Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].O1C=C[CH:16]=[C:15]1P(C1OC=CC=1)C1OC=CC=1.[Cl-].[Li+].C([Sn](CCCC)(CCCC)C=C)CCC>CN(C)C=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I>[N+:11]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH:15]=[CH2:16])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: c1coc(P(c2ccco2)c2ccco2)c1
Agent: [Cu]I
Agent: [Pd]
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: C=Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 349.1 %

Procedure:
1-Chloro-2,6-dinitrobenzene (1.00 g, 4.94 mmoles, purchased from Lancaster) tris(dibenzylideneacetone)dipalladium (0.113 g, 0.123 mmoles), tri-2-furylphosphine (0.229 g, 0.987 mmoles), copper(I) iodide (0.094 g, 0.494 mmoles), and lithium chloride (0.628 g, 14.8 mmoles) in N,N-dimethylformamide (15 mL) were treated with tributylethenylstannane (2.90 mL, 9.87 mmoles). The reaction mixture was degassed with nitrogen, stirred overnight at room temperature and then heated at 80° C. for 4 hours. The reaction mixture was then diluted with ethyl acetate and washed with water and brine. The organic phase was dried with sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 10% ethyl acetate/hexanes) to provide the title compound (0.669 g, 70%). MS (DCI) m/z 194 (M+H)+.
Reaction SMILES: Br[N:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][CH2:3]1.[O-:9][CH2:10][CH3:11].[Na+].CN(C)C=O.O>C(OCC)C>[Br:8][C:6]1[CH:7]=[N:2][CH:3]=[C:4]([O:9][CH2:10][CH3:11])[CH:5]=1
Reactant: BrC1=CN(Br)CC=C1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCOc1cncc(Br)c1
Temperature: 65 °C
Yield: 17.9 %

Procedure:
1,5-Dibromopyridine (98%) was purchased from Lancaster Chemical Company. Sodium ethoxide (96%) and N,N-dimethylformamide (DMF) (99.9+ %. HPLC grade) were purchased from Aldrich Chemical Company. Under a nitrogen atmosphere, a mixture of3,5-dibromopyridine (5.00 g, 21.1 mmol). sodium ethoxide (2.87 g, 42.2 mmol), and DMF (10 mL) was stirred and heated at 65° C. for 15 h. The mixture was poured into water (70 mL), and anhydrous diethyl ether (155 mL) was added. Because of insoluble solids, it was necessary to filter both phases. The aqueous layer was separated and extracted with ether (2 ×25,3 ×50 mL). The combined ether extracts were dried (MgSO4), filtered, and concentrated by rotary evaporation, producing a dark-brown syrup. The brown residue was purified by vacuum distillation, affording 0.76 g (17.9%) of an oil, bp 105° C. at 5 mm Hg. 1HNMR(CDCl3): δ 9.12 (br s, 1H), 8.83 (br s, 1H), 8.42 (dd, 1H), 4.41(q,2H), 1.42(t, 3H). 13C NMR (CDCl3): δ 142.72, 136.50. 1.23.78. 64.31.14.:57.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14](OC)=[O:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([S:21][CH3:22])[N:9]=2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14][OH:15])=[C:12]([CH:18]([CH3:20])[CH3:19])[N:11]=[C:10]([S:21][CH3:22])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(SC)nc1C(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CSc1nc(-c2ccc(F)cc2)c(CO)c(C(C)C)n1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
20 g (62.5 mmol) of methyl 4-(4′-fluorophenyl)-6-isopropyl-2-methylthio-pyrimidin-5-yl-carboxylate (10) and 300 mL of dry anhydrous toluene were loaded in a IL three-neck round bottomed flask, equipped with a mechanical stirrer and an air duct, and stirred under a nitrogen atmosphere. 100 mmol of diisobutyl aluminum hydride (DIBAI-H) was then added in batches into the mixture while cooling in an ice-salt bath. After TLC assay showed that the starting compound (10) was depleted, the reaction mixture was warmed up to room temperature and further reacted for 2-3 hours. 500 mL of water was then added, and the organic layer was collected, washed with water (200 mL×2) and a saturated solution of sodium chloride (200 mL×1), and then dried overnight over anhydrous magnesium sulfate. The mixture was then filtered, evaporated under reduced pressure to remove the solvent, and recrystallized in ethyl acetate, obtaining 16 g of a white crystal, yield 88%.
Reaction SMILES: [C:1]([O:5][CH:6]=[CH2:7])([CH3:4])([CH3:3])[CH3:2].[C:8]([OH:13])(=[O:12])[C:9]([CH3:11])=[CH2:10]>>[C:8]([O:13][CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH3:7])(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: C=COC(C)(C)C
Reactant: C=C(C)C(=O)O
Product: C=C(C)C(=O)OC(C)OC(C)(C)C

