Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]2([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[O:46][CH2:45][CH2:44][O:43]2)[C@@:22]([OH:33])([CH2:30][CH2:31]O)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].C(N(S(F)(F)[F:60])CC)C>O1CCCC1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]2([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[O:46][CH2:45][CH2:44][O:43]2)[C@:22]([CH2:30][CH2:31][F:60])([OH:33])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC2(CCCCCCC)OCCO2)[C@@](O)(CCO)C(=O)OC(C)(C)C)C(=O)OC)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: C1CCOC1
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC2(CCCCCCC)OCCO2)[C@@](O)(CCF)C(=O)OC(C)(C)C)C(=O)OC)cc1
Reaction time: 4 h
Yield: 45.2 %

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-2-(2-hydroxy-ethyl)-undec-4-enoate (157 mg, 0.211 mmol) was dissolved in tetrahydrofuran (5.0 mL), and (diethylamino)sulfur trifluoride (0.0360 mL, 0.273 mmol) was then added at room temperature. The mixture was stirred for 4 hours, then quenched with a saturated aqueous solution (15 mL) of sodium bicarbonate, and extracted with dichloromethane (15 mL). The organic layer was then dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure. The residue was purified on Biotage (silica gel, n-hexane/ethyl acetate) to obtain 71.1 mg (0.0953 mmol, 45% yield) of tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-(2-fluoro-ethyl)-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-undec-4-enoate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11](C)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(COC)OC>[F:15][C:16]1[CH:21]=[C:20]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:3]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1ccc(-c2cccc(Br)c2)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Fc1cccc(-c2cccc(-c3ccccn3)c2)c1

Procedure:
To a 500 mL. three-necked round bottom flask equipped with a stir bar, temperature probe, and a nitrogen inlet were added 2-(3-bromophenyl)-5-methylpyridine (14.7 g, 60 mmol), 3-fluorophenylboronic acid (10.0 g, 72 mmol), palladium (II) acetate (0.335 g, 1.5 mmol), triphenylphosphine (1.56 g, 6.0 mmol), sodium carbonate (17.0 g, 160 mmol), containing dimethoxyethane (120 mL.) and water (80 mL.). The solution was heated at reflux for twenty hours, cooled, and diluted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, and evaporated to dryness to give a brown liquid, which was purified by flash silica gel chromatography using a 5/95 to 10/90 ethyl acetate/hexane gradient, yielding a viscous, colorless liquid (12.5 g 80%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][C:11]([C:19](=[O:22])[CH2:20]Br)=[CH:12][CH:13]=3)[C:8](=[O:23])[C:7]=2[CH:6]=1)=[O:4].[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>O1CCCC1>[CH2:24]([N:26]([CH2:27][CH3:28])[CH2:2][C:3]([C:5]1[CH:18]=[CH:17][C:16]2[O:15][C:14]3[C:9](=[CH:10][C:11]([C:19](=[O:22])[CH2:20][N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])=[CH:12][CH:13]=3)[C:8](=[O:23])[C:7]=2[CH:6]=1)=[O:4])[CH3:25]
Reactant: O=C(CBr)c1ccc2oc3ccc(C(=O)CBr)cc3c(=O)c2c1
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)CC(=O)c1ccc2oc3ccc(C(=O)CN(CC)CC)cc3c(=O)c2c1
Temperature: -20 °C

Procedure:
To a mixture of 2,7-bis(2-bromoacetyl)xanthen-9-one in tetrahydrofuran is added diethylamine, each cooled to -20°C. The reaction mixture is maintained at -20°C. for 24 hours then allowed to warm slowly to room temperature and then maintained at room temperature for 5 days. The mixture is filtered, and the filtrate evaporated to dryness. The resulting residue is dissolved in dilute HCl, filtered and the filtrate is made alkaline, keeping the temperature of the mixture around 0°C. The mixture is extracted with methylene chloride, and the extract acidified to Congo Red. The resulting solid is filtered off and recrystallized from methanol-diethylether to give the desired product.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:18](C(OCC)=O)[C:19]([O:21]CC)=[O:20])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])C1C=CC=CC=1.Cl>C(O)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH2:18][C:19]([OH:21])=[O:20])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc([N+](=O)[O-])c(O)c1
Temperature: 25 °C

