Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[C:6](=[O:29])[O:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=1)[CH:9]=2)=[O:4].[NH2:30][CH2:31][C:32]([O-:34])=[O:33].[Na+]>COC(O)C>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[O:7][C:6](=[O:29])[C:5]=1[C:3]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:4]
Reactant: COC(=O)c1c(O)c2ccc(-c3ccc(Oc4ccccc4)cc3)cc2oc1=O
Reactant: NCC(=O)[O-]
Agent: COC(C)O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2ccc(-c3ccc(Oc4ccccc4)cc3)cc2oc1=O
Yield: 96.1 %

Procedure:
A mixture of 4-hydroxy-2-oxo-7-(4-phenoxy-phenyl)-2H-chromene-3-carboxylic acid methyl ester (75 mg, 0.193 mmol) and sodium glycinate (94 mg, 0.96 mmol) in methoxyethanol (10 mL) was refluxed for 18 h; then cooled, the solvent was removed, the residue was redissolved in water, acidified with 2 M HCl, the precipitates were collected and washed with water, air dried to give the desired title product (80 mg). ESI (m/z): 432 (M+H)+.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[C:5]([CH3:22])=[C:6]([CH3:21])[C:7]2[O:12][C:11]([CH2:14][CH2:15][C:16]([OH:18])=O)([CH3:13])[CH2:10][CH2:9][C:8]=2[C:19]=1[CH3:20].S([O:28][CH3:29])(OC)(=O)=O.Cl.[CH3:31]N(C)C=O>C(O)C>[CH3:31][O:3][C:4]1[C:5]([CH3:22])=[C:6]([CH3:21])[C:7]2[O:12][C:11]([CH2:14][CH2:15][C:16]([O:28][CH3:29])=[O:18])([CH3:13])[CH2:10][CH2:9][C:8]=2[C:19]=1[CH3:20]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCC(=O)O)O2
Reactant: CN(C)C=O
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)CCC1(C)CCc2c(C)c(OC)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
An aqueous solution of potassium hydroxide (7.1 g in 10 ml of water) was added dropwise to a solution composed of 10 g (0.036 mol) of 3-(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)propionic acid and 200 ml of ethanol in a nitrogen atmosphere and the mixture was stirred at room temperature for 30 minutes. The ethanol was distilled off from the reaction mixture under reduced pressure, toluene was added to the residue, and dehydration was effected azeotropically under reduced pressure. To the residue thus obtained, 200 ml of N,N-dimethylformamide was added for dissolution of the residue. To the solution was added dropwise, with vigorous stirring, 4.53 g (3.4 ml) of dimethyl sulfate while maintaining the solution at a temperature of room temperature to 50° C. After the addition, the reaction was conducted at 50° C. for 5 hours. After cooling to room temperature, the reaction mixture was poured into dilute hydrochloric acid and extracted with diethyl ether. The extract was washed with water and then with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then filtered. Low-boiling substances were distilled off from the filtrate under reduced pressure and the residue was purified by silica gel column chromatography to give 5.9 g (53.6% yield) of methyl 3-(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)propionate
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5](=O)[CH2:6][C:7]1[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:10]=[C:9]([O:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH:8]=1.CO>O1CCCC1>[OH:4][CH2:5][CH2:6][C:7]1[N:12]=[C:11]([C:13]([F:15])([F:16])[F:14])[N:10]=[C:9]([O:17][CH:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]2)[CH:8]=1