Procedure:
The reaction procedure of Example 1 was repeated using equimolar amounts of tert-butylvinyl ether and methacrylic acid. The structure of the product, 1-tert-butoxyethyl methacrylate (Compound D) was obtained in 79% yield. Compound D is an example of a mono-functional alpha-alkoxyalkyl(meth)acrylate which may optionally be included with multi-functional alpha-alkoxyalkyl(meth)acrylate compounds in compositions of the present invention. The structure of Compound D was confirmed by 1H NMR and infrared spectral analysis.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[CH2:23]O>>[F:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[CH2:23][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(CO)c(F)c1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Product: Cc1ccc(COc2ccnn2-c2cc(C#N)ccn2)c(F)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2-fluoro-4-methylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 2.36 (3H, s), 5.26 (2H, s), 5.80 (1H, d, J=2.0 Hz), 6.93 (1H, d, J=11.2 Hz), 6.98 (1H, d, J=8.0 Hz), 7.31-7.35 (1H, m), 7.38 (1H, dd, J=1.2 Hz, 4.8 Hz), 7.57 (1H, d, J=1.6 Hz), 8.01 (1H, s), 8.69 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H13FN4O, 309; Found, 309.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:14]([NH:16][C@H:17]([C:21]([OH:23])=O)[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH3:24][O:25][C:26](=[O:39])[C@@H:27]1[CH2:31][CH:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:29][NH:28]1.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C=O.C(OCC)(=O)C.ClCCl>[CH3:24][O:25][C:26](=[O:39])[C@@H:27]1[CH2:31][CH:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:29][N:28]1[C:21](=[O:23])[C@H:17]([CH:18]([CH3:19])[CH3:20])[NH:16][C:14](=[O:15])[C@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[NH:4][C:1](=[O:3])[CH3:2]
Reactant: COC(=O)[C@@H]1CC(Oc2ccccc2)CN1
Reactant: CC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](C(=O)O)C(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CC(Oc2ccccc2)CN1C(=O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(C)=O)C(C)C
Reaction time: 18 h
Yield: 46.3 %

Procedure:
N-Acetyl-tyrosinyl-valine (0.524 g, 1.63 mmol) and 4-phenoxyproline methyl ester (0.381 g, 1.48 mmol) were dissolved in 4 ml each of dimethylformamide and dichloromethane and cooled to 0° C. To the cooled solution was added diisopropylethylamine (258 ul, 1.86 mmol), HOBT (0.24 g, 1.78 mmol), and EDC (0.37 g, 1.92 mmol) and the reaction was stirred for 18 hrs. The mixture was diluted with 400 ml of ethyl acetate and washed with water, 10% sodium hydrogen sulfate, 10% sodium bicarbonate, and water. The organic layer was concentrated to give a residue that was purified by flash chromatography (SiO2) eluting with 94:6:1 (CH2Cl2:i-PrOH:Pyridine) to afford 360 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=O)[C:8]3[N:9]2[CH:12]=[CH:13][N:14]=3)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:31])=O>O.[OH-].[Na+]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([Cl:31])[C:8]3[N:9]2[CH:12]=[CH:13][N:14]=3)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17]
Reactant: O=c1[nH]c2cc(C(F)(F)F)c(Br)cc2n2ccnc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)c1ccccc1
Product: FC(F)(F)c1cc2nc(Cl)c3nccn3c2cc1Br
Temperature: 120 °C
Yield: 80.4 %