Procedure:
A mixture of diethyl 3-benzyloxy-4-nitrophenylmalonate (22.0 g, 57.8 mmol), acetic acid (200 ml) and concentrated hydrochloric acid (100 ml) was heated under reflux for 15 hours under stirring. After the reaction mixture was cooled to room temperature, the solvent was distilled off from the reaction mixture under reduced pressure. The solid thus obtained was collected by filtration under reduced pressure, followed by drying under reduced pressure, whereby the title compound (5.45 g, 48%) was obtained as a pale yellow amorphous substance.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[CH:4][C:5]([CH2:9][OH:10])=[C:6]([OH:8])[CH:7]=1.[Br:12][CH2:13][CH:14](OC)OC.OS(O)(=O)=O>C1COCC1>[Br:1][C:2]1[C:3]([F:11])=[CH:4][C:5]2[CH2:9][O:10][CH:14]([CH2:13][Br:12])[O:8][C:6]=2[CH:7]=1
Reactant: COC(CBr)OC
Reactant: OCc1cc(F)c(Br)cc1O
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: Fc1cc2c(cc1Br)OC(CBr)OC2
Yield: 45.7 %

Procedure:
Preparation according to Preparation 9. 5-bromo-4-fluoro-2-(hydroxymethyl)phenol (2.3 g, 10.4 mmol), 2-bromo-1,1-dimethoxyethane (9.9 ml, 83 mmol), dry THF (30 ml) and concentrated H2SO4 (4 ml) were heated at 55° C. for 2 h. Purification by flash column chromatography (isooctane/EtOAc 10:1) gave the title compound (1.55 g). MS m/z (rel. intensity, 70 eV) 328 (M+, 11), 326 (M+, 23), 324 (M+, 12) 204 (98), 202 (bp), 176 (41), 174 (43), 95 (59).
Reaction SMILES: [CH:1](/[CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].N.[Li]>C(OCC)C.C(O)C>[CH:1](/[C@H:6]1[CH2:7][CH2:8][C@H:9]([OH:12])[CH2:10][CH2:11]1)=[CH:2]\[CH2:3][CH2:4][CH3:5]
Reactant: CCC/C=C/C1CCC(=O)CC1
Agent: N
Agent: [Li]
Solvent: CCOCC
Solvent: CCO
Product: CCC/C=C/[C@H]1CC[C@H](O)CC1
Reaction time: 1.5 h
Yield: 89.1 %

Procedure:
1.63 g of 4-(trans-1-pentenyl)cyclohexanone were dissolved in 8 ml of diethyl ether and 14 ml of ethanol. Subsequently, the solution was treated dropwise with about 70 ml of ammonia and portionwise with lithium wire until the colour of the mixture remained constant for 1.5 hours (about 1.3 g of lithium). Thereafter, the ammonia was removed by evaporation and the mixture was made acid with ammonium chloride and hydrochloric acid and left to stand for 3 days. The mixture was then partitioned in diethyl ether/water and the aqueous phases were back-extracted with diethyl ether. The organic phases were dried over magnesium sulphate, filtered and freed from solvent on a rotary evaporator. Low-pressure chromatography of the resulting, yellow oil on silica gel with ethyl acetate/petroleum ether (vol. 10:90) gave 1.47 g (89.1%) of trans-4-(trans-1-pentenyl)cyclohexanol as a light yellow, viscous oil.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12](I)=[C:13]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1B1OC(C)(C)C(C)(C)O1>>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:28]2[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]=2[F:26])=[C:13]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Product: Cc1ccc(-c2c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3sc4c(c23)CCCC4)c(F)c1

Procedure:
The title compound was prepared from Methyl (2S)-tert-butoxy(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)acetate (Preparation 16, 100 mg, 212 μmol) and 2-(2-fluoro-4-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 19, 99 mg, 424 μmol) using the same method as described in Example 44, Step 1 to yield 100 mg, 96%. Material obtained was a mixture of atropisomers, in a 2:1 ratio.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2Cl.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH:18]=[CH:17]2>ClCCCl.C(O)(C)(C)C>[C:26]1([S:23]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([NH:13][C:5]4[C:4]5[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=5)[N:8]=[CH:7][N:6]=4)=[CH:22][CH:21]=3)[CH:17]=[CH:18]2)(=[O:24])=[O:25])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Nc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reactant: Clc1ncnc2ccc(I)cc12
Solvent: CC(C)(C)O
Solvent: ClCCCl
Product: O=S(=O)(c1ccccc1)n1ccc2cc(Nc3ncnc4ccc(I)cc34)ccc21
Yield: 74.8 %