Reactant: COC(=O)Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)nc(C(F)(F)F)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(CCO)nc(C(F)(F)F)n2)CC1
Reaction time: 2 h

Procedure:
Sodium tetrahydroborate (32 mg, 0.83 mmol) was added to a solution of tert-butyl 4-{[6-(2-methoxy-2-oxoethyl)-2-(trifluoromethyl)pyrimidin-4-yl]oxy}piperidine-1-carboxylate (125 mg, 0.209 mmol, from Step 2) in tetrahydrofuran (2.0 mL). Methanol (0.21 mL) was added in portions. After stirring for 2 hours, the mixture was quenched by the addition of saturated ammonium chloride solution. The reaction was diluted with additional water, and the product was extracted with EtOAc. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography on a 12 g silica gel column, eluting with a gradient from 0-30% EtOAc in hexanes afforded product (26 mg, 32%). 1H NMR (400 MHz, CDCl3) δ 6.74 (s, 1H), 5.35 (tt, J=7.8, 3.7 Hz, 1H), 4.07-3.96 (m, 2H), 3.81-3.61 (m, 2H), 3.31 (ddd, J=13.5, 8.4, 3.7 Hz, 2H), 2.99 (t, J=5.4 Hz, 2H), 2.03-1.92 (m, 2H), 1.79-1.68 (m, 2H), 1.47 (s, 9H); 19F NMR (376 MHz, CDCl3) δ-71.37 (s); LCMS (M+Na)+: 414.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[C:5]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)([OH:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C@@:24]12(O)[N:31](C)[C@@H:28]([CH2:29][CH2:30]1)[CH2:27][CH:26]=C2.[Na].O>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[C:5]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[C:14]([F:19])[CH:13]=1)([OH:11])[C:6]([O:8][C@@:9]12[N:31]([CH3:24])[C@@H:28]([CH2:29][CH2:30]1)[CH2:27][CH:26]=[CH:10]2)=[O:7]
Reactant: CN1[C@@H]2CC=C[C@@]1(O)CC2
Reactant: CCOC(=O)C(O)(c1ccc(F)c(F)c1)c1ccc(F)c(F)c1
Agent: [Na]
Solvent: O
Solvent: CC#N
Product: CN1[C@@H]2CC=C[C@@]1(OC(=O)C(O)(c1ccc(F)c(F)c1)c1ccc(F)c(F)c1)CC2

Procedure:
4.27 g (0.013 mol) of ethyl 3,3′,4,4′-tetrafluorobenzilate 3c, 1.81 g (0.013 mol) of tropenol and 0.03 g sodium are heated as a melt at 75 mbar for 4 hours over a bath of boiling water, shaking from time to time. After cooling, the sodium residues are dissolved with acetonitrile, the solution is evaporated to dryness, and the residue extracted with dichloromethane/water. The organic phase is washed with water, dried over MgSO4, and evaporated to dryness. The residue remaining is mixed with diethylether/petroleum ether (1:9), suction filtered and washed. Yield: 2.50 g (46% of theory); TLC: Rf value: 0.29 (eluent: sec-butanol/formic acid/water (75:15:10)); melting point: 147° C.-148° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br-].[C:31]([C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][Zn+])#[N:32]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:35][C:34]5[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=5[C:31]#[N:32])[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Reactant: N#Cc1ccccc1C[Zn+]
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Br-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3ccccc3C#N)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-cyano-benzylzinc bromide following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 6): tR=1.23 min; Mass spectrum (ESI+): m/z=508 [M+H]+.
