Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([C:31]#[CH:32])[CH:28]=[CH:29][CH:30]=1.C(N(CC)CC)C>CN(C)C=O.[Cu](I)I.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]>[F:23][C:24]([F:33])([F:34])[C:25]1[CH:26]=[C:27]([C:31]#[C:32][C:2]2[N:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]3=[N:4][C:3]=2[CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])[CH:28]=[CH:29][CH:30]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nc2ccccn2c1I
Reactant: C#Cc1cccc(C(F)(F)F)c1
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.8 %

Procedure:
In a flask placed under an argon flow, 2.1 g (5.21 mmol) of 2-((3-iodoimidazo[1,2-a]pyridin-2-yl)methyl)isoindoline-1,3-dione were solubilised in 11 ml of dimethylformamide with magnetic stirring. To this solution, were added: 0.008 g (0.04 mmol) of copper iodide, 0.921 ml (6.25 mmol) of 3-trifluoromethylphenyl acetylene and 10.89 ml (78 mmol) of triethylamine. The reaction medium was degassed with argon for 10 min before adding 0.477 g (0.521 mmol) of Pd2(dba)3. The mixture was stirred at r.t. for 16 h before being filtered on a silica gel cartridge which was then rinsed with 300 ml of ethyl acetate. The organic phase was washed with 3×150 ml of a saturated NaCl aqueous solution, and then dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: heptane/ethyl acetate gradient, from 50% to 40% of heptane, v/v). 1.41 g (yield=59%) of 2-((3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methyl) isoindoline-1,3-dione were obtained as a brown solid. LC-MS: m/z=446 (MH+); UV purity at 254 nm=97%. 1H NMR (300 MHz, DMSO) δ 8.67 (d, J=6.7 Hz, 1H), 7.91 (dd, J=5.6, 3.0 Hz, 2H), 7.82 (dd, J=5.5, 3.1 Hz, 2H), 7.69 (dd, J=12.5, 8.5 Hz, 2H), 7.63-7.52 (m, 2H), 7.52-7.42 (m, 2H), 7.13 (td, J=6.8, 1.1 Hz, 1H), 5.09 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11]O)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH2:11][Br:32])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=[N+]([O-])c1cc(Br)cc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(Br)cc(CBr)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(3-Bromo-5-nitrophenyl)methanol (2.0 g, 8.65 mmol) and triphenylphosphine (4.5 g, 17.3 mmol) were combined in tetrahydrofuran (40 mL) and cooled to 0° C. N-Bromosuccinimide (3.2 g, 18.2 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with concentrated sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (5% ethyl acetate/hexanes) gave 2.2 g (84%) as a white powder. 1H-NMR (CDCl3, 300 MHz) 8.27 (s, 1H), 8.16 (s, 1H), 7.84 (s, 1H), 4.45 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[CH2:8][CH2:7]1.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(OC2CCN(CC3CCNCC3)CC2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
1,1-Dimethylethyl 4-[[4-(3,4-dichlorophenoxy)-1-piperidinyl]methyl]-1-piperidinecarboxylate (1.0 g) was added to a mixture of 20% TFA in dichloromethane (20 mL) and the mixture was stirred at room temperature for 1 h. Solvent was removed by evaporation and 2M sodium hydroxide solution (25 mL) was added to the residue. Product was extracted with ethyl acetate. The organic phase was washed with brine, dried, filtered and evaporated to give the title compound (0.5 g).
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[O:7])[CH2:2][CH2:3][CH3:4].[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:27][CH2:28][CH2:29][CH3:30])[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[C:17]=2[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1>>[NH2:8][C:9]1[C:18]2[N:19]=[C:20]([CH2:27][CH2:28][CH2:29][CH3:30])[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[C:17]=2[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Reactant: CCCCN=C=O
Product: CCCCNC(=O)NCCCCn1c(CCCC)nc2c(N)nc3cccnc3c21
Yield: 65.8 %