Procedure:
6-iodo-4-chloroquinazoline (2.38 g, 8.20 mmol) and 5-amino-1-benzenesulfonylindole (2.46 g, 9.00 mmol) were combined in DCE (20 mL) and t-butanol (20 mL). The resulting mixture was heated at reflux under nitrogen for 18 hours to form a bright yellow suspension. Upon cooling the solids were filtered and rinsed with CH2Cl2 and placed under high vacuum to remove any excess solvent. Quinazoline 14 (3.23g, 75%) was obtained as a yellow solid. 1H NMR (DMSO d6; 400 MHz): δ: 9.24 (s, 1H, NH), 8.84 (s, 1H), 8.33 (dd, 1H, 8.9 Hz, 1.7 Hz), 8.01 (m, 4H), 7.90 (m, 2H), 7.70 (m, 2H), 7.60 (m, 3H), 6.92 (dd, 1 H, J=3.7 Hz, 0.6 Hz).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH:12]([CH2:17][CH2:18][CH3:19])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH:12]([CH2:17][CH2:18][CH3:19])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCC1CN(Cc2ccccc2)CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCC1CN(Cc2ccccc2)CCC1O
Reaction time: 1 h

Procedure:
Sodium borohydride (0.5 g, 15.6 mmole) was added to the stirred solution of 1-benzyl-3-n-propylpiperidin-4-one (4.0 g, 17.3 mmole) in methanol (25 ml) at 0-5° C. over a period of 5 min, and stirring was continued for 1 hr at ambient temperature. The reaction mixture was concentrated to dryness, triturated with water (20 ml) and extracted with ethyl acetate. The ethyl acetate extract was dried (Na2SO4) and concentrated to dryness to furnish 1-benzyl-4-hydroxy-3-n-propylpiperidine as oil. Yield 3.3 g (81%), C15H23NO, m/z 234 (M+l).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6])[CH3:2].ClCCl.Cl[CH2:13]/[CH:14]=[CH:15]\[CH2:16]Cl.CCCCCC>CCCCCC.C(OCC)(=O)C>[N:6]1([C@@H:5]([CH3:7])[C:4]([O:3][CH2:1][CH3:2])=[O:8])[CH2:16][CH:15]=[CH:14][CH2:13]1
Reactant: CCOC(=O)[C@H](C)N
Reactant: ClC/C=C\CCl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](C)N1CC=CC1
Yield: 56.7 %

Procedure:
From L-alanine ethyl ester (383 mg, 3.2 mmol), dichloromethane (0.1 ml) and cis-1,4-dichloro-2-butene (140 mg, 1.0 mmol). Flash chromatography: silica gel, gradient neat hexane to hexane:ethyl acetate (1:2) afforded the product (96 mg, 52%) as yellow oil.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:30]=[CH:31][CH:32]=[CH:33][C:8]1=2)=[O:6])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:40](OC(=O)C)(=[O:42])[CH3:41].[OH-].[Na+]>ClCCl>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:40](=[O:42])[CH3:41])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:27])[F:28])[CH:17]=2)[C:9]2[CH:30]=[CH:31][CH:32]=[CH:33][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.4 %

Procedure:
A solution of crude 5-(3,5-Bis-trifluoromethyl-benzylamino)-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (200 mg, 0.42 mmol) and pyridine (0.85 ml, 10.5 mmol) in dichloromethane (2 ml) at room temperature was treated with acetic anhydride (0.79 ml, 8.4 mmol) via dropwise addition over 4 minutes. The mixture was stirred at room temperature for 20 hours. The mixture was cooled (0° C.) and treated with 1N NaOH and stirred for 30 minutes. The aqueous layer was extracted with dichloromethane. The combined organic phases were washed with 1N HCl, dried (Na2SO4) and concentrated to an oil. Purification by silica gel chromatography (eluent, 2:1 n-hexanes:ethyl acetate) provided 5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (144 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][NH:10][C@@H:9]2[C@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.Br[C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20]([Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[CH:21]=[CH:22][C:15]=12.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[H+].[B-](F)(F)(F)F.C(O[Na])(C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[NH:3][C@@H:4]2[C@H:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[N:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[N:20]([Si:23]([CH:27]([CH3:29])[CH3:28])([CH:30]([CH3:32])[CH3:31])[CH:24]([CH3:25])[CH3:26])[CH:21]=[CH:22][C:15]=23)[CH2:11]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Br)ccnc21
Reactant: CC1(C)CN[C@H]2CCCC[C@@H]2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(N3CC(C)(C)N[C@H]4CCCC[C@@H]43)ccnc21
Yield: 83.7 %