Reaction SMILES: C([N:3]1CC[CH:6](C(O)=O)[CH2:5][CH2:4]1)C.[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])[CH3:13].C(#N)C=C>C(O)(C)C>[CH2:12]([O:14][C:15]([CH:17]1[CH2:22][CH2:21][N:20]([CH2:6][CH2:5][C:4]#[N:3])[CH2:19][CH2:18]1)=[O:16])[CH3:13]
Reactant: CCN1CCC(C(=O)O)CC1
Reactant: CCOC(=O)C1CCNCC1
Solvent: C=CC#N
Solvent: CC(C)O
Product: CCOC(=O)C1CCN(CCC#N)CC1
Yield: 101.5 %

Procedure:
A solution of piperidine-4-carboxylic acid ethyl ester (ethylisonipecotate) (4.7 g, 30 mmol), acrylonitrile (1.7 g, 31 mmol) in isopropyl alcohol (30 ml) was stirred at room temperature for 15 hours, then evaporated to dryness to afford 1-(2-cyano-ethyl)-piperidine-4-carboxylic acid ethyl ester as an oil (6.4 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].Br[C:14]([CH3:21])([CH3:20])[C:15](OCC)=[O:16]>>[Cl:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]2[O:12][C:14]([CH3:21])([CH3:20])[C:15](=[O:16])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Reactant: CCOC(=O)C(C)(C)Br
Product: CC1(C)Oc2cc([N+](=O)[O-])c(Cl)cc2NC1=O

Procedure:
2-amino-4-chloro-5-nitrophenol (10.0 g) and ethyl α-bromoisobutyrate (7.4 mL) were treated in the same manner as described in Reference Example 1(1) to give 6-chloro-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-3(4H)-one (6.82 g) as a pale brown powder.
Reaction SMILES: [CH3:1][NH:2][N:3]=[C:4]([CH3:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7].O1CCCC1.C(N(CC)CC)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33]([CH2:41][CH3:42])=[C:34]([C:36](=[O:40])[C:37](Cl)=[O:38])[CH:35]=2)=[CH:26][CH:25]=1>CCCCCC>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][C:33]([CH2:41][CH3:42])=[C:34]([C:36](=[O:40])[C:37]([N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[CH2:5][S:6]([CH3:9])(=[O:8])=[O:7])=[O:38])[CH:35]=2)=[CH:26][CH:25]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1C(=O)C(=O)Cl
Reactant: CNN=C(C)CS(C)(=O)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C(=O)C(=O)N(C)N=C(C)CS(C)(=O)=O
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a 25 ml volume three-necked flask, 1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine (5-2-1) (670 mg), tetrahydrofuran (anhydrous) (2.25 ml), and triethylamine (390 mg) were added under a nitrogen atmosphere. To the mixture, 2-[5-(4-chlorophenyl)-2-ethylphenyl]-2-oxoacetyl chloride (6-c) (937 mg) was added dropwise at 0° C. and stirred for 2 hours. To hexane (15 ml) in a 50 ml volume three-necked flask, the reaction mixture was added dropwise, stirred for 10 minutes, and filtered. The residue was dried under reduced pressure, dissolved in ethyl acetate, and filtered again. The filtrate was concentrated under reduced pressure to give 853 mg of 1-[2-[5-(4-chlorophenyl)-2-ethylphenyl]-2-oxoacetyl]-1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine ((4-34)-(1)-67). The filtrate from the first filtration was concentrated under reduced pressure, the residue was subjected to column chromatography (hexane:ethyl acetate=1.5:1) to give 240 mg of additional 1-[2-[5-(4-chlorophenyl)-2-ethylphenyl]-2-oxoacetyl]-1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine ((4-34)-(1)-67).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[N+:17]([O-])=O.[H][H]>[Pd].C(OCC)(=O)C>[NH2:17][C:3]1[CH:4]=[C:5]([C:8]([CH3:15])([CH3:16])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: [H][H]
Reactant: CCOC(=O)CC(C)(C)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C)(C)c1ccc(Cl)c(N)c1

Procedure:
40 mg of palladium on carbon (10%) were added to a solution of 213 mg (0.75 mmol) of ethyl 3-(4-chloro-3-nitrophenyl)-3-methylbutanoate in 10 ml of ethyl acetate. The reaction mixture was hydrogenated at RT using a hydrogen pressure of 1 bar overnight. The mixture was then filtered through celite, and the filtrate was concentrated. This gave 166 mg (87% of theory) of the target compound as a yellowish oil.