Procedure:
Using the general method of Example 47, butyl isocyanate (54 μL, 0.48 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.15 g, 0.48 mmole) to provide 0.13 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-butylurea as a white solid. Analysis: Calculated for C22H33N7O: %C, 64.21; %H, 8.08; %N, 23.82; Found: %C, 64.05; %H, 7.97; %N, 24.00.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[C:11]=2[O:19][CH3:20])=[CH:8][CH:9]=1)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:11]=2[O:19][CH3:20])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2cccc([N+](=O)[O-])c2OC)o1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(-c2cccc(N)c2OC)o1
Yield: 83.1 %

Procedure:
5-(2-Methoxy-3-nitro-phenyl)-furan-2-carboxylic acid methyl ester 54a (500 mg, 1.8 mmol) was dissolved in methanol followed by addition of 50 mg of palladium on carbon. The reaction mixture was heated to reflux for 4 hours under hydrogen atmosphere. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure. The resulting residue was recrystallized from a solvent mixture of ethyl acetate/n-hexane (V:V=1:5) and dried to obtain the title compound 5-(3-amino-2-methoxy-phenyl)-furan-2-carboxylic acid methyl ester 54b (370 mg, yield 83%) as a white solid.
Reaction SMILES: FC(F)(F)C([C:5](=[CH:11][N:12]([CH3:14])[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.FC(F)(F)C(=O)CC(OCC)=O>C(O)(=O)C>[CH3:13][N:12]([CH:11]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:14]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)C(F)(F)F
Agent: CCOC(=O)CC(=O)C(F)(F)F
Solvent: CC(=O)O
Product: CCOC(=O)C=CN(C)C

Procedure:
I have found surprisingly conditions which allow the preparation of ethyl 2-trifluoroacetyl-3-(N,N-dimethylamino)-2-propenoate (2) from ethyl trifluoroacetoacetate and DMF acetals according to a general one-step reaction. Specifically, I found that compound 2 can be prepared in good yields (61-85%) by reacting ethyl trifluoroacetoacetate with DMF acetals in the presence of an organic acid such as acetic acid. While not wishing to be bound by theory, the success of this reaction condition appears to lie in the suppression of the loss of the trifluoroacetyl group from (2) through the attack of the alcohol by-products. In the absence of the organic acid, ethyl 3-(N,N-dimethylamino)-2-propenoate (4) is formed as the major product in all cases. My overall result is shown in Scheme 2.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:39])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[N:19]=[C:15]3[C:14]([CH3:27])=[C:13]([CH3:28])[C:12]=2[C@H:29]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:30]([O:32][CH3:33])=[O:31])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:40][C:41]1[CH:46]=[C:45]([F:47])[CH:44]=[C:43]([O:48][C@H:49]([CH2:51][CH:52]=[CH2:53])[CH3:50])[C:42]=1B1OC(=O)CN(C)CC(=O)O1.C(OC1(C)CCN(C2N3C=C(C4C=C(C5C=C(F)C(F)=CC=5O[C@H](CC=C)C)C=CC=4)N=C3C(C)=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)CC1)C=C>>[CH2:1]([O:4][C:5]1([CH3:39])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:42]5[C:43]([O:48][C@H:49]([CH2:51][CH:52]=[CH2:53])[CH3:50])=[CH:44][C:45]([F:47])=[CH:46][C:41]=5[F:40])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[C:14]([CH3:27])=[C:13]([CH3:28])[C:12]=2[C@H:29]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:30]([O:32][CH3:33])=[O:31])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@H](C)Oc1cc(F)cc(F)c1B1OC(=O)CN(C)CC(=O)O1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(Br)c4)cn23)CC1
Agent: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(-c5cc(F)c(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(-c5c(F)cc(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Yield: 99 %

