Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:15].C([O-])([O-])=O.[K+].[K+].[CH2:22]([O:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH2:23][CH3:24].CC#N>O.CCOC(C)=O>[CH2:22]([O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]2=[O:15])[CH2:28][CH2:27]1)[CH2:23][CH3:24]
Reactant: O=c1ccc2ccccc2n1CCCCl
Reactant: CCCOC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCOC1CCN(CCCn2c(=O)ccc3ccccc32)CC1
Temperature: 50 °C
Reaction time: 24 h
Yield: 58.9 %

Procedure:
A 4 mL vial was charged with 1-(3-chloropropyl)-1H-quinolin-2-one (0.069 g, 0.31 mmol), K2CO3 (0.069 g, 0.50 mmol), KI (0.083 g, 0.50 mmol), 4-propoxypiperidine (0.050 g, 0.35 mmol) and dry CH3CN (2 mL). The mixture was shaken at 50° C. for 24 h and thereafter diluted with water (25 mL) and EtOAc (25 mL). The phases were separated and the water phase was extracted with EtOAc (2×50 mL). The combined organic phase was then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash CC (SiO2; EtOAc/MeOH 4:1) followed by prep RP-HPLC to give the title compound (0.060 g, 59%). 1H NMR (CD3OD) δ 7.85 (d, J=9.4 Hz, 1H), 7.65 (brd, J=7.2 Hz, 1H), 7.63 (m, 2H), 7.29-7.22 (m, 1H), 6.62, (d, J=9.4 Hz), 4.36-4.29 (m, 1H), 3.38 (t, J=6.6 Hz, 2H), 3.34-3.24 (m, 1H), 2.78-2.69 (m, 2H), 2.48-2.41 (m, 2H), 2.18-2.09 (m, 2H), 1.94-1.82 (m, 4H), 1.59-1.47 (m, 4H), 0.90 (t, J=7.4 Hz); 13C NMR (CD3OD) δ 162.0, 140.3, 139.0, 131.1, 129.2, 122.6, 121.4, 120.3, 114.7, 74.7, 69.5, 55.4, 51.0, 40.6, 31.0, 24.9, 32.1, 9.9; HPLC-MS (ammonium acetate) [M+H]+=329.3.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[F:34][C:35]1[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1.O>ClCCl>[F:34][C:35]1[CH:36]=[C:37]([S:41]([N:12]2[C:6]3[CH:7]=[N:8][C:9]4[CH:10]=[CH:11][C:2]([CH3:1])=[CH:3][C:4]=4[C:5]=3[N:14]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:19][CH:20]=3)[C:13]2=[O:26])(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: Cc1ccc2ncc3[nH]c(=O)n(-c4ccc(C(C)(C)C#N)cc4)c3c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc2ncc3c(c2c1)n(-c1ccc(C(C)(C)C#N)cc1)c(=O)n3S(=O)(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 3, 100 mg, 0.29 mmol) and triethylamine (60 mg, 0.58 mmol) in dichloromethane (6 ml) was added 3-fluorobenzene-1-sulfonyl chloride (84 mg, 0.44 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 20 mg (14%); 1H NMR (DMSO-d6, 300 MHz): δ 9.341 (s, 1H), 8.039-8.059 (d, 2H, J=6 Hz), 7.939-7.967 (d, 1H, J=8.4 Hz), 7.683-7.811 (m, 6H), 7.469-7.499 (d, 1H, J=9 Hz), 6.433 (s, 1H), 2.112 (s, 3H), 1.780 (s, 6H); MS: m/z 501 (M+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH3:20][C:21]1[C:22]([CH2:27][N:28]([CH2:35][C:36]2[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][N:37]=2)[CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:23][CH:24]=[CH:25][CH:26]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.C1COCC1.[OH-].[Na+].CCOC(C)=O.CN(C=O)C>[CH3:20][C:21]1[C:22]([CH2:27][N:28]([CH2:35][C:36]2[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][N:37]=2)[CH:29]2[CH2:34][CH2:33][N:32]([C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[O:13])[CH2:31][CH2:30]2)=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)c2ccc3ncccc3c2)CC1
Temperature: 0 °C
Yield: 29.3 %

