Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[N:18][C:17]([CH2:20][CH3:21])=[CH:16][N:15]=3)[CH2:10][CH2:9]2)[S:5][CH:6]=1.C(OC(=O)[NH:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[CH:32]2)(C)(C)C>>[CH2:20]([C:17]1[N:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][CH:8]([O:7][C:4]3[S:5][CH:6]=[C:2]([N:34]4[C:35]5[C:31](=[CH:30][C:29]([NH2:28])=[CH:37][CH:36]=5)[CH:32]=[CH:33]4)[N:3]=3)[CH2:9][CH2:10]2)=[N:15][CH:16]=1)[CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]ccc2c1
Reactant: CCc1cnc(N2CCC(Oc3nc(Br)cs3)CC2)cn1
Product: CCc1cnc(N2CCC(Oc3nc(-n4ccc5cc(N)ccc54)cs3)CC2)cn1

Procedure:
The title compound was prepared by following the similar procedure as described in Intermediate-27 using 4-bromo-2-((1-(5-ethylpyrazin-2-yl)piperidin-4-yl)oxy)thiazole and tert-butyl-1H-indol-5-ylcarbamate (0.092 g, 40%); MS: 421.2 (M+1).
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[C:11]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:38]2[CH2:37][CH2:36][N:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[O:28][CH3:27])[CH2:40][CH2:39]2)=[O:26])[C:11]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(Oc2ccccc2)nc1C
Reactant: COc1ccccc1N1CCNCC1
Product: CCc1cc(NC(=O)N2CCN(c3ccccc3OC)CC2)c(Oc2ccccc2)nc1C
Yield: 88 %

Procedure:
Phenyl-N-(5-ethyl-6-methyl-2-phenoxypyridin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[C:15]([O:17]C)=[O:16].[OH-].[K+].C(O)C>O>[F:1][C:2]([F:19])([F:20])[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1ccc2ccccc2c1OCC(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc2ccccc2c1OCC(F)(F)F

Procedure:
A mixture of 10 g. (35 mmoles) of methyl 1-(2,2,2-trifluoroethoxy)-2-naphthoate, 2.9 g., (42 mmoles) of potassium hydroxide, 50 ml. of ethanol and 40 ml. of water is refluxed for one hour, chilled and acidified. The fluffy precipitate is collected, water washed, and air-dried. It is purified by recrystallization first from chloroform and then from aqueous alcohol, m.p. 171.5°-172° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([F:10])[F:9].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([Br:11])([F:10])[F:9]
Reactant: FC(F)c1ccccc1Br
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: FC(F)(Br)c1ccccc1Br
Reaction time: 72 h

Procedure:
A solution of 1-bromo-2-difluoromethylbenzene (9.6 g, 46.8 mmol) and N-bromosuccinimide (24.8 g, 139 mmol) in carbon tetrachloride (100 mL) was irradiated with a sunlamp. After 3 days, the reaction mixture was diluted with hexane, the precipitate was filtered off, and the collected organic filtrate was concentrated in vacuo. Purification by flash chromatography on silica gel (100% hexanes) provided the title compound: 1H NMR (500 M=Hz, CD2Cl2) δ7.74 (d, J=8.0 Hz, 1H), 7.66 (dd, J=8.0, 1.5 Hz, 1H), 7.44 (t, J=7.7 Hz, 1H), 7.37 (td, J=7.7, 1.3 Hz, 1H).
Reaction SMILES: C1([NH:4][C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH2:14][CH2:15][N:16]([S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)(=[O:21])=[O:20])[CH2:17][CH:18]=3)[CH:10]=[CH:9][CH:8]=2)=O)CC1.ClC1C=CC=C(C#N)N=1>>[F:30][C:28]([F:29])([F:31])[C:24]1[CH:23]=[C:22]([S:19]([N:16]2[CH2:15][CH:14]=[C:13]([C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:5]#[N:4])[N:12]=3)[CH2:18][CH2:17]2)(=[O:21])=[O:20])[CH:27]=[CH:26][CH:25]=1
Reactant: O=C(NC1CC1)c1cccc(C2=CCN(S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)n1
Agent: N#Cc1cccc(Cl)n1
Product: N#Cc1cccc(C2=CCN(S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)n1

