Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:4])(=[O:3])C.[CH:5]([OH:7])=O.C(OC(=O)C)(=O)C.[CH3:15][N:16]1[CH2:21][CH2:20][CH:19]([CH:22]2[C:28]3[CH:29]=[CH:30][CH:31]=[C:32]4[CH2:33][CH2:34][N:26]([C:27]=34)[C:25]3[CH:35]=[CH:36][CH:37]=[CH:38][C:24]=3[NH:23]2)[CH2:18][CH2:17]1>CO>[CH:1]([OH:4])=[O:3].[CH:5]([N:23]1[CH:22]([CH:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)[C:28]2[CH:29]=[CH:30][CH:31]=[C:32]3[CH2:33][CH2:34][N:26]([C:27]=23)[C:25]2[CH:35]=[CH:36][CH:37]=[CH:38][C:24]1=2)=[O:7]
Reactant: CN1CCC(C2Nc3ccccc3N3CCc4cccc2c43)CC1
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CO
Solvent: O=CO
Product: CN1CCC(C2c3cccc4c3N(CC4)c3ccccc3N2C=O)CC1
Reaction time: 0.5 h

Procedure:
A solution of acetic acid (14.1 ml) and formic acid (14.8 ml) was prepared at -10° C. (methanol-ice) over a period of 1.5 hours. This solution, the mixed formic/acetic anhydride reagent, was added to 6-(1-methylpiperidin-4-yl)-1,2,6,7-tetrahydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (16 gm) at room temperature in one portion. The mixture was stirred for 30 minutes. The resulting solution was treated with methanol (30 ml) and concentrated to an oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[OH:12][C:13]1[CH:24]=[CH:23][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH2:21])=[O:20])=[CH:15][CH:14]=1.[OH-].[K+]>CS(C)=O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([O:12][C:13]2[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:22])[C:19]([NH2:21])=[O:20])=[CH:23][CH:24]=2)=[CH:3][CH:4]=1
Reactant: CC(Oc1ccc(O)cc1)C(N)=O
Reactant: FC(F)(F)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(N)=O
Reaction time: 5 h
Yield: 50 %

Procedure:
18 g of p-chloro-α,α,α-trifluorotoluene and 18 g of α-(p-hydroxyphenoxy)propionamide were dissolved in 50 ml of dimethyl sulfoxide, and 5.6 g of potassium hydroxide was added. The reaction was performed at 130° to 150° C. for about 5 hours. After the reaction, the reaction product was purified in a customary manner to afford the final product having a melting point of 157° to 158° C. The yield was 50%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:8][CH2:7]1)[CH3:5].[CH3:32][C:33]1[N:41]=[C:40]([Cl:42])[CH:39]=[C:38]([CH3:43])[C:34]=1[C:35](O)=[O:36].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:42][C:40]1[CH:39]=[C:38]([CH3:43])[C:34]([C:35]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]2[CH2:11][CH2:10][CH:9]([N:12]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[CH:23][CH:22]=3)[CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:19]=3[CH3:20])[CH2:8][CH2:7]2)[CH3:5])=[O:36])=[C:33]([CH3:32])[N:41]=1
Reactant: COCCOc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCN)CC2)cc1
Reactant: Cc1cc(Cl)nc(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCOc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)cc(Cl)nc3C)CC2)cc1
Reaction time: 8 h
Yield: 22.8 %

