Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:16][N:17]1[C:21]([C:22](Cl)=[O:23])=[CH:20][C:19]([CH3:25])=[N:18]1>O1CCCC1>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][C:22]([C:21]2[N:17]([CH3:16])[N:18]=[C:19]([CH3:25])[CH:20]=2)=[O:23])[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(O)c1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cccc(O)c2)n(C)n1
Yield: 89.6 %

Procedure:
In the same manner as in Reference Example 11 and using 3-aminophenol (2.11 g, 19.3 mmol), triethylamine (2.81 mL, 20.3 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (3.07 g, 19.4 mmol) and tetrahydrofuran (30 mL) as starting materials, the title compound (4.00 g, 90%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][C:3]=1[CH3:15].Br[N:17]1C(=O)CC[C:18]1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br-].CN>C1COCC1.[W].C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[CH:4][C:3]=1[CH2:15][NH:17][CH3:18]
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Agent: CN
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CNCc1cc(C(=O)OC(C)(C)C)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.2 %

Procedure:
A mixture of tert-butyl 4-fluoro-3-methylbenzoate (9.85 g, 46.9 mmole), N-bromosuccinimide (10 g, 56 mmole), benzoyl peroxide (0.6 g, 2.5 mmole), and CCl4 (100 mL) was heated to reflux with the aid of a 150 W tungsten flood lamp. After refluxing for 24 h, the reaction was cooled to RT and filtered, and the filter pad was washed with CCl4 (25 mL). The filtrate was concentrated to give the crude benzylic bromide (15.11 g, 59% pure by GC, containing 32% dibromide) as a yellow oil. To a solution of this crude bromide in THF (150 mL) was added with stirring at 0° C. a solution of methylamine (40 wt % in H2O, 20 mL, 232 mmole) in one portion. The reaction was allowed to warm to RT and stirred for 18 h, then was concentrated to half its volume. The residue was diluted with H2O (250 mL) and extracted with Et2O (2×150 mL). The combined organic layers were washed sequentially with 1.0 N NaOH (150 mL) and brine (150 mL), dried (Na2SO4), and concentrated. The remaining residue was purified by flash chromatography on silica gel (10% MeOH in 1:1 EtOAc/CHCl3) to give the title compound (4.85 g, 43%) as a yellow oil: MS (ES) m/e 240.0 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[CH:42]([N:45]1[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]1)([CH3:44])[CH3:43]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:51][CH:48]5[CH2:49][CH2:50][N:45]([CH:42]([CH3:44])[CH3:43])[CH2:46][CH2:47]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CC(C)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.9 %

Procedure:
To a mixture of 0.050 g (0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.08 mL (0.44 mmole) of ethyldiisopropyl amine and 0.018 g (0.12 mmole) of 1-isopropyl-piperidin-4-ylamine in 1.5 mL of dimethylformamide was added 0.053 g (0.12 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-85:15) gave 0.010 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-isopropyl-piperidin-4-yl)-3-methoxy-benzamide (I-64) as a white solid.
Reaction SMILES: C(O[CH2:6][CH2:7][CH2:8][CH3:9])(=O)C=C.[S]>>[CH3:6][CH2:7][CH2:8][CH2:9][CH2:6][CH2:7][CH2:8][CH2:9][CH2:6][CH2:7][CH2:8][CH2:9][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C=CC(=O)OCCCC
Agent: [S]
Product: CCCCCCCCCCCCCCCC

Procedure:
Another cetane improver was prepared as in Example 5 except that butyl acrylate was utilized and reacted with sulfur on a 1 to 1.5 mole basis. The desired product was obtained. When the cetane improver was tested at 0.3% in a 50/50% mixture of Fuel #1 and Fuel #2, a cetane improvement of 3.5 was obtained according to A.S.T.M. Test D 976.
Reaction SMILES: [S-2:1].[Na+].[Na+].S.Cl[CH2:6][C:7]1[C:15]([Cl:16])=[C:14]([Cl:17])[C:13]([Cl:18])=[C:12]([Cl:19])[C:8]=1[C:9](Cl)=[O:10].Cl>>[Cl:16][C:15]1[C:14]([Cl:17])=[C:13]([Cl:18])[C:12]([Cl:19])=[C:8]2[C:7]=1[CH2:6][S:1][C:9]2=[O:10]
Reactant: [S-2]
Reactant: O=C(Cl)c1c(Cl)c(Cl)c(Cl)c(Cl)c1CCl
Agent: Cl
Agent: S
Agent: [Na+]
Product: O=C1SCc2c(Cl)c(Cl)c(Cl)c(Cl)c21
Temperature: 10 °C
Reaction time: 6 h

