Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[NH:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1.[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C1(C)C=C(C)C=C(C)C=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[C:10]1([CH3:9])[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:11]=1[C:2]1[NH:6][CH:5]=[C:4]([CH:7]=[O:8])[CH:3]=1
Reactant: O=Cc1c[nH]c(Br)c1
Reactant: Cc1cc(C)c(B(O)O)c(C)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1cc(C)cc(C)c1
Product: Cc1cc(C)c(-c2cc(C=O)c[nH]2)c(C)c1

Procedure:
A mixture of 5-bromo-1H-pyrrole-3-carbaldehyde (0.87 g), 2,4,6-trimethylphenylboronic acid (3.28 g), cesium carbonate (13.0 g), tri-tert-butylphosphine (0.10 g), tris(dibenzylideneacetone)dipalladium (0) (0.23 g) and mesitylene (200 mL) was stirred with heating under reflux for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=3:1) to give the title compound as a brown amorphous form (yield 0.30 g, 28%).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]3[C:11]([CH2:12][OH:13])=[CH:10][N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1>CN(C=O)C.C1(C)C=CC=CC=1.O=[Mn]=O>[F:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]3[C:11]([CH:12]=[O:13])=[CH:10][N:9]=[C:7]3[S:8][C:4]=2[CH:3]=1
Reactant: OCc1cnc2sc3cc(F)ccc3n12
Agent: O=[Mn]=O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=Cc1cnc2sc3cc(F)ccc3n12
Yield: 89.8 %

Procedure:
A solution of 7-Fluoro-imidazo[2,1-b]benzothiazole-3-methanol (Formula L-2) (1.0 g) in DMF (5 mL) was diluted with toluene (200 mL), the warm solution was treated with activated MnO2 (2.34 g) and azeotropically distilled for 4 hours. The cooled suspension ws filtered, the filtrate was concentrated in vacuo and the residue was diluted with ice water. Precipitated 7-Fluoro-imidazo [2,1-b]benzothiazole-3-carboxaldehyde (Formula L-3) was filtered and recrystallized from acetonitrile to yield pure 7-Fluoro-imidazo[2,1-b]benzothiazole-3-carboxaldehyde (Formula L-3) (0.89 g), m.p. 182-183°.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C@H:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH:15]2[CH2:23][CH2:24][CH:25]=[CH:26][N:14]2[C:13]1=[O:27].S(=O)(=O)(O)O.[CH:33]([OH:35])=[O:34].[C]=O>>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH2:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH:15]2[CH2:23][CH2:24][CH2:25][C@@H:26]([C:33]([OH:35])=[O:34])[N:14]2[C:13]1=[O:27]
Reactant: O=CO
Reactant: O=C1[C@@H](N2C(=O)c3ccccc3C2=O)Cc2ccccc2C2CCC=CN12
Agent: O=S(=O)(O)O
Agent: [C]=O
Product: O=C(O)[C@@H]1CCCC2c3ccccc3CC(N3C(=O)c4ccccc4C3=O)C(=O)N21
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Combine (S)-7-[(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)]-1,2,6,7,8,12b-hexahydro-6-oxopyrido[2,1-a][2]benzazepine (800 mg, 2.2 mmol) and sulfuric acid (24 mL) in a pressure vessel. Carefully, add formic acid (4.0 mL, 87 mmol) to minimize mixing and thereby the formation of carbon monoxide. Seal the pressure vessel and add carbon monoxide to 300 psi before stirring. (Caution, upon mixing a sharp rise in pressure will occur.) After 16 hours, vent the vessel and add the reaction mixture to an ice/water mixture (160 mL). Extract repeatedly with ethyl acetate. Combine the organic layers and extract repeatedly with aqueous 10% potassium bicarbonate solution. Combine the potassium bicarbonate solution layers and cool in an ice-bath. Acidify to pH 1 using aqueous 6M hydrochloric acid solution. Extract the acidified aqueous layer repeatedly with ethyl acetate. Combine the organic layers and extract with saturated aqueous sodium chloride solution, dry over MgSO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [CH:1]1([CH2:6]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27]#[N:28])[CH:23]=[CH:24][CH:25]=1.[H-].[Na+]>CN(C=O)C>[CH:1]1([CH2:6][CH:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH3:18])[CH:21]=2)[C:27]#[N:28])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc(CC#N)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(C(C#N)CC2CCCC2)c1
Yield: 50.1 %