Procedure:
Following General Procedure C: To a solution of [1-((R)-3-amino-1-methyl-propyl)-piperidin-4-yl]-[4-(2-methoxy-ethoxy)-phenyl]-(4-methyl-pyridin-3-ylmethyl)-amine (130 mg, 0.31 mmol) and 2,4-dimethyl-6-chloronicotinic acid (68 mg, 0.31 mmol) in DMF (4 mL) was added DIPEA (0.8 mL), HOBT (75 mg, 0.56 mmol) and EDCI (89 mg, 0.46 mmol) and the reaction stirred overnight. Purification of the crude product by column chromatography on silica gel (CH2Cl2/MeOH/NH4OH,) gave 42 mg (23%) of the title compound as a white solid: 1H NMR (CDCl3) δ 1.02 (d, 3H, J=6 Hz) 1.07-1.32 (m, 2H), 1.53-1.61 (m, 1H), 1.83-1.91 (m, 3H), 2.29 (s, 3H), 2.34 (s, 3H), 2.48 (s, 3H, 2.76-2.91 (m, 3H), 3.26-3.39 (m, 3H), 3.43 (s, 3H), 3.68-3.71 (m, 2H), 3.73-3.82 (m, 1H), 4.01-4.04 (m, 4H), 6.64 (d, 2H, J=9 Hz), 6.76 (d, 2H, J=9 Hz), 6.98 (s, 1H), 7.03 (d, 1H, J=6 Hz), 7.97 (br s, 1H), 8.26 (s, 1H), 8.29 (d, 1H, J=6 Hz). 13C NMR (CDCl3) δ 13.60, 19.19, 22.52, 29.68, 30.58, 31.80, 39.70, 44.36, 47.79, 59.57, 60.04, 68.06, 71.53, 115.72, 120.29, 122.88, 125.50, 148.34, 149.57. ES-MS m/z 594 (M+H). Anal. Calcd. for C33H44N5ClO3.0.2CH2Cl2: C, 65.24; H, 7.32; N, 11.46. Found: C, 64.88; H, 7.36; N, 11.54.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11](Cl)=[CH:12][CH:13]=1)=[O:7].C(OC(=O)[NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(C)(C)C.N12CCCN=C1CCCCC2>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:26]2[CH2:27][CH2:28][CH:23]([NH2:22])[CH2:24][CH2:25]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CCNC(=O)c1ccc(N2CCC(N)CC2)nn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To 6-chloropyridazine-3-carboxylic acid (3-methylbutyl)amide (0.140 g, 0.610 mmol) in DMF (7 mL) was added piperidin-4-ylcarbamic acid tert-butyl ester (0.146 g, 0.730 mmol), followed by the addition of 1,8-diazabicyclo[5,4,0]undec-7-ene (0.280 mL, 1.84 mmol) and tetra-n-butylammonium iodide (6 mg). The reaction mixture was stirred at 80° C. for 16 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate, then washed with citric acid, sodium bicarbonate and brine solution. The organic layer was separated, and dried over anhydrous Na2SO4, and evaporated. The residue was purified by column chromatography and then treated with trifluoroacetic acid. The title compound was obtained as a white powder in 50% yield (0.090 g). 1H NMR (300 MHz, DMSO-d6) δ 8.75-8.77 (m, 1H), 7.79 (d, J=9.6 Hz, 1H), 7.34 (d, J=9.6 Hz, 1H), 4.29-4.35 (m, 2H), 3.29-3.22 (m, 1H), 3.06-3.12 (m, 1H), 2.85-2.87 (m, 1H), 2.50 (m, 1H), 1.77-1.80 (m, 2H), 1.56-1.64 (m, 4H), 1.40-1.44 (m, 2H), 1.17-1.25 (m, 1H), 0.90 (d, J=6.6 Hz, 6H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[O:6][C:5]2=[O:12].[CH:13]#[CH:14]>>[C:13]([C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][CH:2]=1)[C:5](=[O:12])[O:6][C:7]2=[O:11])#[C:14][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[O:6][C:5]2=[O:12]
Reactant: C#C
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Product: O=C1OC(=O)c2cc(C#Cc3ccc4c(c3)C(=O)OC4=O)ccc21

Procedure:
According to an aspect of the invention, a 5-haloisobenzofuran-1,3-dione, such as 5-bromoisobenzofuran-1,3-dione, is reacted with ethyne to obtain 5,5′-(ethyne-1,2-diyl)bis(isobenzofuran-1,3-dione).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[S:8])[NH2:7])=[CH:4][CH:3]=1.[Br:11][CH2:12][C:13](=O)[CH2:14][CH3:15]>C(O)C>[BrH:11].[CH2:14]([C:13]1[N:7]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([OH:1])=[CH:3][CH:4]=2)[S:8][CH:12]=1)[CH3:15]
Reactant: NC(=S)c1ccc(O)cc1
Reactant: CCC(=O)CBr
Solvent: CCO
Product: Br
Product: CCc1csc(-c2ccc(O)cc2)n1
Reaction time: 5 h
Yield: 65.2 %