Procedure:
To a cold (0° C.), stirred, mixture of 6-quinoline carboxylic acid (101 mg, 0.59 mmol) in CH2Cl2 (5 mL) was added DMF (0.5 mL) followed by oxalyl chloride (0.25 mL, 2.87 mmol). The mixture was warmed to room temperature. After 15 minutes the mixture was concentrated under reduced pressure and provided a white solid. To a solution of COMPOUND 249 (68 mg, 0.22 mmol) in THF (10 mL) was added the white solid from above followed by DIPEA (0.60 mL, 3.44 mmol). The resultant mixture was stirred at room temperature for 2.5 hours then diluted with 1.0 N NaOH (10 mL) and EtOAc (40 mL). The phases were separated and the organic phase was washed with 1.0 N NaOH (3×10 mL), dried (Na2SO4), and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) followed by radial chromatography on silica gel (1 mm plate, 100:1:1 CH2Cl2-MeOH—NH4OH) provided 30 mg (29%) of COMPOUND 268 as a yellow solid. 1H NMR (CDCl3) δ 1.65-2.03 (m, 4H), 2.10 (s, 6H), 2.64-3.05 (m, 3H), 3.66-3.90 (m, 5H), 4.80-4.88 (m, 1H), 7.10 (dd, 2H, J=7.5, 4.8 Hz), 7.38 (d, 2H, J=7.5 Hz), 7.46 (dd, 1H, J=8.4, 4.2 Hz), 7.72 (dd, 1H, J=8.4, 1.5 Hz), 7.90 (s, 1H), 8.13-8.21 (m, 2H), 8.35 (d, 2H, J=3.6 Hz), 8.97 (d, 1H, J=3.6 Hz); ES-MS m/z 466 (M+H).
Reaction SMILES: [CH2:1]([C:8]1[C:13]([C:14]([OH:16])=[S:15])=[CH:12][N:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17]I>C(#N)C.O>[CH2:1]([C:8]1[C:13]([C:14]([O:16][CH3:17])=[S:15])=[CH:12][N:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(=S)c1cnccc1Cc1ccccc1
Reactant: CI
Solvent: O
Solvent: CC#N
Product: COC(=S)c1cnccc1Cc1ccccc1
Reaction time: 7 h

Procedure:
A suspension of 2.45 g (0.01 mole) of 4-benzylthionicotinic acid in 35 mL of dry acetonitrile was treated with 1.52 g (0.01 mole) of 1,8-diazabicyclo[5,4,0]under-7-ene (DBU). 1.7 g (0.01 mole) of methyl iodide was added and stirring was continued for 7 hours. The reaction was carefully diluted with water to crystallize 430 mg of methyl 4-benzylthionicotinate which melted at 98°-99° C.
Reaction SMILES: Br[C:2]1[C:3]([CH3:9])=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C([Li])CCC.C(O[B:19]1[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]1)(C)C>CCOCC>[CH3:9][C:3]1[C:2]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=1
Reactant: Cc1ccc(Br)c(C)n1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 98.5 %