Reaction SMILES: CN(C)C=O.Br[C:7]1[C:16]([O:17][C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[N:21]=[CH:20][CH:19]=2)=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.C([Sn](CCCC)(CCCC)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)CCC>[Cu]=O.O>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][CH:19]=[C:18]2[O:17][C:16]1[C:7]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3Br)c2cc1OC
Agent: O=[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3-c3ccccn3)c2cc1OC
Temperature: 100 °C
Reaction time: 8 h
Yield: 14.6 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 4-(2-bromo-quinolin-3-yloxy)-6,7-dimethoxy-quinoline (35 mg), tetrakistriphenylphosphine palladium (9.8 mg), tri-n-butyl-(2-pyridyl)-tin (63 mg), and copper(II) oxide (14 mg) under an argon atmosphere, and the mixture was stirred at 100° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-acetone. The purification product was then dissolved in methanol, and the solution was added dropwise to water. The precipitate was collected by filtration to give the title compound (5.1 mg, yield 15%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:16]I>CN(C)C=O.O>[CH3:13][O:12][C:10]([C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][N:1]2[CH3:16])=[CH:5][CH:6]=1)=[O:11]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2ccn(C)c2c1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of methyl 6-indolecarboxylate (5 g) in dry dimethylformamide (30 ml) cooled to 5° C., sodium hydride (60% dispersion in oil, 1.49 g) was added portionwise. The reaction mixture was stirred at 5° C. for 0.5 hour, then a solution of methyliodide (12.18 g) in dry dimethylformamide (10 ml) was added dropwise. After 2 hours, the reaction mixture was diluted with water and the product obtained, after cooling and filtration.
Reaction SMILES: [CH2:1]1[C@@H:5]2[C@H:6]3[C:11](=[O:12])[N:10]([OH:13])[C:8](=[O:9])[C@H:7]3[C@H:2]1[CH:3]=[CH:4]2.[O-]CC.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(O)C.CCOCC>[OH:13][N:10]1[C:11](=[O:12])[CH:6]2[CH:7]([CH:2]3[CH2:1][CH:5]2[CH:4]=[CH:3]3)[C:8]1=[O:9]
Reactant: O=C1[C@@H]2[C@H](C(=O)N1O)[C@@H]1C=C[C@H]2C1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CC[O-]
Solvent: CCO
Solvent: CCOCC
Product: O=C1C2C3C=CC(C3)C2C(=O)N1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
endo-N-Hydroxy-5-norbornene-2,3-dicarboximide (NBD) (3.59 g, 20 mmol) is dissolved in absolute ethanol (100 mL), and is then evaporated to dryness in vacuo to remove the residual moisture from the reagent. The residue is redissolved in freshly prepared absolute ethanol (60 mL), and thallous ethoxide (1.42 mL, 20 mmol) is added dropwise with vigorous stirring. The solution is stirred for 3 h at room temperature and then overnight at 4° C. The white precipitate which forms in the course of the reaction is collected by filtration, washed with cold ethanol, and dried under high vacuum. The solid material is suspended in methylene chloride (100 mL), and di-tert-butyl dicarbonate (4.37 g, 20 mmol) is added dropwise. The solution is stirred overnight at room temperature and is then washed with water (2×10 mL). The organic layer is dried over anhydrous MgSO4, filtered, and evaporated to dryness to give the crude product as a white solid. The solid is suspended, with vigorous stirring, in anhydrous ether (60 mL) for 2 h, followed by filtration, to give 3.0 g of the pure product. Upon storage of the filtrate at −20° C. overnight, additional pure product precipitates giving a total of 3.63 g of the title compound in two crops in an overall yield of 65%.