Procedure:
1′-(3-Trifluoromethylbenzenesulfonyl)-1′,2′,3′,6′-tetrahydro-[2,4′]bipyridinyl-6-carbonitrile (32) was synthesized similarly to compound 7 in Example 1 starting with 2-chloro-6-cyanopyridine (22) instead of compound 1. 1H NMR (400 MHz, CD3OD): δ 8.15 (d, 1H, J=8.4 Hz), 8.12 (s, 1H), 8.00 (d, 1H, J=7.6 Hz), 7.92 (m, 1H), 7.86 (m, 1H), 7.80 (m, 1H), 7.70 (m, 1H), 6.76 (m, 1H), 3.93 (m, 2H), 3.43 (m, 2H), 2.73 (m, 2H); MS: 394 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=O)[C:4]([CH3:11])=[N:3]1.S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:8]([C:5]4[C:4]([CH3:11])=[N:3][N:2]([CH3:1])[C:6]=4[CH3:7])=[O:10])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: Cc1nn(C)c(C)c1C(=O)O
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nn(C)c(C)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 3 h
Yield: 55.6 %

Procedure:
A dry flask was charged with 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid (0.122 g, 0.791 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (8 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.200 g, 0.793 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and subsequently vacuum filtered. The solid was washed with 0° C. THF (˜5 mL) and collected to afford the 1,3,5-Trimethyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.169 g, 0.440 mmol, 56%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]([F:15])=[CH:12][C:13]=1[I:14])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:15][C:11]1[N:10]=[CH:9][C:8]([NH2:7])=[C:13]([I:14])[CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(F)cc1I
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cnc(F)cc1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(6-Fluoro-4-iodopyridin-3-yl)-carbamic acid tert-butyl ester (1.75 g, 5.18 mmol) was dissolved in DCM (25 mL) and TFA (5 mL) added. The mixture was stirred at ambient temperature for 1 h and then evaporated in vacuo. The resultant residue was treated with saturated aqueous sodium hydrogen carbonate solution (25 mL), diluted with water (100 mL) and extracted into ethyl acetate (2×100 mL). The organic layer was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford the title compound as an orange oil, which crystallized on standing (1.23 g, 99%). 1H NMR (CDCl3, 300 MHz): 7.61 (d, J=1.6 Hz, 1H), 7.28-7.25 (m, 1H), 3.99 (s, 2H). LCMS (Method B): RT=2.52 min, M+H+=239.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]([OH:16])=O)=[CH:4]1)[CH3:2].C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[NH4+:26].[OH-]>CN(C=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]([NH2:26])=[O:16])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c2ccc(OC)cc21
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCn1cc(C(N)=O)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
1-Ethyl-6-methoxy-1H-indole-3-carboxylic acid (250 mg, 1.14 mmol) is suspended in a solution of CH2Cl2 (12.5 mL) and DMF (10 μL). Oxalyl chloride (230 μL, 2.64 mmol) is added, and the reaction mixture is stirred for 1 hour at room temperature. This mixture is then slowly poured into a rapidly stirring solution of concentrated NH4OH (5 mL). This is then partitioned in H2O and EtOAc. The residue from the ethyl acetate layer is triturated with acetone to yield 1-ethyl-6-methoxy-1H-indole-3-carboxamide (134 mg, 54%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1.[CH3:50][NH:51][CH2:52][CH2:53][CH2:54][CH3:55]>C(O)C>[CH3:50][N:51]([CH2:52][CH2:53][CH2:54][CH3:55])[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:22][N:23]=[N:24][N:25]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Reactant: CCCCNC
Solvent: CCO
Product: CCCCN(C)c1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 73 %

Procedure:
A solution of 6-chloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.5 g) and N-methylbutylamine (0.2 g) in ethanol (10 ml) was heated under reflux for 8 hours. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-dilute hydrochloric acid. The organic layer was washed with water, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give pale yellow amorphous powders (0.26 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.N[CH2:11][CH2:12][OH:13].N>C([O-])(=O)C.[Zn+2].C([O-])(=O)C.C1(C)C(C)=CC=CC=1>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[O:13][CH2:12][CH2:11][N:7]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: NCCO
Agent: CC(=O)[O-]
Agent: N
Agent: [Zn+2]
Solvent: Cc1ccccc1C
Product: Nc1ccc(C2=NCCO2)cc1
Yield: 82 %