Procedure:
A solution of 3-bromo-2,6-dimethylpyridine (5.10 g, 27.4 mmol) in anhydrous ether (160 ml) cooled to −78° C. under a nitrogen atmosphere was treated dropwise with n-butyl lithium (4.1 ml, 10 M in hexane) and stirred at −78° C. for 45 minutes. 2-isopropoxy-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (10.2 g, 54.8 mmol) in 20 ml of ether was added dropwise at −78° C. and stirred at −78° C. for 3 hours. The mixture was quenched with 10 ml of isopropanol, and allowed to warm to room temperature. 150 ml of saturated aqueous NaCl solution was added. The aqueous phase was separated and extracted with dichloromethane (100 ml×6). The combined organic phases were dried and concentrated to provide the title compound as light brown oil (6.29 g, 98.4%). 1H NMR (300 MHz, CDCl3) δ ppm 7.92 (d, J=7.46 Hz, 1H) 6.96 (d, J=7.80 Hz, 1H) 2.73 (s, 3H) 2.53 (s, 3H) 1.34 (s, 12H). MS: (M+H)+=234.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:17])[C@H:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH2:9])([CH3:5])([CH3:4])[CH3:3].[C:18]1([C:24]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:25]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=3)=[N:28][N:27]=[N:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(OCC)(=O)C>[C:2]([O:6][C:7](=[O:17])[C@H:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:9][CH2:42][C:39]1[CH:38]=[CH:37][C:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[C:29]2[N:25]([C:24]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:26]=[N:27][N:28]=2)=[CH:41][CH:40]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 25 %

Procedure:
L-phenylalanine t-butyl ester hydrochloride (Bachem Bioscience, Inc.) (1.0 g, 3.9 mmol) was suspended in ethyl acetate, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered and the solvent removed in vacuo. This residue was dissolved in 20 mL of THF and 1.95 g (3.5 mmol) of 2'-(N-triphenylmethyl tetrazol-5-yl)-4-bromomethylbiphenyl (prepared as described in EP 0 324 377) and 0.54 mL (3.9 mmol) triethylamine were added. The reaction was stirred at room temperature for 5 days. The THF was removed in vacuo and the residue dissolved in ethyl acetate. This was extracted 3× with K2CO3 and 1× with brine, dried over (MgSO4), filtered, and the solvent removed in vacuo. The product was purified by silica gel chromatography eluting with ethyl acetate-hexanes to yield 0.61 g (25%) of a white glass.
Reaction SMILES: [CH2:1]([C:4]1([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH2:7][CH:6]([CH3:8])[CH2:5]1)[CH:2]=C.C[N+]1([O-])CCOCC1.I([O-])(=O)(=O)=O.[Na+].[CH3:31][C:32]([S@:35]([NH2:37])=[O:36])([CH3:34])[CH3:33]>CC(O)(C)C.O.C1COCC1.O.[Os](=O)(=O)(=O)=O>[Si:10]([O:9][C:4]1([CH2:1]/[CH:2]=[N:37]/[S:35]([C:32]([CH3:34])([CH3:33])[CH3:31])=[O:36])[CH2:5][CH:6]([CH3:8])[CH2:7]1)([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:11])[CH3:12]
Reactant: CC(C)(C)[S@](N)=O
Reactant: C=CCC1(O[Si](C)(C)C(C)(C)C)CC(C)C1
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)(C)O
Product: CC1CC(C/C=N/S(=O)C(C)(C)C)(O[Si](C)(C)C(C)(C)C)C1
Reaction time: 6 h