Procedure:
Prepared from (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate and (S)-2-(2,4-difluoro-6-(pent-4-en-2-yloxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione in 99% yield following the same procedure as (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′,5′-difluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. LCMS (ESI, M+1): 716.4.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:20][CH3:21])=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:27]=[C:26]([CH2:28][C:29]([OH:31])=[O:30])[NH:25][N:24]=1.C(OCC)C>CC(N(C)C)=O.Cl.O1CCOCC1>[CH3:21][O:20][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH2:28][C:29]([OH:31])=[O:30])[CH:27]=3)=[N:3][CH:4]=[N:5]2)=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:9]=1
Reactant: COc1cc(OC2CCN(C)CC2)c2c(Cl)ncnc2c1
Reactant: Nc1cc(CC(=O)O)[nH]n1
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: COc1cc(OC2CCN(C)CC2)c2c(Nc3cc(CC(=O)O)n[nH]3)ncnc2c1
Yield: 91.3 %

Procedure:
4-chloro-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinazoline (307 mg, 0.85 mmol) was condensed with (3-amino-1H-pyrazol-5-yl)acetic acid (132 mg, 0.93 mmol) in dimethylacetamide (3 ml) and hydrochloric acid in dioxane (4.0 N solution, 467 μl) at 90° C. for 1 hour. The solvent was evaporated, and the residual oil was triturated with ethanol:diethyl ether to yield [5-({7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinazolin-4-yl}amino)-1H-pyrazol-3-yl]acetic acid as a beige solid (320 mg, 78% yield):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([OH:13])[CH:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:17])(=O)=O>O1CCCC1.C1C=CC=CC=1>[Cl:17][C:9]1[C:10]([OH:13])=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: Oc1cc(-c2ccc(Cl)cc2)on1
Reactant: O=S(=O)(Cl)Cl
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: Oc1noc(-c2ccc(Cl)cc2)c1Cl
Temperature: 5 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a solution of 5-(4-chlorophenyl)-3-hydroxyisoxazole (50.0 g) in dry tetrahydrofuran (300 ml), a solution of sulfuryl chloride (34.5 g) in dry benzene (50 ml) was added dropwise with stirring at 5° C. The resulting mixture was stirred at the same temperature for 30 minutes and then at room temperature for one hour and further refluxed for 3 hours. The solvent of the reaction mixture was evaporated under reduced pressure, and the solid thus obtained was recrystallized from ethanol to obtain the title compound (44.2 g, 76.8%) as colorless needle-like crystals.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[C:10]3=[N:9][C:8]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+].Cl>C1COCC1.CO.O>[C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:10]3=[N:9][C:8]=2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCCCCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 7-(2,3-diphenyl-7,8-dihydropyrido[3,2-b]pyrazin-5(6H)-yl)heptanoate (step 2)(6.1 g, 13.8 mmol) in THF (300 ml) and MeOH (100 ml) was treated with a solution of lithium hydroxide monohydrate (3.5 g, 83 mmol) in water (100 ml). The reaction mixture was heated at reflux for 5 h and allowed to cool to room temperature. The pH of the mixture was adjusted to <pH5 using 2M HCl. The volatile solvents were removed in vacuo and the remaining residue was diluted with water (50 ml) and extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield a greenish grey solid. The crude material was dissolved in MeOH (30 ml) and purified in 2 portions on a cartridge packed with 113 g LiChroprep® RP-18 (40-63 μm, supplier Merck, reverse phase column) eluting with 10-100% MeCN in water. The resulting solid was re-crystallized from a hot mixture of EtOH (120 ml) and water (90 ml). After seeding and stirring for 1 h at 5° C., the crystals were filtered off and the product dried for 2 days at 40° C. in a vacuum oven to afford the title compound;
Reaction SMILES: [Br:1][CH2:2][CH:3]=[CH:4][CH2:5]Br.[CH2:7]([O:9][P:10]([O:14]CC)[O:11][CH2:12][CH3:13])[CH3:8]>>[CH2:7]([O:9][P:10]([CH2:5][CH:4]=[CH:3][CH2:2][Br:1])(=[O:14])[O:11][CH2:12][CH3:13])[CH3:8]
Reactant: BrCC=CCBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CC=CCBr)OCC
Yield: 55.2 %