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:23]2[CH:30]=[CH:29][C:26]([CH:27]=O)=[C:25]([CH3:31])[CH:24]=2)([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][C:13]=1[CH3:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.Cl.[NH2:45][CH2:46][CH2:47][S:48]([CH3:51])(=[O:50])=[O:49]>CO.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[Si:1]([O:8][CH:9]([C:33]([CH3:34])([CH3:35])[CH3:36])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][NH:45][CH2:46][CH2:47][S:48]([CH3:51])(=[O:50])=[O:49])=[C:25]([CH3:31])[CH:24]=2)([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][C:13]=1[CH3:32])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCC(CC)(c1ccc(C=O)c(C)c1)c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1
Reactant: CS(=O)(=O)CCN
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(CNCCS(C)(=O)=O)c(C)c1)c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1
Reaction time: 1 h
Yield: 50.5 %

Procedure:
To a mixture of 4-(1-{4-[2-(t-butyldimethylsilanyloxy)-3,3-dimethylbutoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzaldehyde (2.40 g, 4.71 mmol), Et3N (0.9 ml, 6.12 mmol), and 2-aminoethylmethylsulfone hydrochloride (0.78 g, 5.18 mmol) is treated with Ti(OiPr)4 (1.8 ml, 6.12 mmol). The mixture is stirred for 1 h, diluted with CH3OH (20 mL), then NaBCNH3 (0.33 g, 5.18 mmol) is added. The mixture is stirred overnight, quenched with H2O (3 mL), stirred for 1 h., and filtered through SiO2 with EtOAc (100 mL) wash. The filtrate is concentrated and chromatographed (75-80% EtOAc) to give the title compound (1.47 g, 2.38 mmol, 51%).
Reaction SMILES: [NH:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].C(=O)([O-])O.[Na+].C1COCC1.[O:20](C(OC(C)(C)C)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O>O>[C:24]([O:23][C:21]([N:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4])=[O:20])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=C(O)CNCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CC(=O)O)CC(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of iminodiacetic acid (5.1 g, 38.3 mmol) and sodium hydrogen carbonate (NaHCO3, 12.9 g, 153 mmol) were dissolved in 50 mL of water. Once the bubbling subsided, 50 mL of THF was added followed by 10.0 g (46.0 mmol) of BOC2O. The mixture was stirred at ambient temperature for 2 days when starting materials were completely consumed as detected by ESI. The reaction was worked up by removing THF and washing the aqueous layer with Et2O twice. The pH of the aqueous layer was then adjusted to 1 using conc. HCl. The product was extracted with EtOAc and solvent removed in vacuo to provide the product as a white solid. The product was purified by crystallization from EtOAc to give 8.04 g (90%) of clear crystals of 27. ES MS [M−H]−232.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([CH2:11][CH3:12])([CH3:10])[CH2:8][CH3:9])=[N:5][N:6]=1.N1C=C[CH:16]=[CH:15][CH:14]=1.[O:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)(=O)C1C=CC=CC=1>[CH2:8]([C:7]([C:4]1[S:3][C:2]([NH:1][C:23](=[O:19])[C:22]2[CH:16]=[CH:15][CH:14]=[CH:20][CH:21]=2)=[N:6][N:5]=1)([CH3:10])[CH2:11][CH3:12])[CH3:9]
Reactant: C1CCOC1
Reactant: c1ccncc1
Reactant: CCC(C)(CC)c1nnc(N)s1
Solvent: O=C(Cl)c1ccccc1
Product: CCC(C)(CC)c1nnc(NC(=O)c2ccccc2)s1
Yield: 35 %

Procedure:
To a stirred suspension of 3.3 g of 2-amino-5-(1-ethyl-1-methylpropyl)-1,3,4-thiadiazole in 30 ml of tetrahydrofuran were added in one portion 2.8 g of benzoyl chloride. The reaction mixture was stirred at room temperature while a solution of 1.6 g of pyridine in 20 ml of tetrahydrofuran was added dropwise over thirty minutes. Following complete addition, the reaction mixture was heated at reflux for three hours. The mixture was then filtered to remove the pyridine hydrochloride, and the filtrate was washed several times with 1N hydrochloric acid solution. The organic layer was separated and the solvent was removed by evaporation under reduced pressure to provide a yellow gum. The gum was crystallized from ethanol and water to afford 1.85 g of N-[5-(1-ethyl-1-methylpropyl)-1,3,4-thiadiazol-2-yl]benzamide.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:24][Mg].[NH4+].[Cl-].CC[O:30][C:31]([CH3:33])=[O:32]>O1CCCC1.CCOCC>[C:31]([OH:32])(=[O:30])/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18].[F:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:31]([CH3:33])([OH:32])[CH3:24])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: C[Mg]
Reactant: CCOC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)CCN1CCC(c2noc3cc(F)ccc23)CC1
Product: O=C(O)/C=C/C(=O)O
Reaction time: 16 h

Procedure:
To a solution of ethyl 3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propionate (3.21 g, 10 mmol) in tetrahydrofuran (THF, 100 ml), was added methylmagnesium bromidde (10 ml, 30 mmol, 3M solution in ether) dropwise over 15 minutes at room temperature under N2. The resulting mixture was stirred for 16 hours. The mixture was slowly hydrolyzed with aqueous NH4Cl solution. The THF solution was diluted with EtOAc (300 ml), then was washed with water and brine. The organic solution was separated and dried over MgSO4. After removal of solvent, the crude product was purified by flash chromatography (25 g, SiO2 ; eluted with 1 CH3OH:99 DCM). The material thus purified weighed 2.36 g (77%) as white crystals. This was converted to the fumarate salt by treatment with fumaric acid (895 mg) in ethanol. Recrystallization from ethanol yielded white crystals, 2.47 g, m.p.=156-158° C.
Reaction SMILES: COC1C=C(C(C2C=CC(OC)=C(OC)C=2)=CC([O-])=O)C=CC=1OC.[CH2:26]([O:28][C:29]1[CH:30]=[C:31]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=O)[CH3:27].C(OP([CH2:53][C:54]#[N:55])(=O)OCC)C.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>>[CH2:26]([O:28][C:29]1[CH:30]=[C:31]([C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:53][C:54]#[N:55])[CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[CH3:27]
Reactant: CCOc1cc(C(=O)c2ccccc2)ccc1OC
Reactant: CCOP(=O)(CC#N)OCC
Agent: COc1ccc(C(=CC(=O)[O-])c2ccc(OC)c(OC)c2)cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCOc1cc(C(=CC#N)c2ccccc2)ccc1OC

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-3-phenylacrylonitrile was prepared analogously to 3,3-bis-(3,4-dimethoxyphenyl)acrylate using 3-ethoxy-4-methoxybenzophenone (1.3 g, 5 mmol), diethylcyanomethylphosphonate (0.9 mL, 5.5 mmol) and lithium hexamethyldisilazide (4.2 mL, 5.5 mmol, 1.3M) with a reaction time of 24 hours at room temperature. The crude mixture was purified by flash column chromatography (silica gel, methylene chloride) to afford 1.35 g (96%) of a mixture of the E and Z isomers as a white solid: mp 74-77° C.; 1H NMR (CDCl3) δ7.50-7.24 (m, 10 H), 7.07-6.75 (m, 6 H), 5.67 (s, 1 H), 5.60 (s, 1 H), 4.15-3.95 (m, 4 H), 3.92 (s, 3 H), 3.89 (s, 3 H), 1.50-1.36 (m, 6 H); 13C NMR (CDCl3) δ162.8, 162.7, 151.4, 150.9, 148.1, 147.1, 147.9, 139.3, 137.1, 131.3, 130.2, 129.9, 129.5, 129.3, 128.6, 128.5, 128.4, 123.1, 122.0, 118.3, 118.2, 113.9, 112.5, 110.9, 93.3, 92.9, 64.4, 55.9, 55.9, 14.6; Anal. Calcd for C18H17NO2. Theoretical: C, 77.40; H, 6.13; N, 5.01. Found: C, 77.14; H, 6.06; N, 4.75.