Procedure:
(1-Allyl-3-methylcyclobutoxy)(tert-butyl)dimethylsilane (4.1000 g, 17.05 mmol) was dissolved in 150 ml of t-BuOH/H2O/THF (2/2/1) and osmium tetroxide (10.84 ml, 0.8525 mmol, 2.5 wt %) and 4-methylmorpholine oxide (2.996 g, 25.58 mmol) were added. The mixture was stirred for 6 h and the mixture was diluted with 250 ml water and extracted with EtOAc. The combined organic extracts were evaporated and re-dissolved in 150 ml of t-BuOH/H2O/THF (2/2/1). Sodium periodate (4.741 g, 22.17 mmol) was added and stirring was continued for 6 h. The mixture was filtered and diluted with 250 ml of water. The mixture was extracted with Et2O and the combined organic extracts were dried over MgSO4, evaporated and re-dissolved in 100 ml CH2Cl2. Cupric sulfate anhydrous (8.164 g, 51.15 mmol), and (r)-(+)-2-methyl-2-propanesulfinamide (4.133 g, 34.10 mmol) were added at RT and stirring was continued over night. The reaction was filtered and hydrolyzed with 30 ml water. The mixture was extracted 3×EtOAc (3×150 ml) and the combined organic extracts were dried over MgSO4 and evaporated. Glass col. chrom. (20-50% EtOAc in Hex) provided (E)-N-(2-(1-(tert-butyldimethylsilyloxy)-3-methylcyclobutyl)ethylidene)-2-methylpropane-2-sulfinamide. Mixture of cis/trans at the cyclobutylring (4:1).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:14][CH:13]2[N:15]([CH2:16][CH2:17][CH2:18][C:19]3[N:23](CCC#N)[C:22]4[CH:28]=[CH:29][CH:30]=[CH:31][C:21]=4[N:20]=3)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C)C.[Na].C(OCC)(=O)C>C(=O)(O)[O-].[Na+].C(N(CC)CC)C.CO>[CH2:1]([CH:8]1[CH2:9][CH:10]2[N:15]([CH2:16][CH2:17][CH2:18][C:19]3[NH:20][C:21]4[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=4[N:23]=3)[CH:13]([CH2:12][CH2:11]2)[CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCn1c(CCCN2C3CCC2CC(Cc2ccccc2)C3)nc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: c1ccc(CC2CC3CCC(C2)N3CCCc2nc3ccccc3[nH]2)cc1

Procedure:
A mixture of 0.4 g of 3-{2-[3-(3-benzyl-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-benzimidazol-1-yl }-propionitrile, 20 mL of isopropanol and 2 mL of 0.4M sodium in isopiopanol was heated to reflux for 2 h. Conversion was complete by TLC (80:20:1 ethyl acetate:methanol:triethylamine). The mixture was cooled, diluted with 10 mL of saturated sodium bicarbonate and concentrated. The residue was partitioned between 3×100 mL of chloroform and 50 mL of water. After drying over magnesium sulfate and concentration under reduced pressure, the residue was purified by preparative TLC eluting with 400:100:25 ethyl acetate:methanol:triethylamine. The major band (UV visualization) was 2-[3-(3-benzyl-8-aza-bicyclo[3.2.1]oct-8-yl)-propyl]-1H-benzimidazole (258 mg): MS (m+1)=362.5; 1H NMR (400 MHz, CDCl3) 7.58 (d, 1H), 7.52 (d, 1H), 7.6-7.2 (complex, 7H), 3.38 (s, 2H), 3.18 (m, 2H), 2.82 (m, 2H), 2.6 (m, 2H), 2.22 (m, 2H), 2.1 (m, 2H), 1.85 (m, 5H), 1.6 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]([O:10]CC2C=CC=CC=2)=[O:9])=[C:6]([CH:18]=[O:19])[NH:5][C:4]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:2].C1CC=CCC=1>C(O)C.[Pd]>[C:23]([O:22][C:20]([C:4]1[NH:5][C:6]([CH:18]=[O:19])=[C:7]([C:8]([OH:10])=[O:9])[C:3]=1[CH2:1][CH3:2])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCc1c(C(=O)OC(C)(C)C)[nH]c(C=O)c1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: CCc1c(C(=O)OC(C)(C)C)[nH]c(C=O)c1C(=O)O
Reaction time: 2 h