Procedure:
A toluene (5 mL) suspension of (4aS,8aS)-2,2-dimethyldecahydroquinoxaline (200 mg, 1.19 mmol), 4-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (462 mg, 1.31 mmol), Pd(OAc)2 (13.3 mg, 0.0594 mmol), tBu3P.HBF4 (17.2 mg, 0.0594 mmol), and t-BuONa (137 mg, 1.43 mmol) was stirred at 100° C. for 4 hours in a nitrogen atmosphere. Insoluble matter was filtered through celite, and the filtrate was concentrated. The obtained residue was purified by basic silica gel column chromatography (AcOEt/hexane) to obtain (4aS,8aS)-3,3-dimethyl-1-(1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)decahydroquinoxaline (439 mg, 84%) in a white amorphous solid form.
Reaction SMILES: BrBr.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:23])[CH2:11][CH2:12][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:6][CH:5]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>CCOCC.O1CCOCC1>[N:24]([CH:11]([C:10]([C:7]1[CH:6]=[CH:5][C:4]([Br:3])=[CH:9][CH:8]=1)=[O:23])[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CCC(=O)c1ccc(Br)cc1)OCc1ccccc1
Agent: BrBr
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: [N-]=[N+]=NC(CC(=O)OCc1ccccc1)C(=O)c1ccc(Br)cc1
Reaction time: 6 h
Yield: 95 %

Procedure:
Bromine (2.5 mL, 46.1 mmol) was added to a solution of Example J5, benzyl 4-(4-bromophenyl)-4-oxobutanoate (16 g, 46.1 mmol) in ether (200 mL) and 1,4-Dioxane (50 mL) and the solution was stirred for 6 hours before being concentrated by rotory evaporation and taken up in acetonitrile (450 mL). Sodium azide (3.0 g, 46.1 mmol) was added and the reaction mixture stirred 18 hours. The solvent was removed upon concentration and the residue taken up in ethyl acetate and wash with water, brine, dried Na2SO4, and filtered. Concentration gave benzyl 3-azido-4-(4-bromophenyl)-4-oxobutanoate 17 g (95%) which was carried forward without further purification. Tin (II) chloride dehydrate (24.9 g, 131 mmol) was added to a solution of benzyl 3-azido-4-(4-bromophenyl)-4-oxobutanoate (17 g, 43.8 mmol) in CH3OH (550 mL) and stirred for 14 hours at 65° C. The reaction was concentrated by rotory evaporation and dried under high vacuum for 18 hours to give a mixture of benzyl and Example J6, methyl 3-amino-4-(4-bromophenyl)-4-oxobutanoate, (transesterification had occurred) and carried forward with purification. RT=1.3 minutes (condition 1); LCMS: Anal. C11H12BrNO3 Calcd. 286.0; found: 286.14 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH:12]1[CH3:21].Cl[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH:12]2[CH3:21])=[CH:25][CH:26]=1
Reactant: COC(=O)N1CCC(Nc2nc3ccccc3[nH]2)C(C)C1
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)C(C)C1
Temperature: 70 °C
Yield: 38 %

Procedure:
A mixture of 19 parts of methyl 4-(1H-benzimidazol-2-ylamino)-3-methyl-1-piperidinecarboxylate, 11 parts of 1-(chloromethyl)-4-fluorobenzene, 6 parts of sodium carbonate and 135 parts of N,N-dimethylformamide is stirred and heated overnight at 70° C. The reaction mixture is cooled and poured onto water. The product is extracted three times with methylbenzene. The combined extracts are dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 8 parts (38%) of methyl 4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-3-methyl-1-piperidinecarboxylate; mp. 172.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:13]2[CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C=O.[C:26]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:9]2[CH:13]1[CH2:12][N:11]([CH3:26])[CH2:10]2)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C2CNCC21
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CC2C(C1)N(C(=O)OC(C)(C)C)CCN2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
Added to a solution of 29 mg of the thus obtained 2,5-bis-tert-butoxycarbonyl-2,5,8-triazabicyclo[4,3,0]-nonane in acetonitrile (0.7 ml) were 0.038 ml (0.51 mmol) of a 37% aqueous solution of formaldehyde and 9.4 mg (0.15 mmol) of sodium cyanoborohydride. After the mixture was stirred for 1 hour and 20 minutes at room temperature, acetic acid was added until the reaction mixture reached pH 4, and the resultant mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure, and the resultant crude oil was purified by column chromatography on silica gel, thereby obtaining 29 mg (yield: 96%) of the title compound as a colorless oil.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl.C(O)C>C(O)C>[N:1]1([CH2:6][CH2:7][O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)CCc1ccccc1COCCN1CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1ccccc1COCCN1CCCC1