Procedure:
Using known procedures for the synthesis of cyclic imino ethers from nitriles (18,26), 4-aminobenzonitrile was treated with an excess of 2-aminoethanol (1 part nitrile/2 parts aminoalcohol) in refluxing xylene, with 3.5 wt. % zinc acetate catalyst, with all under a slow nitrogen stream. The solution was heated until no NH3 was detected in the off gas. After removal of the xylene, the crude solid product was obtained in high yield. The crude product was recrystallized from acetonitrile to obtain an 82% yield of white, crystalline 4-APOXO having mp 163-165° C., reported 158-160° C. The structure of the monomer was confirmed by FT-IR and 1H NMR. Structure of 4-APOXO is as follows:
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11]O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(Cl)([Cl:25])=O>>[CH2:1]([O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:11][Cl:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCOc1ccc(CO)cc1OCCCCCC
Product: CCCCCCOc1ccc(CCl)cc1OCCCCCC
Temperature: 25 °C

Procedure:
Thionyl chloride (140 ml.) and 3,4-dihexoxybenzyl alcohol (14.0 g.) are combined and stirred at room temperature for one-half hour, at which time gas evolution ceases. The mixture is refluxed for one-half hour and then distilled to remove thionyl chloride (about 100 ml.). The residue is poured into ice-water (250 g. of each) and the aqueous solution extracted with chloroform (3×100 ml.). The chloroform extracts are combined, washed successively with saturated sodium bicarbonate solution (2×100 ml.) and water (3×100 ml.). It is then dried (Na2SO4) and concentrated to give 3,4-dihexoxybenzyl chloride as a brown oil (11.7 g.).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[NH:10][C:11]1[C:20]([Br:21])=[C:19]2[C:14]([C:15](=[O:32])[C:16]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[C:17]([CH:22]([CH3:24])[CH3:23])[O:18]2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:40](Br)[CH:41]=[CH2:42]>CN(C)C=O.O>[CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:42][CH:41]=[CH2:40])[C:11]1[C:20]([Br:21])=[C:19]2[C:14]([C:15](=[O:32])[C:16]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[C:17]([CH:22]([CH3:24])[CH3:23])[O:18]2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1oc2c(Br)c(NC(=O)OCc3ccccc3)ccc2c(=O)c1-c1ccc(Cl)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN(C(=O)OCc1ccccc1)c1ccc2c(=O)c(-c3ccc(Cl)cc3)c(C(C)C)oc2c1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of [8-bromo-3-(4-chlorophenyl)-2-isopropyl-4-oxo-4H-chromen-7-yl]carbamic acid benzyl ester (0.231 g, 0.44 mmol) and cesium carbonate (0.228 g, 0.701 mmol, 1.6 eq.) in N,N-dimethylformamide (10 ml) is treated with allyl bromide (0.058 g, 0.042 ml, 0.48 mmol, 1.1 eq.), and the mixture is stirred at room temperature for 4 h. The mixture is diluted with water and washed twice with ethyl acetate. The aqueous phase is additionally washed with methylene chloride. The combined organic phases are dried (magnesium sulfate) and filtered and the solvent is removed by evaporation in vacuo to afford the title compound as a yellow solid. The product is used in the next step without further purification.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH2:5]([N:12]1[CH2:19][C@H:18]2[C@H:14]([CH2:15][O:16][C:17]2=[O:20])[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Cl-].[NH4+]>O1CCCC1>[CH2:3]([C:18]12[CH2:19][N:12]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:13][CH:14]1[CH2:15][O:16][C:17]2=[O:20])[CH:2]=[CH2:1]
Reactant: O=C1OC[C@@H]2CN(Cc3ccccc3)C[C@H]12
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC12CN(Cc3ccccc3)CC1COC2=O
Temperature: 25 °C
Yield: 29.9 %