Procedure:
A mixture of 4.6 parts of 4-hydroxybenzothioamide, 4.5 parts of 1-bromo-2-butanone and 79 parts of ethanol was stirred for 5 hours at reflux temperature. After cooling, the precipitate was filtered off and dried in vacuo at 50° C., yielding 5.6 parts (65.2%) of 4-(4-ethyl-2-thiazolyl)phenol hydrobromide (interm. 14).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:32]=[C:33]([O:44][CH2:45][CH2:46][O:47][C:48](=[O:56])[NH:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=3)[C:34]=2[O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:42][CH3:43])[C:18]([NH:20][CH2:21][C:22]([O:24]CC2C=CC=CC=2)=[O:23])=[O:19])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:32]=[C:33]([O:44][CH2:45][CH2:46][O:47][C:48](=[O:56])[NH:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][N:51]=3)[C:34]=2[O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:42][CH3:43])[C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc(C(=O)NCC(=O)OCc2ccccc2)cc1OCCOC(=O)Nc1ccccn1
Agent: [Pd]
Solvent: CO
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc(C(=O)NCC(=O)O)cc1OCCOC(=O)Nc1ccccn1

Procedure:
By hydrogenating benzyl {3-(4-tert-butyl-benzenesulphonylamino)-4-(2-methoxy-phenoxy)-5-[2-(pyridin-2-ylcarbamoyloxy)-ethoxy]-benzoylamino}-acetate, described in Example 18, in methanol over palladium/charcoal at RT and under normal pressure there was obtained {3-(4-tert-butyl-benzenesulphonylamino)-4-(2-methoxy-phenoxy)-5-[2-(pyridin-2-ylcarbamoyloxy)-ethoxy]-benzoylamino}-acetic acid.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].C([Li])CCC.Br[CH2:11][C:12]1[C:16]2[N:17]([CH3:27])[CH:18]=[C:19]([C:22]([O:24]CC)=O)[C:20](=[O:21])[C:15]=2[S:14][CH:13]=1.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>C1COCC1.CN(C=O)C.CCOCC>[CH2:1]([O:4][CH2:11][C:12]1[C:16]2[N:17]([CH3:27])[CH:18]=[C:19]([C:22]([NH:34][CH2:33][C:32]3[CH:35]=[CH:36][C:29]([Cl:28])=[CH:30][CH:31]=3)=[O:24])[C:20](=[O:21])[C:15]=2[S:14][CH:13]=1)[CH:2]=[CH2:3]
Reactant: NCc1ccc(Cl)cc1
Reactant: C=CCO
Reactant: CCOC(=O)c1cn(C)c2c(CBr)csc2c1=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCOCc1csc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 120 °C
Reaction time: 0.08 h

Procedure:
To a cold (0° C.), stirred solution of 0.82 mL of allyl alcohol in 12 mL of dry THF, under argon, is added 2.1 mL of a 2.5 M solution of butyllithium in hexanes. The solution is stirred for 5 min, then added via cannula to a cold (0° C.), stirred mixture of 1.25 g of ethyl 3-(bromomethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate (Preparation 19) in 8 mL of dry DMF. The resulting solution is stirred at 0° C. for 20 min, then quenched with dil. HCl. Aqueous workup (EtOAc/dil HCl) followed by flash chromatography on silica using 3% MeOH in CH2Cl2 affords a mixture of ethyl and allyl esters (873 mg). A mixture of 165 mg of the mixed esters and 580 mg of p-chlorobenzylamine is heated at 120° C. for 18 h, then cooled and diluted with ether. The resulting solid is filtered, washed well with ether, and dried in vacuo. Flash chromatography of the solid on silica using 2% MeOH in CH2Cl2 provides 922 mg of the title compound as a pale yellow solid. Recrystallization from EtOAc affords glistening yellow prisms.
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:14][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:15]([O-:17])=[O:16])[C:8]=1[S:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1
Reactant: Sc1ncc[nH]1
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(Cl)c1Sc1ncc[nH]1
Temperature: 0 °C
Yield: 94 %