Procedure:
A solution of 1,4-dibromo-2-butene (20 g, 93.5 mmol) and triethylphosphite (23.7 g, 142.6 mmol) is heated at 85° C. under reduced pressure for four hours. The reaction mixture is purified directly on silica gel using ethyl acetate as eluant to give 14 g of a clear oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=O)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27]C)=[O:25])C.[C:30](=O)([O-])[O-].[K+].[K+].C/C(/[O-])=C(/P(OC)(OC)=O)\[N+]#N>CO>[CH3:1][O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[CH:30])[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCC=O)c1CCC(=O)OCC
Agent: COP(=O)(OC)/C([N+]#N)=C(/C)[O-]
Agent: [K+]
Solvent: CO
Product: C#CCCCCCc1cccc(OCCCC(=O)OC)c1CCC(=O)OC
Temperature: 0 °C
Reaction time: 5 h
Yield: 71.3 %

Procedure:
To a solution of 4-[2-(2-ethoxycarbonyl-ethyl)-3-(6-oxo-hexyl)-phenoxy]-butyric acid ethyl ester (7.0 g, 17.24 mmol) was added a solution of potassium carbonate (7.14 g, 51.72 mmol) in MeOH (200 mL) and the resulting mixture was cooled to 0° C. Then the Ohira's reagent (ref. cited in Synlett, 1996, 521) (6.3 g, 32.8 mmol) in MeOH (50 mL) was added slowly. The cooling bath was removed upon the end of addition and the reaction mixture was stirred at room temperature for 5 hr. The reaction was then extracted into ethyl acetate and washed with brine. The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by column chromatography using 50% ethyl acetate-hexanes as eluant to give the title compound (4.6 g, 71%) as a light yellow oil.
Reaction SMILES: C(OO)(=[O:3])C.[CH3:6][C:7](=[CH:9][CH2:10][CH2:11][CH:12]([CH2:14][CH2:15][OH:16])[CH3:13])[CH3:8].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:13][CH:12]([CH2:11][CH2:10][CH:9]1[O:3][C:7]1([CH3:8])[CH3:6])[CH2:14][CH2:15][OH:16]
Reactant: CC(C)=CCCC(C)CCO
Reactant: CC(=O)OO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(CCO)CCC1OC1(C)C
Reaction time: 4 h
Yield: 83 %

Procedure:
210 g (1.1 M) of 40% peracetic acid were added dropwise within 1 h to a stirred suspension of 156 g (0.95 M; purity 95%) of citronellol kept at 0° and 53 g (0.5 M) of sodium carbonate in 200 ml of toluene. The reaction mixture was kept under stirring at 20° during 4 h then it was washed with water, a 5% solution of sodium sulfite and a 10% aqueous solution of NaHCO3. After drying over anhydrous sodium sulfate, evaporation of the solvent and distillation (70°-78°/20×102Pa), 139 g (yield 83%; purity 98%) of the desired epoxyde were obtained.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].Br[C:10]1[S:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:14]=1.[OH-].[Na+]>C(OCC)(=O)C.O1CCCC1>[F:3][C:4]([F:8])([F:7])[CH2:5][O:6][C:10]1[S:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][N:14]=1
Reactant: OCC(F)(F)F
Reactant: COC(=O)c1cnc(Br)s1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(OCC(F)(F)F)s1
Yield: 79 %