Procedure:
By working in a way similar to that described in example 2 but using toluen-4-sulphonic acid cyclopentylmethyl ester (5.09 g, 20 mmoles), obtained as described in example 6, 3-methoxy-phenyl-acetonitrile (2.94 g, 20 mmoles), NaH (55-65%, 880 mg, 22 mmoles) and DMF (25 ml), 2.3 g of the title compound were obtained (yield: 50.1%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:3]1=[O:22].CN(C=O)C.CCN(C(C)C)C(C)C.[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>CO>[F:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([N:16]([S:13]([C:10]2[CH:11]=[CH:12][C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([OH:1])[C:3]3=[O:22])=[CH:8][CH:9]=2)(=[O:14])=[O:15])[C:17]2[S:18][CH:19]=[CH:20][N:21]=2)(=[O:46])=[O:45])=[CH:40][CH:39]=1
Reactant: O=C1[C@H](O)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C1[C@H](O)CCN1c1ccc(S(=O)(=O)N(c2nccs2)S(=O)(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.5 %

Procedure:
Synthesized according to General Procedure 8. To a stirred solution of (R)-4-(3-hydroxy-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (5.0 g, 14.8 mmol) and DMF (25 mL), under N2, at 5° C. (ice bath) was added DIEA (2.5 mL, 14.8 mmol). To this solution was added 4-fluorobenzenesulfonyl chloride (2.9 g, 14.8 mmol) portionwise over 10 minutes. The solution was stirred at ambient temperature for 20 minutes. To this solution was added MeOH (75 mL). The mixture was cooled to 5° C. via an ice bath and stirred for 30 minutes. The precipitate was filtered, washed with MeOH (20 mL), and vacuum dried to give [(R)-4-fluoro-N-(4-(3-hydroxy-2-oxopyrrolidin-1-yl)phenylsulfonyl]-N-(thiazol-2-yl)benzenesulfonamide as a white solid (6.5 g, 13.1 mmol, 89% yield). 1H-NMR (400 MHz, DMSO) δ 8.03-7.96 (m, 2H), 7.83-7.80 (m, 2H), 7.72 (d, J=5.1 Hz, 1H), 7.61 (dd, J=1.8, 7.1 Hz, 1H), 7.59 (s, 1H), 7.37 (s, 1H), 7.37 (dd, J=2.0, 15.6 Hz, 1H), 7.02 (d, J=5.1 Hz, 1H), 5.88 (d, J=5.9 Hz, 1H), 4.38-4.32 (m, 1H), 3.83-3.78 (m, 1H), 3.71 (td, J=9.5, 5.4 Hz, 1H), 2.52-2.42 (m, 1H), 1.87 (td, J=9.4, 4.1 Hz, 1H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=498.3; tR=1.32 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.O[CH:11]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:11]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:18]2)=[CH:5][CH:4]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(O)c3ccccc3)CC2)c1
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OC(CCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c2ccccc2)cc1

Procedure:
Prepared by Procedure A and Scheme AN using 4-methoxyphenol and N-{3-[1-(6-hydroxy-6-phenylhexyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 529.6 (M+H)+.
Reaction SMILES: [CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16](=[CH2:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:24])(=[O:6])=[O:5])([CH3:3])[CH3:2].[Cl:25]N1C(=O)CCC1=O>O1CCCC1>[CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16](=[CH:23][Cl:25])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:24])(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: C=C(c1ccccc1)c1ccc2nc(N)n(S(=O)(=O)C(C)C)c2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(=CCl)c3ccccc3)cc21
Temperature: 25 °C
Yield: 34 %