Procedure:
Allyl bromide (2.48 mL, 29.3 mmol) was added to a solution of (1R*,5S*)-7-benzyl-3-oxa-7-azabicyclo[3.3.0]octan-2-one (4.25 g, 19.6 mmol) in tetrahydrofuran (98 mL) with stirring under salt-ice cooling. A 1 M solution of lithium hexamethyldisilazide in tetrahydrofuran (23.5 mL, 23.5 mmol) was added dropwise under cooling with ice-acetone. The mixture was stirred for two hours while gradually heating to room temperature. A saturated ammonium chloride solution (200 mL) was added to the reaction solution, followed by extraction with ethyl acetate (100 mL×2). The organic layer was washed with water (250 mL) and brine (250 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→84:16→80:20→75:25→66:34→50:50) to give 1.51 g of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:12]=3)[N:8]=[C:7]([C:24]#[N:25])[C:6]=2[N:26]=1.[NH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:8]=[C:7]([C:24]#[N:25])[C:6]3[N:26]=[C:3]([CH2:2][NH:27][C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[NH:4][C:5]=3[CH:10]=2)=[CH:12][C:13]=1[C:20]([F:23])([F:22])[F:21])[CH3:19]
Reactant: Nc1cccnc1
Reactant: CCOc1ccc(-c2cc3[nH]c(CCl)nc3c(C#N)n2)cc1C(F)(F)F
Product: CCOc1ccc(-c2cc3[nH]c(CNc4cccnc4)nc3c(C#N)n2)cc1C(F)(F)F

Procedure:
A solution of 2-chloromethyl-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5,c]pyridine-4-carbonitrile (20 mg, 0.052 mmol), diisoproplylethylamine (28.4 uL,0.16 mmol) and 3-aminopyridine (9.8 mg, 0.1 mmol) dimethylsulfoxide (500 μL) was heated in the Creator microwave at 120° C. for 5 minutes. The mixture was filtered and purified by preparative HPLC to afford the title compound. 1H NMR (MeOH) δ 8.3-8.2 (m, 5H), 7.76-7.74 (m, 2H), 7.27 (d, 1H), 6.07 (s, 2H) 4.23 (q, 2H) 1.45 (t, 3H) MS m/z 439.1 (m+1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[CH3:19][OH:20]>F[B-](F)(F)F.C[N+](C)(C)C>[F:18][C:2]([F:17])([F:1])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[O:20][CH3:19])=[O:7]
Reactant: O=C(c1cccc(C(F)(F)F)c1)N1CCCCC1
Reactant: CO
Agent: C[N+](C)(C)C
Agent: F[B-](F)(F)F
Product: COC1CCCCN1C(=O)c1cccc(C(F)(F)F)c1
Yield: 88.2 %

Procedure:
In the same manner as in Example 5, there are electrolyzed 13.5 g of 1-(3'-trifluoromethylbenzoyl)-piperidine and 84.1 g of methanol in the presence of 0.11 g of tetramethylammonium tetrafluoroborate as conducting salt. After throughput of 2.5 Faraday per mol of 1-(3'-trifluoromethylbenzoyl)-piperidine the current is switched off. The calculated mean cell voltage is 34.1 volts. Work-up of the electrolysis solution gives 13.3 g of 1-(3'-trifluoromethylbenzoyl)-2-methoxypiperidine (boiling point 75°-80° C./0.2 mm Hg; nD25 = 1.4905) are obtained which corresponds to a product yield of 88.8% and a current efficiency of 70.6%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[C:22]4[N:18]([CH:19]=[CH:20][CH:21]=4)[C:17]([C:23]([OH:25])=O)=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.Cl.[NH2:62][CH2:63][C:64]1[CH:65]=[CH:66][C:67]2[C:71]([CH3:73])([CH3:72])[O:70][B:69]([OH:74])[C:68]=2[CH:75]=1>CN(C=O)C.CC(=O)OCC>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:26]([F:28])([F:27])[F:29])[O:13][N:12]=[C:11]([C:14]3[C:22]4[N:18]([CH:19]=[CH:20][CH:21]=4)[C:17]([C:23]([NH:62][CH2:63][C:64]4[CH:65]=[CH:66][C:67]5[C:71]([CH3:73])([CH3:72])[O:70][B:69]([OH:74])[C:68]=5[CH:75]=4)=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC1(C)OB(O)c2cc(CN)ccc21
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2cccn12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1(C)OB(O)c2cc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)cc(Cl)c5)(C(F)(F)F)C4)c4cccn34)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
To a solution of 8-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-5-carboxylic acid (23 mg, 0.052 mmol), HATU (30 mg, 0.078 mmol) and Et3N (0.02 mL, 0.104 mmol) in DMF (10 mL) was added 6-(aminomethyl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (24 mg, 0.104 mmol). The mixture was stirred at rt overnight. EA (50 mL) was added and the mixture was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound 8-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)indolizine-5-carboxamide (13 mg, yield 40%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.50 (t, J=6.0 Hz, 1H), 9.05 (s, 1H), 8.19 (s, 1H), 7.83 (s, 1H), 7.67 (s, 3H), 7.47 (d, J=8.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.11 (s, 1H), 6.94 (s, 1H), 4.57 (d, J=6.0 Hz, 2H), 4.48 (d, J=18.0 Hz, 1H), 4.38 (d, J=18.0 Hz, 1H), 1.44 (s, 6H) ppm; HPLC purity: 100.0% at 220 nm and 100.0% at 254 nm; MS: m/z=616.0 (M+1, ESI+).
Reaction SMILES: CC(C)C[N:4]1[CH2:8][C:7](=[O:9])[NH:6]C1C1C=CC=CC=1.[OH:17][CH:18]([CH3:23])[CH2:19][C:20]([O-:22])=O>CS(C)=O.O>[CH2:19]1[C:20](=[O:22])[N:4]([CH2:8][C:7]([NH2:6])=[O:9])[CH2:23][CH:18]1[OH:17]
Reactant: CC(O)CC(=O)[O-]
Reactant: CC(C)CN1CC(=O)NC1c1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)CN1CC(O)CC1=O