Procedure:
8-Bromo-7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-4(5H)-one (9.4 g, 0.0283 mol) is stirred under nitrogen with N,N-dimethylaniline (14.5 mL, 0.1123 mol) and phosphoryl chloride (190 mL, 2.0119 mol) at reflux (120° C.) for 1.5 hour. After cooling down to room temperature, the mixture is slowly poured in a mixture of water (2 L) and sodium hydroxide 5N (1 L) below 10° C. The mixture is extracted four times with ethyl acetate (200 mL) and the combined organic phases are washed with water (200 mL), dried over sodium sulfate and concentrated to about 100 mL. Cyclohexane (500 mL) is added at room temperature. The mixture is cooled to 0-5° C. and filtered. The cake is washed with cyclohexane and dried under vacuum to afford the title compound as a yellow solid (7.98 g, 80.4%)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[CH:8]=[CH:9][C:10]=1[S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12])(=O)[CH3:2]>C1COCC1>[CH2:1]([NH:4][C:5]1[CH:6]=[C:7]([N:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:24][CH2:25]2)[CH:8]=[CH:9][C:10]=1[S:11]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])[CH3:2]
Reactant: CC(=O)Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1S(=O)(=O)c1ccccc1
Solvent: C1CCOC1
Product: CCNc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To a mixture of tert-butyl 4-[3-(acetylamino)-4-(phenylsulfonyl)phenyl]-1-piperazinecarboxylate (0.44 g, 0.96 mmol) in 7 nL of dry THF is added borane-methyl sulfide complex (0.28 mL, 2.8 mmol, 10.0 M). The mixture is stirred at rt overnight. The reaction is quenched upon dropwise addition of 10% HCl. Water (3.0 mL) and KOH (2.0 g) are added, the mixture heated at reflux for 6 h. At that time methanol (2 mL) is added and the mixture stirred at reflux overnight. After cooling to rt, the organics are removed under reduced pressure, the aqueous layer is saturated with NaCl, and extracted with CH2Cl2 (3×10 mL). The combined organic layers are dried over MgSO4, filtratered, and concentrated to give the crude product. Purification by column chromatography (15% EtOAc/hexane) gave 0.18 g (43%) of the pure title compound as an oil.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[CH:21]=[N:22][C:23]([NH:26][C@@H:27]([CH3:30])[CH2:28][OH:29])=[N:24][CH:25]=1>>[OH:29][CH2:28][C@@H:27]([NH:26][C:23]1[N:24]=[CH:25][C:20]([NH:19][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:21][N:22]=1)[CH3:30]
Reactant: C[C@@H](CO)Nc1ncc(N)cn1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Product: C[C@@H](CO)Nc1ncc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 43 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [2-((S)-2-hydroxy-1-methyl-ethylamino)-pyrimidin-5-yl]-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and (S)-2-(5-amino-pyrimidin-2-ylamino)-propan-1-ol. LCMS calcd for C18H16F3N5O3 (m/e) 407, obsd 408 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9])[CH2:2][CH:3]=[CH2:4].[BH4-].[Na+]>CO>[CH2:1]([C:5]1[CH:6]=[C:7]([CH2:8][OH:9])[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C=CCCc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
A mixture of 3-(but-3-en-1-yl)benzaldehyde (300 mg, 1.873 mmol) in MeOH (5 mL) was added sodium borohydride (142 mg, 3.75 mmol) and the mixture was stirred at rt for 1 h. It was then added water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 10% EtOAc/hexane to obtain (3-(but-3-en-1-yl)phenyl)methanol (167 mg, 1.029 mmol, 55.0% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.45-7.10 (m, 4H), 5.88 (ddt, J=17.0, 10.4, 6.5 Hz, 1H), 5.15-4.94 (m, 2H), 4.70 (br. s., 2H), 2.84-2.71 (m, 2H), 2.48-2.34 (m, 2H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:9](Cl)=[O:10].[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:14]1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][CH:13]([NH:12][C:9]([C@@H:2]3[CH2:3][CH:4]4[CH2:7][CH2:8][N:1]3[CH2:6][CH2:5]4)=[O:10])[CH2:14]2)=[CH:21][CH:22]=1
Reactant: O=C(Cl)C1CC2CCN1CC2
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Product: O=C(NC1CCN(CCc2ccc(F)cc2)C1)[C@@H]1CC2CCN1CC2

Procedure:
Quinuclidine-2-carbonyl chloride and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 53 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-quinuclidine-2-carboxamide.
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:4][CH:3]1[C:5](=O)[CH2:6][C:7]#[N:8].[NH2:11][NH2:12]>C(O)C>[F:1][C:2]1([F:10])[CH2:4][CH:3]1[C:5]1[CH:6]=[C:7]([NH2:8])[NH:12][N:11]=1
Reactant: N#CCC(=O)C1CC1(F)F
Reactant: NN
Solvent: CCO
Product: Nc1cc(C2CC2(F)F)n[nH]1
Yield: 82.1 %

Procedure:
Crude 3-(2,2-difluorocyclopropyl)-3-oxo-propionitrile (2 g) was dissolved in ethanol (18 mL) and treated with hydrazine (2.5 mL, 0.050 mol) at reflux for 24 hours. The reaction mixture was concentrated, diluted with brine and extracted into ethyl acetate (2×50 mL). The combined organic layers were dried (MgSO4), concentrated and purified by silica gel chromatography eluting with 1-15% methanol in methylene chloride to afford 3-(2,2-difluorocyclopropyl)-1H-pyrazol-5-amine (1.8 g, 54% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=O)=[CH:5][C:4]=1[CH3:25].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27].C1(C)C(C)=CC=CC=1>C1CCCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[S:27])=[CH:5][C:4]=1[CH3:25]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccccc2)cc1C
Solvent: Cc1ccccc1C
Solvent: C1CCCCC1
Product: COc1ccc(C(=CC(=S)N2CCOCC2)c2ccccc2)cc1C