Procedure:
To a solution of 4-benzyl 2-tert-butyl 3-ethyl-5-formyl-1H-pyrrole-2,4-dicarboxylate (1.316 g, 3.682 mmol) in ethanol (15.0 mL) was added 10% palladium on carbon (1.300 g, 3.68 mmol) and 1,4-cyclohexadiene (3.50 mL, 36.82 mmol). The reaction was stirred under N2 for 2 h prior to filtration through a pad of Celite. The filtrate was washed with 50 mL of ethyl acetate and the combined organics concentrated in vacuo. The resultant residue was purified by preparative reverse phase HPLC. Proton NMR for the product was consistent with the title compound. 1H NMR (500 MHz, CD3OD) δ 10.23 (s, 1H); 3.10 (q, J=7.3 Hz, 2H); 1.61 (s, 9H); 1.16 (t, J=7.3 Hz, 3H). HRMS (ES) exact mass calculated for C13H17NNaO5 (M+Na+): 290.1001. Found 290.1001.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[N:17]=[C:18]2[C:23](Br)=[CH:22][CH:21]=[CH:20][N:19]2[CH:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:23]1[C:18]2[N:19]([CH:25]=[C:16]([C@@H:12]3[CH2:13][CH2:14][CH2:15][N:11]3[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[N:17]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1c1cn2cccc(Br)c2n1
Reactant: OB(O)c1ccccc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(OCc1ccccc1)N1CCC[C@H]1c1cn2cccc(-c3ccccc3F)c2n1
Yield: 100 %

Procedure:
Following the procedures of example 14, (S)-benzyl-2-(8-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate (0.2489 g, 0.62 mmol), 2-fluorophenyl boronic acid (0.1217 g, 0.87 mmol), potassium carbonate (0.1449 g, 1.05 mmol), and tetrakis(triphenylphosphine)-palladium(0) (0.0532 g, 0.05 mmol) produced the crude material which was adsorbed onto silica gel and purified by flash chromatography (4 g SiO2, 0-60% ethyl acetate in hexanes) to give (2S)-benzyl 2-(8-(2-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate (0.62 mmol, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.C([Li])CCC.CCCCCC.C(Br)(Br)(Br)[Br:23]>C(OCC)C.C(OCC)(=O)C.O>[Br:23][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[O:9][CH3:10]
Reactant: COc1cccc(OC)c1
Reactant: BrC(Br)(Br)Br
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1cccc(OC)c1Br
Temperature: 0 °C
Reaction time: 20 h
Yield: 57.3 %

Procedure:
In a solution of 1,3-dimethoxybenzene (3.0 g, 21.7 mmol) dissolved in diethyl ether (90 ml), a 1.65M solution of n-butyl lithium in n-hexane (19.8 ml, 32.7 mmol of n-butyl lithium) was added at room temperature, and a reaction mixture was heated to reflux for 4 hours. After cooling the reaction mixture to 0° C., a solution of carbon tetrabromide (15.8 g, 47.7 mmol) in diethyl ether (60 ml) was added to the mixture, and stirred at room temperature for 20 hours. A small amount of water was added to the reaction mixture, and then the reaction mixture was diluted with ethyl acetate (90 ml). The organic layer was washed with water and dried over anhydrous magnesium sulfate. Thereafter, the solvent was evaporated off, and the residue was purified by column chromatography to obtain 1-bromo-2,6-dimethoxybenzene (2.70 g).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH2:27][CH2:26][C:21]4([O:25][CH2:24][CH2:23][O:22]4)[CH2:20][CH:19]=3)=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]>C1(C)C=CC=CC=1.C(O)C.[Pd]>[CH2:1]([CH:4]1[CH2:5][CH2:6][CH:7]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH:18]3[CH2:19][CH2:20][C:21]4([O:22][CH2:23][CH2:24][O:25]4)[CH2:26][CH2:27]3)=[CH:16][CH:17]=2)[CH2:8][CH2:9]1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(/C=C/c2ccc(C3=CCC4(CC3)OCCO4)cc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCC1CCC(CCc2ccc(C3CCC4(CC3)OCCO4)cc2)CC1
Reaction time: 96 h
Yield: 71.4 %