Procedure:
Acetonitrile (20 ml) suspension of 2-mercaptoimidazole (1.0 g) and 2,3-dichloronitrobenzene (2.1 g), potassium carbonate (1.7 g) was stirred under refluxing for 6.5 hours. The reaction mixture was poured into ice-water. The deposited solids were collected by filtration, and washed with n-hexane. The thus obtained solids were dried, there was obtained 2-(2-chloro-6-nitrophenylthio)imidazole (2.4 g, yield: 94%) as yellow powdery product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>C(Cl)Cl>[ClH:1].[CH:17]([C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8]([C:7]2[C:2]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])=[CH:12][CH:13]=1)([CH3:19])[CH3:18]
Reactant: NCc1ccncc1
Reactant: CC(C)c1ccc(NC(=O)c2cccnc2Cl)cc1
Solvent: ClCCl
Product: CC(C)c1ccc(NC(=O)c2cccnc2NCc2ccncc2)cc1
Product: Cl
Temperature: 130 °C

Procedure:
A mixture of (2-chloro(3-pyridyl))-N-(4-isopropylphenyl)carboxamide (1.5 g, from Step A) and 4-aminomethylpyridine (0.71 ml) was heated at 130° C. neat for 3 h. The reaction was cooled and diluted with CH2Cl2 and washed with H2O twice followed by brine. The organic layer was dried with Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography with EtOAc and further mixed with MeOH and 1 N HCl/Et2O (2 ml). The solution was evaporated to furnish the titled compound. MS (ES+): 347 (M+H)+; (ES−): 345 (M−H). Calc'd. for C21H22N4O—346.18.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@@H:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27]([OH:29])=O)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:33]C[C@H](C1C=CC=CC=1)O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[N:8]=[C:9]([C@@H:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27]([NH2:33])=[O:29])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC[C@@H](O)c1ccccc1
Reactant: O=C(O)c1cccc(C[C@@H]2CCC[C@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(C[C@@H]2CCC[C@H]2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 122 %

Procedure:
To a mixture of 3-{[(1S,2R)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}benzoic acid (76 mg, 0.18 mmol) and (S)-2-amino-1-phenylethanol (30 mg, 0.22 mmol) in DMF (4 ml) was added 1-hydroxybenzotriazole (36 mg, 0.27 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (69 mg, 0.36 mmol). After stirring the resulting mixture at room temperature for 2 hours, the reaction mixture was diluted with EtOAc (30 ml), washed with 1N-hydrochloric acid, water, saturated sodium hydrogencarbonate solution, water and brine successively, dried dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:EtOAc, 1:1 elution) to give N-1(2S)-2-hydroxy-2-phenylethyl]-3-{[(1S,2R)-2-(4,5-diphenyloxazol-2-yl)-1-cyclopentyl]methyl}benzamide (92.8 mg, 95%).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].Br[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26]>>[NH2:15][C:7]1[C:6]([C:4]([C:20]2[CH:21]=[C:22]([F:24])[CH:23]=[CH:18][C:19]=2[C:25]([F:26])([F:27])[F:28])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: Fc1ccc(C(F)(F)F)c(Br)c1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Product: CCSc1ncc(C(=O)c2cc(F)ccc2C(F)(F)F)c(N)n1