Procedure:
The solution of ethyl 3-(2-{[2-(1-pyrrolidinyl)ethoxy]methyl}phenyl)propanoate (8.10 g, 26.5 mmol) in ethanol (40 ml) and 5N NaOH aq. solution (32.0 mmol, 6.4 ml) was stirred at room temperature for 15 h. The mixture was neutrallized with 1N HCl-ethanol (32 ml) at 0° C. The solvents were removed by simple distillation procedure at ˜1 atom (oil bath temperature; 105˜110° C.). The residue was then diluted with acetonitrile (50 ml) and then the solvents were removed by distillation (oil bath temperature; 105˜110° C.) for azeotropic removal of water and ethanol until inner temperature 79.5° C.˜80.5° C. The residue was then diluted with acetonitrile (60 ml) and dried over sodium sulfate. After filtration, the filtrate was evaporated in vacuo to afford the titled compound (quant.) as a dark yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:5][CH:4]=1)#[CH:2].[CH3:16][C:17]1([CH3:24])[C:21]([CH3:23])([CH3:22])[O:20][BH:19][O:18]1>C1(C)C=CC=CC=1>[CH3:16][C:17]1([CH3:24])[C:21]([CH3:23])([CH3:22])[O:20][B:19](/[CH:2]=[CH:1]/[C:3]2[CH:15]=[CH:14][C:6]([CH2:7][N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)=[CH:5][CH:4]=2)[O:18]1
Reactant: CC1(C)OBOC1(C)C
Reactant: C#Cc1ccc(CN2CCOCC2)cc1
Solvent: Cc1ccccc1
Product: CC1(C)OB(/C=C/c2ccc(CN3CCOCC3)cc2)OC1(C)C
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
An oven-dried round-bottom flask was cooled under N2 (g) and then charged with 4-(4-ethynylbenzyl)morpholine (120 mg, 0.596 mmol), toluene (2.5 mL), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.43 mL, 2.98 mmol). The mixture was stirred for 15 min while purging the solution with N2 (g). HRuCl(CO)(PPh3)3 (29 mg, 0.030 mmol) was then added and the reaction heated to 50° C. for 18 h. The reaction was quenched with NaHCO3 (sat.) (10 mL), extracted with EtOAc, and the organic layer washed with brine (2×) and then dried over MgSO4. The solvent was removed and the resulting residue purified by column chromatography (silica gel, Hexanes/EtOAc, 2:3 to 1:2) to give a white solid (155 mg, 79%). 1H NMR (400 MHz, CDCl3) δ 7.44 (d, 2H, J=8.0 Hz), 7.38 (d, 1H, J=18.8 Hz), 7.30 (m, 2H), 6.15 (d, 1H, J=18.5 Hz), 3.72 (bs, 4H), 3.49 (bs, 2H), 2.45 (bs, 4H), 1.31 (s, 12H); MS ESI 330.1 [M+H]+, calcd for [C19H28BNO3+H]+330.22.
Reaction SMILES: O1CCC[CH2:2]1.CC(C)([O-])C.[K+].[CH:12]([Si:15]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[O:16][CH2:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])=O)=[CH:20][CH:19]=1)([CH3:14])[CH3:13]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH:12]([Si:15]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[O:16][CH2:17][C:18]1[CH:33]=[CH:32][C:21]([C:22]([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[C:27]#[N:28])=[CH2:2])=[CH:20][CH:19]=1)([CH3:14])[CH3:13]
Reactant: C1CCOC1
Reactant: CC(C)[Si](OCc1ccc(C(=O)c2cccc(C#N)c2)cc1)(C(C)C)C(C)C
Agent: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Product: C=C(c1ccc(CO[Si](C(C)C)(C(C)C)C(C)C)cc1)c1cccc(C#N)c1
Temperature: 0 °C

Procedure:
A mixture of methyltriphenylphosphonium bromide (0.2 g, 0.56 mmol) and tetrahydrofuran (10 mL) is stirred at 0° C. Potassium tert-butoxide (72 mg, 0.64 mmol) is added and the yellow solution is stirred 10 min at room temperature. The solution is cooled to 0° C. and 3-(4-Triisopropylsilanyloxymethyl-benzoyl)-benzonitrile (0.2 g, 0.51 mmol) is added. The resulting orange reaction is stirred 1 hr at room temperature. The reaction is diluted with water and extracted with ethyl acetate (2×50 mL). The extracts are combined, dried on magnesium sulfate, filtered, and concentrated. The residue is purified via silica chromatography eluting with hexanes to 9:1 hexanes:ethyl acetate to give 90 mg, 45%, as a colorless wax. 1H NMR (CDCl3) δ 7.60-7.67 (m, 3H), 7.47 (t, 1H), 7.37-7.40 (m, 2H) 7.27-7.28 (2H), 5.60 (s, 1H), 5.50 (s, 1H), 1.10-1.29 (m, 21H).