Procedure:
48 g (0.2 mole) of sodium sulfide containing water of crystallization (Na2S. 9H2O) were dissolved in 300 ml of methanol. 6.8 g (0.2 mole) of hydrogen sulfide were passed into this solution at 10° to 20°C and 32.7 g (0.1 mole) of 2-chloromethyl-3,4,5,6-tetrachlorobenzoyl chloride were then introduced at 20° to 30°C. The mixture was boiled for 6 hours under reflux and after cooling to 10°C was acidified to pH 5 with concentrated hydrochloric acid. The crystal paste which separated out was filtered off, and the residue was washed with water and acetone and dried. The yield was 27.5 g (representing 95.5% of theory) of almost colorless crystalline powder of melting point 181°-183°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH:10]=[CH:11][C:12](=O)[CH3:13])=[C:5]([CH3:15])[C:4]=1[CH3:16].Br[CH2:18]/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22]>>[CH3:24][O:23][C:21](=[O:22])[CH:20]=[CH:19][CH:18]=[C:12]([CH3:13])[CH:11]=[CH:10][C:6]1[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:16])[C:5]=1[CH3:15]
Reactant: COc1cc(C)c(C=CC(C)=O)c(C)c1C
Reactant: COC(=O)/C=C/CBr
Product: COC(=O)C=CC=C(C)C=Cc1c(C)cc(OC)c(C)c1C

Procedure:
In a manner similar to Example 5, reaction of 4-(4-methoxy-2,3,6-trimethylphenyl)-3-buten-2-one with methyl 4-bromocrotonate afforded the desired compound. Crystallization from ether-petroleum ether gave yellow crystals, m.p. 104°-109° C. MS(EI): 300(m+), 285(m+ --CH3), 241(m+ --CO2CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11]COC)=[CH:7][C:4]=1[CH:5]=[O:6].Cl.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[OH:11][C:8]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([CH:7]=1)[CH:5]=[O:6]
Reactant: COCOc1ccc(OC)c(C=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(O)cc1C=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To a solution of 2-methoxy-5-(methoxymethoxy)benzaldehyde (33.5 g, 0.17 mol, 1 eq.) in THF (150 mL) was added HCl (3 N, 250 mL, 4.4 eq.). The reaction was stirred at 50° C. for 1 h, cooled to rt, and diluted with water (500 mL). The mixture was neutralized to pH 7-8 with solid K2CO3. The pale yellow solid was collected, washed with water, and dried to give 5-hydroxy-2-methoxybenzaldehyde (17.9 g, 74.6%) as a pale yellow solid. 1H NMR (400 MHz; DMSO) δ=10.31 (s, 1H), 8.03 (s, 1H), 6.89 (s, 1H), 3.80 (s, 3H). LRMS (M+H+) m/z 154.0.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:12]([CH2:22][OH:23])[CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[C@H:12]([CH2:22][O:23][C:27](=[O:28])[NH:26][CH2:24][CH3:25])[CH2:11]2)=[O:8])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1CO
Reactant: CCN=C=O
Solvent: Cc1ccccc1
Product: CCNC(=O)OC[C@@H]1C[C@@H](NC(=O)c2ccc(Cl)s2)CN1C(=O)OC(C)(C)C

Procedure:
120.0 mg (0.3 mmol) tert. Butyl (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-2-hydroxymethyl-pyrrolidine-1-carboxylate are refluxed in 5 ml of toluene with 30 μl (0.38 mmol) ethylisocyanate for three hours. Then 100 μl ethyl isocyanate are added three times at three hour intervals and the mixture is refluxed for a further 16 hours. Then the mixture is cooled, evaporated to dryness and purified by flash chromatography on silica gel (eluant DCM/methanol 100:3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6](O)=[O:7].C(Cl)(=O)C(Cl)=O.[CH3:18][NH2:19]>CN(C=O)C.C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:19][CH3:18])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1O
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(F)cc1O
Reaction time: 2 h