Procedure:
To a tetrahydrofuran solution (5.0 mL) of sodium hydride (465 mg, 11.6 mmol) and 2,2,2-trifluoroethanol (1.70 mL, 23.3 mmol), methyl 2-bromothiazole-5-carboxylate (517 mg, 2.33 mmol) was added and the resultant mixture was stirred at room temperature for 2 hours. After completion of the reaction, 1 M sodium hydroxide aqueous solution was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of the title compound (444 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]([N:9]([CH3:11])[CH3:10])=[O:8])=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1)(=O)=O>C(#N)C>[Br:1][C:2]1[C:3]([C:7](=[O:8])[N:9]([CH3:11])[CH3:10])=[N:4][N:5]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[CH:6]=1
Reactant: CN(C)C(=O)c1n[nH]cc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)C(=O)c1nn(C2CCN(C(=O)OC(C)(C)C)CC2)cc1Br
Yield: 41.1 %

Procedure:
4-bromo-N,N-dimethyl-1H-pyrazole-3-carboxamide (450 mg), potassium carbonate (456 mg) and tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (900 mg) in acetonitrile (13 mL) were stirred at 90° C. overnight. The mixture was concentrated and the residue was dissolved in ethylacetate, washed with water, brine dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 50 to 90% ethyl acetate in petroleum ether. The solvent was evaporated to dryness to afford tert-butyl 4-[4-bromo-3-(dimethylcarbamoyl)pyrazol-1-yl]piperidine-1-carboxylate (340 mg). NMR Spectrum: (DMSOd6) 1.41 (s, 9H), 1.73 (dd, 1H), 1.78 (dd, 1H), 1.96-1.05 (m, 2H), 2.89 (bs, 2H), 2.95 (s, 3H), 2.87 (s, 3H), 3.92-4.10 (m, 2H), 4.33-4.44 (m, 1H), 8.15 (s, 1H); Mass spectrum: M+H+ 401-403
Reaction SMILES: [C:1]([NH:5][C:6](=[O:12])[C@H:7]([CH:9]([CH3:11])[CH3:10])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH2:13]1[CH2:19][S:16](=[O:18])(=[O:17])[O:15][CH2:14]1>O1CCOCC1>[C:1]([NH:5][C:6]([C@@H:7]([NH:8][CH2:14][CH2:13][CH2:19][S:16]([OH:18])(=[O:17])=[O:15])[CH:9]([CH3:10])[CH3:11])=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H](N)C(=O)NC(C)(C)C
Reactant: O=S1(=O)CCCO1
Solvent: C1COCCO1
Product: CC(C)[C@H](NCCCS(=O)(=O)O)C(=O)NC(C)(C)C
Temperature: 25 °C
Yield: 30.2 %

Procedure:
To a solution of L-valine tert-butylamide (1.87 g, 11.0 mmol) in 1,4-dioxane (20 mL) was added 1,3-propanesultone (1.07 g, 9.0 mmol). The solution was stirred at reflux for 5 hours. The reaction was cooled to room temperature. The solid was collected by filtration, washed with acetone (2×30 mL) and dried in vacuo, affording the title compound (801 mg, 25%). 1H NMR (D2O, 500 MHz) δ ppm 3.43 (m, 1H), 3.00 (m, 2H), 2.85 (m, 2H), 2.03 (m, 3H), 1.21 (m, 9H), 0.92 (d, 3H, J=6.3 Hz), 0.85 (d, 3H, J=6.8 Hz). 13C (D2O, 125 MHz) δ ppm 166.47, 66.55, 52.56, 48.23, 46.11, 29.91, 27.81, 21.29, 18.30, 17.44. [α]D=−11.6° (c=0.0023 in water), ES-MS 293 (M−1).
Reaction SMILES: [CH3:1][CH:2]([CH:4]([NH2:8])[CH:5]([CH3:7])[CH3:6])[CH3:3].[F:9][C:10]1[C:15]([F:16])=[C:14]([C:17](O)=[O:18])[C:13]([F:20])=[C:12]([F:21])[C:11]=1[CH3:22]>>[CH3:1][CH:2]([CH:4]([NH:8][C:17](=[O:18])[C:14]1[C:13]([F:20])=[C:12]([F:21])[C:11]([CH3:22])=[C:10]([F:9])[C:15]=1[F:16])[CH:5]([CH3:7])[CH3:6])[CH3:3]
Reactant: Cc1c(F)c(F)c(C(=O)O)c(F)c1F
Reactant: CC(C)C(N)C(C)C
Product: Cc1c(F)c(F)c(C(=O)NC(C(C)C)C(C)C)c(F)c1F