Procedure:
The 8-{4-[(E)-2-(4-propylcyclohexyl)ethenyl]phenyl}-1,4-dioxaspiro[4.5]dec-7-en (6.1 g, 16.64 mmol) was dissolved in a mixture of toluene and ethanol (toluene:EtOH=1:3). Pd/C (0.14 g) was added to 200 mL of the resulting solution and hydrogenated for 4 days. After reaction, Pd/C was removed by filtration, and the residue was purified column chromatography (hexane:ether=8:1) to obtain 8-{4-[2-(4-propylcyclohexyl)ethyl]phenyl}-1,4-dioxaspiro[4.5]decane (4.40 g, 72%).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[C:20]([NH:26][C@H:27]([C:30]([OH:32])=O)[CH2:28][OH:29])(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].[CH:33]1[C:43]2[CH:42]=[CH:41][C:40]3[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=3[C:38](=[C:48]3[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]3)[C:37]=2[CH:36]=[CH:35][CH:34]=1.Cl>ClCCl>[CH:33]1[C:43]2[CH:42]=[CH:41][C:40]3[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=3[C:38](=[C:48]3[CH2:49][CH2:50][N:51]([C:30](=[O:32])[C@@H:27]([NH:26][C:20](=[O:25])[C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:28][OH:29])[CH2:52][CH2:53]3)[C:37]=2[CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)C(=O)N[C@@H](CO)C(=O)O
Reactant: C1=Cc2ccccc2C(=C2CCNCC2)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)N[C@@H](CO)C(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
880 mg (4.59 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride, 0.63 ml (4.52 mmol) of triethylamine and 860 mg (4.55 mmol) of pivaloyl-L-serine were added to 1.231 g (4.50 mmol) of 4-(5H-dibenzo[a,d][7]annulen-5-ylidene)piperidine in 20 ml of dichloromethane in ice bath, and they were stirred at room temperature overnight. 1 N hydrochloric acid was added to the reaction mixture. After extracting with dichloromethane, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by the silica gel chromatography (hexane:ethyl acetate=7:3 to 1:2) to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=2[O:23][C:24]([F:27])([F:26])[F:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=2[O:23][C:24]([F:26])([F:27])[F:25])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc([N+](=O)[O-])ccc2OC(F)(F)F)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(N)ccc2OC(F)(F)F)CC1
Reaction time: 3 h
Yield: 97.6 %

Procedure:
0.41 g of 4-(5-Nitro-2-trifluoromethoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (1.055 mmol) were dissolved in 10 mL ethyl acetate and 10 mL acetic acid. 0.12 g 10% Palladium/charcoal were added and the mixture hydrogenated for 3 h at room temperature. The catalyst was filtered over Celite, washed with ethyl acetate and the combined filtrates evaporated to dryness. The residue was treated with water, the pH adjusted to 9-10 with 1 N aquous sodium hydroxide and the aquous phase extracted twice with dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to yield 0.372 g of the product.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[C:20]([NH:27][C@H:28]([C:36](O)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[C:23]([O:22][C:20]([NH:27][C@@H:28]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:36]([NH:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19])=[O:37])=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NC1N=C(c2ccccc2)c2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(RS)-Amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (1.3 g, 5.17 mmole), Boc-L-phenylalanine (1.37 g, 5.17 mmole), HBT (0.70 g, 5.17 mmole), and EDC (0.99 g, 5.17 mmole) were combined in DMF (30 ml) and stirred at room temperature. The pH of the mixture was adjusted to 9.5 with triethylamine. After 1/2 hour, the DMF was removed in vacuo and the residue treated with 10% citric acid (10 ml), neutralized with Na2CO3 and extracted with CH2Cl2 (3×15 ml). The combined organic layers were washed with water, dried over Na2SO4, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on silica gel (90/3/0.3/0.3 CH2Cl2 /MeOH/H2O/HOAc) and the combined product fractions evaporated to dryness in vacuo. The residue was dissolved in CH2Cl2 (10 ml), washed with saturated Na2CO3 solution (2 ml), dried over Na2SO4, filtered and evaporated to dryness. The residue was treated with Et2O and evaporated five times to give the title compound as a mixture of diastereomers (m.p. 143-153° C.). TLC: silica gel (90/10/1/1 CH2Cl2 /MeOH/MoAc/H2O), Rf =0.58