Procedure:
DMF (2 drops) was added to a mixture of 4-fluorosalicylic acid (2 g, 12.8 mmol) and oxalyl chloride (2.85 mL, 32.0 mmol) in THF (15 mL). The reaction was stirred for 2 hours then reduced in vacuo. The residue was dissolved in THF (10 mL) and added dropwise to 2M methylamine in THF (32 mL) at 0° C. The reaction was stirred at RT for 72 hours and the THF removed in vacuo. The residue was partitioned between ethyl acetate (80 mL) and water (80 mL). The aqueous layer was further extracted into ethyl acetate (80 mL) and the combined organics washed with brine (50 mL), dried (MgSO4), and reduced in vacuo to give a white solid. The material was chromatographed on silica, eluting with 5-40% ethyl acetate in isohexane, to give the desired compound as a white solid (1.43 g).
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34](Br)(Br)([Br:36])[Br:35]>C(Cl)Cl>[Br:35][C:34]([Br:36])=[CH:1][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1C=C(Br)Br
Yield: 47.9 %

Procedure:
Following the procedure of Example 3, 6.8 g of (S)-2-formyl-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester in 20 ml of methylene chloride is reacted with 40 g of triphenylphosphine, 26 g of carbon tetrabromide in 700 ml of methylene chloride to give 5.8 g of the desired product as a colorless solid, mp 58°-59° C., [α]D26° =+24°±1 (C=1.048%, methylene chloride).
Reaction SMILES: [CH:1]1([N:6]([CH:38]([CH3:40])[CH3:39])[CH2:7][CH2:8][NH:9][C:10]([NH:12][CH2:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][NH:20]3)=[C:16]([NH:23][CH2:24][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:15]=2)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:41]([O:44][C@H:45]1[C@@H:49]([O:50][C:51](=[O:53])[CH3:52])[CH:48](OC(=O)C)[O:47][C@@H:46]1[C:58]1[N:59]=[N:60][N:61]([CH2:63][CH3:64])[N:62]=1)(=[O:43])[CH3:42]>>[C:51]([O:50][C@@H:49]1[C@H:45]([O:44][C:41](=[O:43])[CH3:42])[C@@H:46]([C:58]2[N:59]=[N:60][N:61]([CH2:63][CH3:64])[N:62]=2)[O:47][C@H:48]1[N:20]1[CH:19]=[N:18][C:17]2[C:21]1=[N:22][C:14]([CH2:13][NH:12][C:10]([NH:9][CH2:8][CH2:7][N:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:38]([CH3:40])[CH3:39])=[O:11])=[N:15][C:16]=2[NH:23][CH2:24][CH:25]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:53])[CH3:52]
Reactant: CC(C)N(CCNC(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1)C1CCCC1
Reactant: CCn1nnc([C@H]2OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Product: CCn1nnc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(CNC(=O)NCCN(C(C)C)C5CCCC5)nc43)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1

Procedure:
Prepared from N-{2-[cyclopentyl(isopropyl)amino]ethyl}-N′-({6-[(2,2-diphenyl-ethyl)amino]-9H-purin-2-yl}methyl)urea (Preparation 44) and (2R,3R,4R)-4,5-bis(acetoxy)-2-(2-ethyl-2H-tetrazol-5-yl)tetrahydro-3-furanyl acetate (WO 9967265) by a similar procedure to Preparation 26. The title compound was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([O:22][CH3:23])=[O:21])[N:15]=2)=[O:13])[CH:9]=[CH:8][C:7]=1[OH:24].Br[CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]/[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([O:22][CH3:23])=[O:21])[N:15]=2)=[O:13])[CH:9]=[CH:8][C:7]=1[O:24][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]/[C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1
Reactant: COc1ccc(/C=C/CCCCBr)cc1
Reactant: COC(=O)CCc1cc(C(=O)c2cccc(C(=O)OC)n2)ccc1O
Product: COC(=O)CCc1cc(C(=O)c2cccc(C(=O)OC)n2)ccc1OCCCC/C=C/c1ccc(OC)cc1
Yield: 73.9 %

Procedure:
Under the conditions of example 1A, 640 mg of 3-[5-(6-methoxycarbonyl-2-pyridylcarbonyl)-2-hydroxyphenyl]-propionic acid methyl ester is reacted with 505 mg of (1E)-6-bromo-l-(4-methoxyphenyl)- 1-hexene, worked up and the crude product chromatographed on silica gel with hexane/ethyl acetate (0-15%). 732 mg of 3-{5-[6-methoxycarbonyl-2-pyridylcarbonyl]-2-[6-(4-methoxyphenyl)-(5E)-5-hexenyloxy]-phenyl}-propionic acid methyl ester of melting point 80°-82° C. is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C(#N)C>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=2)[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: Clc1cncc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1