Procedure:
Prepared in a similar manner to Example 162 using 2,4-dimethylpentan-3-amine and 2,3,5,6-tetrafluoro-p-toluic acid (90%). 1H NMR (CDCl3) δ 0.91 (d, J=6.7 Hz, 6H), 1.00 (d, J=6.8 Hz, 6H), 1.85 (m, 2H), 2.29 (m, 3H), 3.82 (m, 1H), 5.52 (bd, 1H). MS (306.1, M+H) m.p. 184-187° C.
Reaction SMILES: [CH:1]([N:4]1[CH:8]([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:23])=[O:22])[CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:7][NH:6][C:5]1=[O:25])([CH3:3])[CH3:2].[H-].[Na+].[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>>[CH2:28]([S:30]([N:6]1[CH2:7][CH:8]([C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([S:21]([CH3:24])(=[O:22])=[O:23])[CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[N:4]([CH:1]([CH3:3])[CH3:2])[C:5]1=[O:25])(=[O:32])=[O:31])[CH3:29]
Reactant: CC(C)N1C(=O)NCC1c1cccc(-c2cccc(S(C)(=O)=O)c2)c1
Reactant: CCS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: CCS(=O)(=O)N1CC(c2cccc(-c3cccc(S(C)(=O)=O)c3)c2)N(C(C)C)C1=O

Procedure:
In analogy to example 13, step 2,1-isopropyl-5-(3′-methanesulfonyl-biphenyl-3-yl)-imidazolidin-2-one (example 13, step 1) was reacted with sodium hydride and ethanesulfonyl chloride to give 1-ethanesulfonyl-3-isopropyl-4-(3′-methanesulfonyl-biphenyl-3-yl)-imidazolidin-2-one as a colorless solid. MS: 468.3 ([M+NH4]+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.CO[CH:21](OC)[N:22]([CH3:24])[CH3:23]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[C:10]([C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=[CH:21][N:22]([CH3:24])[CH3:23]
Reactant: Cc1ccc(CC(=O)c2ccc(Cl)cc2Cl)cc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=CN(C)C)C(=O)c2ccc(Cl)cc2Cl)cc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To a solution of the ketone product from Step A (11.79 g; 42.4 mmol) in DMF (150 mL) in an oven-dried round bottom flask was added N,N-dimethylformamide dimethyl acetal (22.5 mL; 169 mmol) under a nitrogen atmosphere. The reaction was stirred at 75° C. for 16 hours. Most of the volatiles were removed in vacuo to afford the crude product as a oil which was used in the next step without further purification.
Reaction SMILES: O.[NH2:2][NH2:3].[OH:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[C:7]([CH2:9][CH2:10][C:11](O)=[O:12])=O>O>[OH:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[C:7]1[CH2:9][CH2:10][C:11](=[O:12])[NH:2][N:3]=1
Reactant: O=C(O)CCC(=O)c1ccccc1O
Reactant: NN
Solvent: O
Product: O=C1CCC(c2ccccc2O)=NN1

Procedure:
Hydrazine hydrate (1.2 ml) was added to a stirred suspension of 3-(2-hydroxybenzoyl)propionic acid (3.1 g) in water (20 ml), and the mixture was heated under reflux for 3/4 hour. The mixture was diluted with an equal volume of water, allowed to cool, and filtered to give 6-(2-hydroxyphenyl)-4,5-dihydro-3(2H)pyridazinone (2.6 g) m.p. 211°-212°.