Procedure:
6.75 g (20 mmols) of 3-(4-methoxy-3-methylphenyl)-3-phenylacrylic acid morpholide and 2.22 g (10 mmols) of finely ground phosphorus pentasulfide were refluxed unit 50 ml of absolute xylene for 3 horus. After cooling, the insoluble matter was filtered off, and the filtrate was washed with water, dried and concentrated by evaporation in vacuo. This concentrate was purified on a silica gel column. Elution was carried out first with toluene and then with a toluene/diisopropylether mixture in the proportions 90:10, then in the proportions 80:20. The fractions containing the substance with Rf 0.59 (toluene/diisopropylether 1:1) were concentrated by evaporation in vacuo, and the yellow oil obtained thereby was dissolved in cyclohexane, while heating. Upon cooling, the desired substance crystallized out.
Reaction SMILES: C[O:2][C:3](=[O:30])[C@:4]([CH3:29])([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)=[CH:20][CH:19]=1)[N:5]([C:7](=[O:16])[C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)[CH3:6].[OH-].[K+]>C(O)C.O>[CH3:14][C:12]1[CH:13]=[C:8]([CH:9]=[C:10]([CH3:15])[CH:11]=1)[C:7]([N:5]([CH3:6])[C@:4]([CH3:29])([C:3]([OH:30])=[O:2])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:28]=[CH:27][S:26][CH:25]=2)=[CH:20][CH:19]=1)=[O:16]
Reactant: COC(=O)[C@](C)(Cc1ccc(-c2ccsc2)cc1)N(C)C(=O)c1cc(C)cc(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)cc(C(=O)N(C)[C@@](C)(Cc2ccc(-c3ccsc3)cc2)C(=O)O)c1

Procedure:
A stirred solution of N-(3,5-dimethylbenzoyl)-N-methyl-2-methyl-3-[4-(3-thienyl)phenyl]alanine methyl ester (100 mg, 0.245 mmol) and potassium hydroxide (40 mg, 0.72 mmol) in ethanol (5 ml) is refluxed overnight. The mixture is diluted with water and washed with ether. The aqueous layer is washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give the corresponding crude N-(3,5-dimethylbenzoyl)-N-methyl-2-methyl-3-[4-(3-thienyl)phenyl]alanine
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:34][N:35]1[CH2:41][CH:40]2[NH:42][CH:37]([CH2:38][CH2:39]2)[CH2:36]1>>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:42]4[CH:40]5[CH2:39][CH2:38][CH:37]4[CH2:36][N:35]([CH3:34])[CH2:41]5)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CN1CC2CCC(C1)N2
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CN1CC2CCC(C1)N2C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-methyl-3,8-diaza-bicyclo[3.2.1]oct-8-yl)-thiazol-4-one was prepared from 5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and 3-methyl-3,8-diaza-bicyclo[3.2.1]octane following General Procedure C.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]([OH:14])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[CH3:12][O:11][C:9](=[O:10])[C:8]1[CH:13]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[O:14][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(C(C)=O)ccc1OCc1ccccc1
Temperature: 85 °C
Yield: 100 %