Procedure:
A mixture of 10 mmol 2,6-dichloropyrazine and 21 mmol of N-BOC-piperazine in 15 ml acetonitrile was heated under reflux for 1.5 hours. The reaction mixture was concentrated and purified by chromatography (SiO2; dichloromethane/methanol 95:5) to yield the title compound as a colorless solid. MS (m/e): 299.2 (MH+, 100%)
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:5](=[CH:7][CH:8]=[CH:9][C:10]=2[OH:11])[CH:6]=1.[Si:12](Cl)(C(C)(C)C)(C)C.[Si](Cl)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C.C1COCC1.C(#N)C>[SiH3:12][O:11][C:10]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc2ccccc12
Agent: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: [SiH3]Oc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76 %

Procedure:
Naphthols 3a, 12 (18.7 mmol) was dissolved in dry DCM (100 mL) and cooled to 0° C. under N2 atm. Either TBDMS chloride or TBDPS chloride (20.5 mmol) was then added and the mixture stirred 5 minutes at 0° C. (Note: ACN, THF, and DMF can also be used as solvents or co-solvents). DIEA (28.0 mmol) was then added by syringe over 15 minutes and the resulting mixture was allowed to warm to rt overnight. (Note: Heat was required to drive the reaction when TBDPS chloride was used; reactions were monitored by TLC). Upon completion, the crude reaction mixture was washed with DI water and the organics dried over anhydrous Na2SO4, filtered, and the solvent removed under vacuum. Purification of the resulting residue by column chromatography on silica gel with 9:1 hexanes:EtOAc afforded silyl ether 109 in 76-96% yield.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].[CH2:6]([O:8][SiH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])[CH3:7]>C1C=CC=CC=1>[CH3:2][CH2:1][O:3][CH2:4][CH2:5][Si:9]([O:13][CH2:14][CH3:15])([O:10][CH2:11][CH3:12])[O:8][CH2:6][CH3:7]
Reactant: CCO[SiH](OCC)OCC
Reactant: C=COCC
Solvent: c1ccccc1
Product: CCOCC[Si](OCC)(OCC)OCC
Yield: 91 %

Procedure:
390 g vinylethylether, 600 g triethoxysilane, 3 g of a catalyst prepared according to Example 1 and 1000 ml of benzene were introduced into a reaction vessel and the mixture heated for 1.5 hours to boiling. After distillation, 786 g of CH3CH2OCH2CH2Si(OC2H5)3 were obtained (90% of the theoretical amount).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1I.C([O:13][B:14](OC(C)C)[O:15]C(C)C)(C)C.C([Li])CCC.Cl>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[B:14]([OH:15])[OH:13]
Reactant: Clc1ccc(Cl)c(I)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1cc(Cl)ccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cold (-78° C.) solution of 2,5-dichloroiodobenzene (50 g) and triisopropoxyborane (46.5 ml) in tetrahydrofuran (500 ml) was added dropwise n-butyllithium in hexane (1.69 M, 119 ml). The mixture was stirred at -78° C. for 30 minutes. The reaction mixture was poured into 2M hydrochloric acid solution (180 ml) and stirred for 10 minutes. The product was extracted with ether (200 ml) 2 times, and the organic layers were combined, washed with brine, dried over magnesium sulfate and evaporated in vacuo. To the residue was added n-hexane (60 ml) and the crystalline was collected, washed with n-hexane and dried to give 2,5-dichlorophenyl-dihydroxyborane (21.0 g).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]([N:19]1[CH2:24][CH:23]=[CH:22][CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:16][C:15]([O:14][C:12]([N:19]1[CH2:20][CH2:21][CH:22]2[CH:23]([O:6]2)[CH2:24]1)=[O:13])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2OC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
A solution of 3-chloroperoxybenzoic acid (2.96 g, 12.0 mmol) in DCM (20 mL) was added to a solution of N-boc-1,2,3,6-tetrahydropyridine (2.0 g, 10.9 mmol) in DCM (10 mL) at 0° C. The mixture was stirred at room temperature overnight and then a 10% solution of Na2S2O3 was added and the mixture basified with a saturated solution of Na2CO3. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylic acid 1,1-dimethylethyl ester (2.18 g, 100% yield) that was used in the next step without further purification. C10H17NO3 GCMS (EI): Rt 8.96, MW (theor) 199; m/z [M]+ 199 (using method, GC-MS Method 1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][Si](C(C)C)(C(C)C)C(C)C)[C:14]=3[O:30][CH3:31])[N:10]([C:32]([C:34]3[C:39]([F:40])=[CH:38][C:37]([F:41])=[CH:36][C:35]=3[F:42])=[O:33])[N:9]=2)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C[O:62][C:63](=[O:72])[C:64]1[CH:69]=[CH:68][C:67]([CH2:70]Br)=[CH:66][CH:65]=1.[Li+].[OH-]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][CH:11]([C:13]3[C:14]([O:30][CH3:31])=[C:15]([CH:16]=[CH:17][CH:18]=3)[O:19][CH2:70][C:67]3[CH:68]=[CH:69][C:64]([C:63]([OH:72])=[O:62])=[CH:65][CH:66]=3)[N:10]([C:32](=[O:33])[C:34]3[C:35]([F:42])=[CH:36][C:37]([F:41])=[CH:38][C:39]=3[F:40])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: COc1c(O[Si](C(C)C)(C(C)C)C(C)C)cccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Li+]
Solvent: CO
Product: COc1c(OCc2ccc(C(=O)O)cc2)cccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Reaction time: 0.5 h

