=O)C>O1CCOCC1>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[O:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: COC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCC(=O)O)c(Cl)cc2F)c1=O
Temperature: 0 °C
Yield: 64.8 %

Procedure:
0.4 g of methyl [2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate [Compound 3-11 of the present invention] was dissolved in 4 ml of 1,4-dioxane, to this was added a mixed solution of 1 ml of conc. hydrochloric acid and 1 ml of water while stirring, then, the mixture was heated for 12 hours while stirring under reflux condition. Thereafter, the solution was allowed to cool, and ice water was poured into the reaction solution, ethyl acetate and saturated saline were added to the solution which was separated subsequently, and aqueous sodium hydrogen carbonate was added to the organic layer before separation, aqueous hydrochloric acid was added to the aqueous layer to acidify it, then, ethyl acetate was added before separation, the organic layer was washed with saturated saline, and dried over magnesium sulfate, then, concentrated to obtain 0.252 g of [2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetic acid.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12.C([O-])([O-])=O.[K+].[K+].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24].C(OCC)(=O)C>CN1CCCC1=O>[C:19]1([CH3:24])[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:1]1[C:5](=[O:6])[CH2:4][N:3]2[C:7](=[O:10])[CH2:8][CH2:9][CH:2]12
Reactant: O=C1CN2C(=O)CCC2N1
Reactant: Cc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Cc1ccccc1N1C(=O)CN2C(=O)CCC21
Yield: 15.4 %

Procedure:
To a solution of tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione (1.3 g, 9.28 mmol, prepared as described in J. Med. Chem. 36, 4214, 1994) in N-methylpyrrolidone (NMP, 12 cc), Cul (0.5 g, 2.62 mmol), K2CO3 (1.3 g, 9.28 mmol) and 2-bromotoluene (6 g, 35 mmol) were added under stirring. The suspension was heated in a microwave apparatus (250 Watt) for 1 h. Ethyl acetate was added to the suspension and the solid was filtered. The organic phase was washed with water and the aqueous phase was re-extracted with CH2Cl2. The organic phases were gathered and dried over Ma2SO4, filtered and concentrated to dryness. The residue was triturated with Et2O. The solid was filtered, and crystallized the first time with IPrOH and then with AcOEt to yield 0.33 g of the title compound, mp=138-139° C.