Procedure:
A solution of 0.65 g 2-methylpropyl 2-phenyl-4-oxoimidazolidine-β-hydroxybutanoate in 1.5 ml dimethyl sulfoxide and 0.5 ml water is heated at reflux for 16 h. After evaporating, the residue is chromatographed on silica, eluting with 7:3 ethyl acetate/methanol. Oxiracetam is obtained as a white powder, m.p. 167°-70° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:26](Br)[CH:27]=[CH2:28]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:28][CH:27]=[CH2:26])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 75 °C
Reaction time: 4 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.79 g, 2.50 mmol) and sodium hydride (0.13 g, 60%n in oil, 3.254 mmol) in dimethylformlamide (10 mL). After 30 minutes add allyl bromide (0.35 mL, 3.25 mmol). Heat to 75° C. After 4 hours, cool the reaction mixture, dilute with dichloromethane, and extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 1-(t-butoxycarbonyl)-4-(1-allyl-1H-benzimidazol-2-yl)[1,4]diazepane: Rf=0.83 (silica gel, dichloromethane/methanol/concentrated ammonium hydroxide 90/10/0.1).
Reaction SMILES: C([O-])([O-])=O.[Cs+:5].[Cs+].[C:7]([OH:26])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(=O)=O>C(O)CCC>[C:7]([O-:26])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[Cs+:5]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Cs+]
Solvent: CCCCO
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
A mixture of Cs2CO3 and stearic acid was added to butanol in the ratio 1:2 and kept at reflux temperature until no more CO2 formed. Subsequently, butanol was separated on the rotary evaporator, the residue mixed with ether and aspirated, m.p.:263-269° C.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=2[F:21])[CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31].C([O-])(O)=O.[Na+].[F-].[Cs+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:2]2[S:10][C:9]3[C:4](=[N:5][CH:6]=[CH:7][C:8]=3[O:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=3[F:21])[CH:3]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(Br)sc23)c(F)c1
Reactant: COc1ccc(B(O)O)cc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cc1OC
Temperature: 25 °C
Yield: 59.3 %

Procedure:
To a stirred solution of 50 (400 mg, 1.08 mmol) in DME (20 ml) was added 3,4-dimethoxyphenylboronic acid (394 mg, 2.17 mmol), NaHCO3 (273 mg, 3.25 mmol), CsF (494 mg, 3.25 mmol), Pd(PPh3)4 (125 mg, 0.11 mmol) and water (10 ml). The reaction mixture was degassed for 15 min with a nitrogen stream, and was heated to reflux for 2.5 hrs under nitrogen. After cooling to room temperature the reaction mixture was diluted with AcOEt and successively washed with water, sat. NH4Cl, brine, dried over anhydrous MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography (eluents AcOEt/CH2Cl2: 5/95 to 30/70) and triturated in AcOEt/hexanes to afford title compound 331 (273 mg, 59% yield) as a yellow solid. MS (m/z): 427.1 (M+H)+.