Procedure:
To a stirred solution of 4.0 g. of 1-isopropylsulfonyl-2-amino-6-(α-methylenebenzyl)benzimidazole (from U.S. Pat. No. 4,118,742) in 100 ml. of tetrahydrofuran was added in one portion 1.56 g. of N-chlorosuccinimide. The reaction mixture was heated at reflux for two and one-half hours, and then cooled to room temperature. The reaction solvent was removed by evaporation under reduced pressure to provide the crude product as a gum. The gum was suspended in water, and then was extracted into chloroform. The chloroform extracts were combined, washed with fresh water, dried, and the solvent was removed by evaporation under reduced pressure. The product thus formed was dissolved in 50 ml. of diethyl ether, and after concentrating the volume of the mixture to about 25 ml., a white crystalline product precipitated and was identified as 1.5 g. of trans-1-isopropylsulfonyl-2-amino-6-(α-chloromethylenebenzyl)benzimidazole. M.P. 180°-181° C. Yield 34%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([C:28]([O:30]C)=[O:29])[C:17]3[CH:18]=[N:19][N:20]([CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[C:21]=3[CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[C:16]([C:28]([OH:30])=[O:29])[C:17]3[CH:18]=[N:19][N:20]([CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)[C:21]=3[CH:22]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)cc2c1cnn2C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cc(C(=O)O)c3cnn(C4CCCC4)c3c2)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
To a stirred solution of methyl 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1-cyclopentyl-1H-indazole-4-carboxylate (2 g, 4.67 mmol) in methanol (20 mL), was added aqueous NaOH solution (0.373 g, dissolved in 10 mL water, 9.34 mmol) and the reaction mixture stirred at 60° C. for 4 h. On completion, ethanol was removed under reduced pressure and the residue acidified with 1N HCl to pH 6. The precipitate was filtered, washed with water and dried to obtain pure 6-(4-(tert-butoxycarbonyl)piperazin-1-yl)-1-cyclopentyl-1H-indazole-4-carboxylic acid (1.7 g, 88%).
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:33][CH2:34][N:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=3)[CH2:30][CH2:31]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: Cc1ccc(N2CCNCC2)cc1
Product: CCc1cc(NC(=O)N2CCN(c3ccc(C)cc3)CC2)c(OC)nc1C
Yield: 87 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-methylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH:1]1([C:6](O)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:32]=[N+:33]=[N-:34].[Na+].OS(O)(=O)=O.[NH4+].[OH-]>C(Cl)(Cl)Cl>[N:32]([C:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH2:9][CH2:8]1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(OCCCN2CCC(C(O)(c3ccccc3)C3CCCC3)CC2)cc1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(OCCCN2CCC(C(N=[N+]=[N-])(c3ccccc3)C3CCCC3)CC2)cc1
Temperature: 25 °C
Yield: 8.5 %

Procedure:
A CHCl3 (4.78 mL, 0.25 M) solution of 4-(3-(4-(cyclopentyl(hydroxy)(phenyl)methyl)piperidin-1-yl)propoxy)benzonitrile (0.5 g, 1.19 mmol) and sodium azide (1.16 g, 17.9 mmol) was cooled to 0° C. To the solution H2SO4 was added dropwise (0.28 mL, 9.3 mmol). The mixture was allowed to warm to rt over 4 h with stirring, then re-cooled to 0° C. and treated with NH4OH till pH was basic. The biphasic solution was extracted with DCM (3×) and the organic layers combined and dried over MgSO4. Concentration under reduced pressure and drying in vacuo afforded a crude oil. Purification by flash chromatography (DCM, MeOH, NH4OH) afforded 4-(3-(4-(azido(cyclopentyl)(phenyl)methyl)piperidin-1-yl)propoxy)benzonitrile (45 mg, 10%): LC-MS (>98%) m/z=444.3 [M+H].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:15]([CH3:23])([CH3:22])[C:14]4[C:9]3=[C:10]([CH:11]=[C:12](Br)[CH:13]=4)[C:4]=2[CH:3]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:23][C:15]1([CH3:22])[C:14]2[C:9]3=[C:10]([C:4]4[CH:3]=[C:2]([C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:7]=[CH:6][C:5]=4[N:8]3[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=3)[CH:11]=[C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:13]=2
Reactant: OB(O)c1ccccc1
Reactant: CC1(C)c2ccccc2-n2c3ccc(Br)cc3c3cc(Br)cc1c32
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)cc1c32