Procedure:
[5-(4-fluoro-phenyl)-2-(2-methoxy-3-triisopropylsilanyloxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2,4,6-trifluoro-phenyl)-methanone (0.02 mmol) is treated with tetrabutylammonium fluoride (1.0 M in THF) (0.04 mmol) at room temperature for 30 minutes. The reaction is complete by LC/MS analysis. 4-Bromomethyl-benzoic acid methyl ester (0.04 mmol) is added. After 30 minutes, the reaction is complete as determined by LC/MS. After dilution with MeOH (0.5 mL), LiOH (1 M) (0.5 mL) is added. After stirring for 1 hour, the solvent is removed from the reaction mixture. A mixture of MeOH/DMSO is added to the residue and resultant solution is filtered. The clear solution is purified by preparative LC/MS (20-100% MeCN/H2O) to give 4-{3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxymethyl}-benzoic acid as white solid after removal of solvent: 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=8 Hz, 2H), 7.53-7.58 (m, 5H), 7.03-7.05 (m, 3H), 6.94-6.95 (m, 2H), 6.77 (t, J=8.2 Hz, 2H), 5.2 (s, 2H), 4.08 (s, 3H); LC/MS (ES+): (M+1) 597.3.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:20].[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](O)=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:20])[N:2]([NH:1][C:30](=[O:31])[CH2:29][C:24]3[CH:23]=[C:22]([F:21])[CH:27]=[C:26]([F:28])[CH:25]=3)[N:11]=2)=[CH:18][CH:17]=1
Reactant: Nn1nc(Cc2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(Cc2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 144A and 2-(3,5-difluorophenyl)acetic acid were treated using a method similar to that described in Example 17C to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 11.68 (s, 1H), 8.32 (dd, J=7.9, 1.4 Hz, 1H), 7.98 (d, J=7.9 Hz, 1H), 7.91-7.95 (m, 1H), 7.85-7.89 (m, 1H), 7.32-7.38 (m, 4H), 7.11-7.19 (m, 3H), 4.33 (s, 2H), 3.76 (s, 2H); LC/MS (APCI) M/Z 440 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][C:16]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([CH3:18])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:27])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)N[Si](C)(C)C.[Li].Cl[C:40]([O:42][CH3:43])=[O:41]>O1CCCC1>[CH3:43][O:42][C:40]([N:14]1[C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:28])=[C:8]([CH3:27])[CH:9]=2)=[CH:17][C:16]([C:19]2[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=2)([CH3:18])[O:15]1)=[O:41]
Reactant: Cc1cc(C2=NOC(C)(c3cc(Cl)cc(Cl)c3)C2)ccc1C(=O)OC(C)(C)C
Reactant: COC(=O)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: COC(=O)N1OC(C)(c2cc(Cl)cc(Cl)c2)C=C1c1ccc(C(=O)OC(C)(C)C)c(C)c1
Temperature: -78 °C

Procedure:
To a solution of 4-[5-(3,5-Dichloro-phenyl)-5-methyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (1.3 g) in dry tetrahydrofuran (15 ml) stirred under argon at −78° C., was added lithium hexamethyldisilazane (“LHMDS”) (1 M in hexane) (3.45 ml). The solution was stirred at −78° C. until deprotonation was completed as monitored by thin layer chromatography. Then, to this solution was added methyl chloroformate (0.465 ml) and the reaction mixture was stirred at −78° C. for 2 hours. The mixture was quenched with saturated ammonium chloride and then extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: heptane/diisopropylether 1:1) to give 3-(4-tert-butoxycarbonyl-3-methyl-phenyl)-5-(3,5-dichloro-phenyl)-5-methyl-5H-isoxazole-2-carboxylic acid methyl ester (472 mg) as a yellow foam.