Procedure:
The compound was prepared from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, Example 1, and 2-bromo-4-fluoro-1-trifluoromethyl-benzene (Aldrich) in an analogous manner as described in Example 169.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:23])[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Cl)=[CH:29][CH:28]=1>CN(C)C=O>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][O:1][C:2]2[CH:3]=[C:4]([C:8](=[O:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][CH:7]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)CCC(C(=O)c1cccc(O)c1)c1ccccc1C
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCC(C(=O)c1cccc(OCc2ccc(Cl)cc2)c1)c1ccccc1C
Temperature: 60 °C
Yield: 87.2 %

Procedure:
A stirred solution of methyl (RS)-5-[3-(hydroxy)phenyl]-4-(2-methylphenyl)-5-oxo-pentanoate (1.68 g) in dimethylformamide (20 mL) is treated with 60% sodium hydride in oil (237 mg). After 15 minutes the mixture is treated with 4-chlorobenzyl chloride (953 mg) and heated at 60° C. for 1 hour. The reaction mixture is evaporated, the residue is dissolved in diethyl ether, washed with water, dried, and evaporated, to give methyl (RS)-5-[3-(4-chlorobenzyloxy)phenyl]-4-(2-methylphenyl)-5-oxopentanoate (2.05 g), in the form of a colouriess oil. [NMR(CDCl3):- 2.0-2.5(4H,m),2.5(3H,s), 3.65(3H,s), 4.8(1H,m),5.0(2H,q),7.0-7.5(12H)].
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]2[CH:13]=[C:12]([CH2:14][CH2:15][CH:16]=O)[O:11][N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:18]([N:25]1[CH2:30][CH2:29][N:28]([CH2:16][CH2:15][CH2:14][C:12]2[O:11][N:10]=[C:9]([CH:8]=[CH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:13]=2)[CH2:27][CH2:26]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=CCCc1cc(C=Cc2ccccc2)no1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C(=Cc1cc(CCCN2CCN(Cc3ccccc3)CC2)on1)c1ccccc1
Yield: 68.4 %

Procedure:
About 2 min after dissolving 3-[3-(2-phenylvinyl)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-benylpiperazine (7.6, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (28 mg, 0.13 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 16.4 hr and followed the same processes as in Example 1 to obtain 10.6 mg (62.2%) of the target compound.
Reaction SMILES: [Br-:1].O([CH2:9][CH2:10][P+:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C1C=CC=CC=1.[CH3:30][NH2:31]>C(O)C>[Br-:1].[PH4+:11].[CH3:30][NH:31][CH2:9][CH2:10][P+:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Br-:1]
Reactant: CN
Reactant: c1ccc(OCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCO
Product: CNCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [PH4+]

Procedure:
The required β-methylaminoethyltriphenylphosphonium phosphonium bromide was prepared by heating a mixture of β-phenoxyethyltriphenyl phosphonium-bromide (46.2 g.) dissolved in ethanol (80 ml.) and 33% ethanolic methylamine (130 ml.) in an autoclave at 100°C for three hours. After cooling, the product was precipitated by addition of dry ether (2 1.) filtered, washed with ether and dried, and had a melting point of 226°C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:12])=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(C(C)C)CC)(C)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>CC#N.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)c1ccc(Br)cc1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)o1
Reaction time: 12 h
Yield: 63.3 %