Procedure:
Methyl 5-acetylsalicylate (100 g, 0.515 mol) was dissolved in acetonitrile (1 L) in a 2 L flask under reflux conditions and a nitrogen atmosphere. Potassium carbonate (213.5 g, 1.545 mol) was added portion-wise over 15 min. Benzyl bromide (67.4 mL, 0.566 mol) was added using a dropping funnel over 15 min. The reaction was heated to 85° C. for 9 h, and then filtered and rinsed with acetonitrile (100 mL). The solution was concentrated to about 300 mL volume under reduced pressure and partitioned between water (1 L) and ethyl acetate (1 L). The organic layer was washed with saturated sodium chloride (250 mL), dried using magnesium sulfate (75 g), and then filtered and rinsed with ethyl acetate (100 mL). The organic layer was concentrated to give 2-benzyloxy-5-acetylbenzoic acid methyl ester as a solid (100% yield).
Reaction SMILES: C([O:5][C:6](=[O:53])[CH2:7][CH2:8][S:9][CH2:10][CH:11]([O:35][C:36](=[O:52])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][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][CH3:33])(C)(C)C.ClCCl>FC(F)(F)C(O)=O>[CH2:16]([NH:15][C:14]([O:13][CH2:12][CH:11]([O:35][C:36](=[O:52])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:10][S:9][CH2:8][CH2:7][C:6]([OH:53])=[O:5])=[O:34])[CH2:17][CH2:18][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][CH3:33]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CSCCC(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of 7-octadecylcarbamoyloxy-6-palmitoyloxy-4-thiaheptanoic acid t-butyl ester as obtained in Reference Example 8 (3.425 g) in trifiuoroacetic acid (5 ml)-dichloromethane (3 ml) was stirred at room temperature for 1 hour, followed by solvent concentration under reduced pressure, to yield the title compound (3.14 g, yield 99%) as a colorless solid.
Reaction SMILES: [C:1]([C:3](=[CH:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[C:4]([NH:6][C:7](=O)[O-:8])=[O:5])#[N:2].C(N(CC)CC)C>C(#N)C>[O:8]=[C:7]1[NH:6][C:4](=[O:5])[C:3]([C:1]#[N:2])=[CH:10][N:11]1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1
Reactant: N#CC(=CNc1cccc(C(F)(F)F)c1)C(=O)NC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1cn(-c2cccc(C(F)(F)F)c2)c(=O)[nH]c1=O
Reaction time: 6 h
Yield: 91.9 %

Procedure:
To a suspension of 2-cyano-3-(3-(trifluoromethyl)phenylamino)acryloylcarbamate (prepared in Reference Example 111) (26.2 g) in acetonitrile (300 ml) was added triethylamine (111 ml) and the resulting mixture was stirred for six hours with heating under reflux. The reaction solutions were concentrated under reduced pressure, and to the residue was added 1M hydrochloric acid and the resulting mixture was extracted with ethyl acetate twice. The organic layer was washed with 1M hydrochloric acid and saturated saline. The resulting mixture was dried over anhydrous magnesium and then concentrated under reduced pressure to afford 2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-carbonitrile (22.7 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([F:12])=[CH:5]2.C([O:15][B:16](OCC)[O:17]CC)C.C([Li])CCC>C1COCC1>[F:12][C:6]1[N:7]=[CH:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([B:16]([OH:17])[OH:15])=[CH:11][CH:10]=2
Reactant: Fc1cc2cc(Br)ccc2cn1
Reactant: CCOB(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2cnc(F)cc2c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
A solution of 6-bromo-3-fluoroisoquinoline (9.10 g, 40.3 mmol) and triethylborate (11.8 g, 80.5 mmol) in THF (100 mL) was cooled to −78° C. Butyllithium (1.6 M in hexanes 50.3 mL, 80.5 mmol) was added dropwise over 45 minutes. Over the course of the addition, the solution changed color from colorless to a light tan. The solution was stirred at −78° C. for 3 hours. The mixture was quenched with HCl (5 N, 120 mL) while in the cold bath at −78° C., diluted with water (100 mL), and then extracted with EtOAc (3×200 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated. The solid residue was triturated with DCM (200 mL), and the solid was recovered by filtration to provide the title compound (6.0 g, 78%). LCMS (API-ES) m/z: 192 (M+H+).
Reaction SMILES: [CH:1]1[C:6](/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[C:11](N2CCCCC2)=[O:12])=[CH:5][C:4]2[O:19][CH2:20][O:21][C:3]=2[CH:2]=1.[OH-:22].[K+].CO.Cl>O>[CH2:20]1[O:19][C:4]2[CH:5]=[C:6](/[CH:7]=[CH:8]/[CH:9]=[CH:10]/[C:11]([OH:12])=[O:22])[CH:1]=[CH:2][C:3]=2[O:21]1
Reactant: O=C(/C=C/C=C/c1ccc2c(c1)OCO2)N1CCCCC1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)/C=C/C=C/c1ccc2c(c1)OCO2

Procedure:
To piperine (1) (2 g, 0.7 mmol, 1 eq), 20% of methanolic KOH (100 ml) was added and refluxed for 2 days. After completion of the hydrolysis, methanol was removed under reduced pressure and a yellow coloured oily solid was obtained. This residue was dissolved in water (50 ml) and acidified with 6N HCl to pH<1 yielding a yellowish precipitate of piperinic acid. Recrystallization from methanol gave yellow needles (0.9 g, 60% yield). m.p. 206°-208° C. (Lit m.p. 217°-218° C.)1