Procedure:
19.8 g (45 mmol) of 3,6-dibromo-8,8-dimethyl-8H-indolo[3,2,1-de]acridine, 11.4 g (94 mmol) of phenylboronic acid and 164 ml of saturated NaHCO3 solution are suspended in 1500 ml of toluene and 150 ml of ethanol. 1.9 g (1.6 mmol) of Pd(PPh3)4 are added to this suspension, and the reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, filtered through silica gel, washed three times with 200 ml of water and subsequently evaporated to dryness.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH:25]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]1>>[C:32]([O:31][C:29]([N:27]1[CH2:28][CH:25]([NH:24][C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[O:21])[CH2:26]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CN(C(=O)OC(C)(C)C)C2)cn1
Yield: 86 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using 3-amino-1-N-Boc-azetidine instead of 2-aminoethyl isopropylether, to the title compound (257 mg, 86%) which was obtained as a white solid. MS: m/e=463.3 [M−H]−.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[Cu][C:17]#[N:18].Cl>CN1CCCC1=O>[CH3:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]([N+:13]([O-:15])=[O:14])=[C:2]([CH:7]=1)[C:17]#[N:18]
Reactant: N#C[Cu]
Reactant: Cc1cc(Br)c([N+](=O)[O-])cc1C(F)(F)F
Agent: Cl
Solvent: CN1CCCC1=O
Product: Cc1cc(C#N)c([N+](=O)[O-])cc1C(F)(F)F
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 88.1 %

Procedure:
A mixture of 1-bromo-5-methyl-2-nitro-4-trifluoromethyl-benzene from step 2 (49.80 g, 175 mmol) and copper(I) cyanide (16.5 g, 184 mmol) in 1-methyl-2-pyrrolidone (NMP) (180 mL) was heated up to 150° C. and stirred for 30 min under nitrogen atmosphere. The mixture was cooled to 23° C. and poured into 1 N HCl, extracted with TBME, washed with brine and dried over Na2SO4. Removal of the solvent in vacuum left a brown oil, which was purified by silica gel column chromatography with heptane/ethyl acetate 4:1->2:1 to give the title compound as a light yellow solid (35.48 g, 88%). MS (EI) 230.1 [M].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:12][C:13](=[O:31])[CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[C:20]([F:30])[CH:19]=1)=[O:16].O>C1COCC1>[F:30][C:20]1[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH2:14][C:13](=[O:31])[CH2:12][O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:23]=[CH:22][C:21]=1[N:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: O=C(CBr)CC(=O)Nc1ccc(N2CCOCC2)c(F)c1
Reactant: Oc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(COc1cccc(F)c1)CC(=O)Nc1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 2.2 %

Procedure:
To a solution of 3-fluorophenol (2.33 g, 20.8 mmol) in anhydrous THF (20 mL) was added NaH (909 mg, 22.7 mmol, 60%) and the mixture was stirred at rt for 3 h. A solution of 4-bromo-N-(3-fluoro-4-morpholinophenyl)-3-oxobutanamide (6.8 g, 18.9 mmol) in THF (40 mL) was added. The resulting mixture was stirred at rt overnight. The reaction mixture was then poured into 100 mL of water and the mixture was extracted with EtOAc (30 mL×5). The combined organic phases were washed with brine (50 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as a yellow solid (0.16 g, 2%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](O)[C@@H:10]([N:14]=[N+:15]=[N-:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COCCN(S(F)(F)[F:27])CCOC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([F:27])[C@@H:10]([N:14]=[N+:15]=[N-:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@H](N=[N+]=[N-])[C@@H](O)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(F)[C@@H](N=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 60.5 %

Procedure:
37.1 To stirred, cooled (−78° C.) solution of 695 mg (3S,4S)-3-azido-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (example 22.2) in 5 ml CH2Cl2 under an argon atmosphere were added 2.69 g bis(2-methoxyethyl)aminosulphur trifluoride (50% solution in THF). The dry ice bath was removed and the mixture was allowed to warm to r.t. and stirring was continued for 22 h. The mixture was poured into 10% aq. Na2CO3. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography (silica gel; gradient: cyclohexane->cyclohexane/EtOAc 3:2) to give 424 mg (S)-3-azido-4-fluoro-pyrrolidine-1-carboxylic acid tert-butyl ester as light yellow oil. MS 409.0 ([M+H]+)
Reaction SMILES: N#N.[F:3][C:4]([F:21])([F:20])[C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]1)=[O:6].C(=O)=O.CC(C)=O.[CH3:29][O:30][CH2:31][CH2:32][CH2:33][CH2:34][Mg]Cl.[NH4+].[Cl-]>C(OCC)C.C1COCC1>[F:21][C:4]([F:3])([F:20])[C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:8]1)([OH:6])[CH2:34][CH2:33][CH2:32][CH2:31][O:30][CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)C(F)(F)F)C1
Reactant: COCCCC[Mg]Cl
Agent: N#N
Agent: O=C=O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(C)=O
Product: COCCCCC(O)(C1CCCN(C(=O)OC(C)(C)C)C1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 15 %