Procedure:
To a solution of the product of Step 1 (1.00 g, 2.43 mmol), PPh3 (1.00 g, 3.71 mmol) and diisopropylethylamine (1.3 mL, 7.28 mmol) in CH3CN (30 mL) was added hexachloroethane (0.812 g, 3.43 mmol) as a solid, portion-wise. The mixture was allowed to stir for 12 hours. TLC (3:1 hexanes:ethyl acetate) indicated the presence of starting material. Therefore, additional PPh3 (0.65 g, 2.43 mmol) and hexachloroethane (0.575 g, 2.43 mmol) were added and stirring continued for 4 hours. The solvent was removed in vacuo, the residue diluted with ethyl acetate-H2O and the layers separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed (H2O, brine), dried (Na2SO4), and filtered. The solvent was removed in vacuo and the residue purified by flash column chromatography (3:1 hexanes:ethyl acetate) to provide (S)-tert-butyl 2-(5-(4-bromophenyl)oxazol-2-yl)pyrrolidine-1-carboxylate (0.605 g, 63%). 1HNMR (400 MHz, DMSO-d6) δ 7.60-7.68 (m, 5H), 4.80-4.91 (m, 1H), 3.46-3.51 (m, 1H), 3.33-3.39 (m, 1H), 2.18-2.31 (m, 1H), 1.84-1.99 (m, 3H), 1.36 (s, 4H), 1.15 (s, 5H). LCMS: Anal. Calcd. for C18H21BrN2O3: 392. found: 393 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH2:12]([S:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH3:13].[CH3:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:32][C@@H:33]1[CH2:37][CH2:36][CH2:35][NH:34]1>>[CH2:12]([S:14]([C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([N:34]3[CH2:35][CH2:36][CH2:37][C@H:33]3[CH2:32][N:28]3[CH2:29][CH2:30][CH2:31][C@H:27]3[CH3:26])=[O:8])=[C:4]([F:11])[CH:3]=2)=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH3:13]
Reactant: CCS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Reactant: O=C(O)c1ccc(Br)cc1F
Product: CCS(=O)(=O)c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCC[C@H]3C)c(F)c2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure A′, T′ and B′ starting from 4-bromo-2-fluoro-benzoic acid, 4-ethanesulfonylphenyl boronic acid and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine. MS (M+H) 459.2
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[C:19]([N:27]3[CH2:32][CH2:31][CH2:30][C@H:29]([NH:33]C(=O)OC(C)(C)C)[CH2:28]3)=[C:20]3[CH2:26][CH2:25][CH2:24][C:21]3=[N:22][CH:23]=2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:41].C(O)(C(F)(F)F)=O>C(Cl)Cl.CO.[NH4+].[OH-]>[NH2:33][C@H:29]1[CH2:30][CH2:31][CH2:32][N:27]([C:19]2[C:18]([NH:17][C:15]([C:13]3[CH:12]=[CH:11][C:10]([F:41])=[C:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[N:14]=3)=[O:16])=[CH:23][N:22]=[C:21]3[CH2:24][CH2:25][CH2:26][C:20]=23)[CH2:28]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: N[C@H]1CCCN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
A solution of tert-butyl {(3S)-1-[3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]piperidin-3-yl}carbamate (4.0 mg, 0.0070 mmol) in DCM (0.02 mL) was treated with TFA (0.03 mL, 0.4 mmol). The resulting reaction mixture was stirred at room temperature for 30 min. and then concentrated to give a residue, which was diluted with MeOH and neutralized with small amount of NH4OH. After filtration, the crude was purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to afford the title compound (2.2 mg, 67%). LCMS calc. for C25H25F3N5O (M+H)+: m/z=468.2. Found: 468.1.
Reaction SMILES: [C:1]([C:5]1[C:18]2[C:19]3=[C:20]4[C:15](=[CH:16][CH:17]=2)[CH:14]=[CH:13][CH:12]=[C:11]4[CH:10]=[CH:9][C:8]3=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:28])C(=O)C1>COCCOC>[Br:28][C:6]1[CH:7]=[C:8]2[C:19]3=[C:20]4[C:15]([CH:14]=[CH:13][CH:12]=[C:11]4[CH:10]=[CH:9]2)=[CH:16][CH:17]=[C:18]3[C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2ccc3cccc4ccc1c2c34
Reactant: O=C1CCC(=O)N1Br
Solvent: COCCOC
Product: CC(C)(C)c1c(Br)cc2ccc3cccc4ccc1c2c34
Temperature: 0 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Next, 25.0 g (0.10 mol) of tert-butylpyrene and 250 ml of DME (1,2-dimethoxyethane) were charged in a reaction vessel, and the mixture was cooled to 0° C. Next, NBS was added in an amount of 4 equivalents relative to tert-butylpyrene, and the resulting mixture was stirred overnight at room temperature, filtered, and recrystallized to produce 29.5 g of bromo-tert-butylpyrene crystals in a yield of 90%.