Procedure:
Under protection of N2 gas, tert-butyl 3-(2,2,2-trifluoroacetyl)piperidine-1-carboxylate (102 mg, 0.363 mmol) was dissolved dry THF (8 mL) and cooled to −78° C. (dry ice/acetone bath). 1.22 M methoxybutylmagnesium chloride in THF (600 μL, 2 equiv) solution was added slowly. After 10 min, the reaction was allowed to warm up to rt slowly. After 2 h, satd aq NH4Cl (15 mL) solution was added to the reaction mixture. The mixture was diluted with diethyl ether and the layers were separated. The aqueous layer was extracted with diethyl ether (3×10 mL). The combined organic layers were washed with brine (10 mL) and dried over Na2SO4. After concentration, the crude product was purified by prep HPLC to afford tert-butyl 3-(1,1,1-trifluoro-2-hydroxy-6-methoxyhexan-2-yl)piperidine-1-carboxylate (20 mg, 15%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=2)[N:20]=1)[C:5]([NH:7][CH2:8][C:9]1[C:10](=[O:17])[NH:11][C:12]([CH3:16])=[CH:13][C:14]=1[CH3:15])=[O:6].B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[C:21]1([C:2]2[CH:3]=[C:4]([CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=3)[N:20]=2)[C:5]([NH:7][CH2:8][C:9]2[C:10](=[O:17])[NH:11][C:12]([CH3:16])=[CH:13][C:14]=2[CH3:15])=[O:6])[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc(-c3ccc(CN(C)C)cc3)c2)c(=O)[nH]1
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: OBO
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCCCC3)nc(-c3ccc(CN(C)C)cc3)c2)c(=O)[nH]1
Temperature: 100 °C

Procedure:
To a stirred solution of 2-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(4-((dimethylamino)methyl)phenyl)isonicotinamide (0.11 g, 0.25 mmol), boronic acid (0.059 g, 0.27 mmol) in dioxane/water mixture (3 mL+1.5 mL), Na2CO3 (0.098 g, 3.6 mmol) was added and reaction mass purged with argon for 15 min. Then Pd(PPh3)4 (0.028 g, 0.025 mmol) was added and argon was purged again for 10 min. Reaction mass was heated at 100° C. for 3 h. On completion, reaction mass filtered through celite and celite bed washed with ethyl acetate. Combined filtrates were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column over silica gel to obtain 2-(cyclohex-1-en-1-yl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(4-((dimethylamino)methyl)phenyl)isonicotinamide.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[C:19]1[CH2:22][CH:21]([C:23]([O:25][CH3:26])=[O:24])[CH2:20]1>O1CCCC1>[C:7]([CH:9]=[C:19]1[CH2:22][CH:21]([C:23]([O:25][CH3:26])=[O:24])[CH2:20]1)#[N:8]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COC(=O)C1CC(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C1CC(=CC#N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of 1.0000 M of potassium tert-butoxide in tetrahydrofuran (26.7 mL) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (4.53 mL, 0.0280 mol) in tetrahydrofuran (50 mL, 0.6 mol). The reaction was warmed to rt and then cooled at 0° C. again. To the reaction mixture was a solution of methyl 3-oxocyclobutanecarboxylate (3.26 g, 0.0254 mol) in tetrahydrofuran (20 mL, 0.3 mol). The reaction was allowed to warm up to rt and stirred at rt overnight. After quenching with water, the mixture was extracted with ether. The combined organic layers were washed with water, brine, dried and evaporated to dryness. The crude mixture was purified on silica gel, eluting with 0 to 40% EtOAc in hexane, to give the desired product (3.12 g, 81.12%). LCMS calculated for C8H10NO2(M+H)+: 152.1. Found: 152.3.