Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH3:11][CH2:12]N(CC)CC.ClC(OCC)=O.CCO>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cccc(Br)n1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cccc(Br)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-bromopicolinic acid from Step 1 (92 g, 0.455 mol) and Et3N (69 g, 0.68 mol) in THF (1.1 L) at 0° C. there was slowly added ethyl chloroformate (61.6 g, 0.57 mol). The resulting suspension was stirred at 0° C. for 15 min., EtOH (250 mL) was added, and the mixture was stirred at r.t. overnight. After filtration, the filtrate was evaporated down, the residue was taken up in ET2O (1 L) and filtered again. The filtrate on evaporation of the solvents afforded the title compound as an oil which was immediately used as such.
Reaction SMILES: [C:1]([N:4]1[CH:11]=[C:10]([F:12])[C:8](=[O:9])[NH:7][C:5]1=[O:6])(=[O:3])[CH3:2].[H-].[Na+].Br[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18](=[O:19])[O:17]1.O>CN(C=O)C>[C:1]([N:4]1[CH:11]=[C:10]([F:12])[C:8](=[O:9])[N:7]([CH:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:18](=[O:19])[O:17]2)[C:5]1=[O:6])(=[O:3])[CH3:2]
Reactant: O=C1OC(Br)c2ccccc21
Reactant: CC(=O)n1cc(F)c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)n1cc(F)c(=O)n(C2OC(=O)c3ccccc32)c1=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
In 8 ml of DMF was dissolved 3.44 g of 1-acetyl-5-fluorouracil and 0.80 g of sodium hydride (60% content) was added to the stirred solution mentioned above under ice cooling. Then, a solution of 4.69 g of 3-bromophthalide in 7 ml of DMF was added dropwise to the mixture. After completion of the dropwise addition, the mixture was stirred for 3.5 hours at room temperature. Then, 100 ml of water was added to the mixture and the mixture was extracted with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate and then, the solvent was distilled off. The residue was washed twice with 25 ml each of n-hexane to obtain crude N1 -acetyl-N3 -phthalidyl-5-fluorouracil. To this product were added 50 ml of 0.05N hydrochloric acid and 50 ml of ethanol and the mixture was refluxed for 15 minutes. After the solvent was distilled off, water was added to the residue and the colorless crystal produced was collected by filtration. After washing with water and drying, the product was heated with 15 ml of chloroform under reflux for 3 minutes. After filtration while hot, there was obtained 2.65 g (50%) of colorless crystal. This was recrystallized from methanol to obtain colorless needles having a melting point of 234°-237°.
Reaction SMILES: O1CCCC1.[CH2:6]([O:13][C:14]([NH:16][C:17]1([C:30](O)=[O:31])[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(Cl)(=O)OCC.[BH4-].[Na+]>O.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:6]([O:13][C:14]([NH:16][C:17]1([CH2:30][OH:31])[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])[CH2:21][CH2:22]1)=[O:15])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(=O)O)CC1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CO)(NC(=O)OCc2ccccc2)CC1
Temperature: -15 °C
Reaction time: 1 h

Procedure:
To 20 mL of a tetrahydrofuran suspension containing 1.0 g of 4-(((benzyloxy)carbonyl)amino)-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid, 0.41 mL of triethylamine was added at room temperature, then the mixture cooled to −15° C., and thereto was added dropwise 0.28 mL of ethyl chlorocarbonate. The reaction mixture was stirred at 5 to 10° C. for 1 hour. Thereto were added 0.11 g of sodium borohydride and 3 mL of water, and the mixture was stirred at room temperature for 1 hour, and stood still overnight. The reaction mixture was added with ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, and the resultant solution was washed with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.55 g of a colorless oily substance, tert-butyl 4-(((benzyloxy)carbonyl)amino)-4-(hydroxymethyl)piperidine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]([C:15](OC)=[O:16])#[C:10][C:11]([O:13][CH3:14])=[O:12]>CO>[CH3:14][O:13][C:11]([C:10]1[CH:9]=[C:15]([OH:16])[C:6]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:8][CH:7]=2)[N:5]=1)=[O:12]
Reactant: Nc1cccc(Cl)c1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)c1cc(O)c2ccc(Cl)cc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a stirred solution of 3-chloroaniline (40.8 g, 320 mmol) in MeOH (500 mL) at rt was added dimethyl acetylene dicarboxylate (50 g, 352 mmol). After addition, the reaction was kept at reflux for 2 h, then cooled to rt. After evaporating methanol in vacuo, the resulting crude adduct was dissolved in Ph2O (160 mL), and was added dropwise to a hot solution of Ph2O (800 mL) in a three-neck flask at 250° C. The reaction mixture was kept at 250° C. for an additional 30 min, and was cooled to rt. The reaction mixture was diluted with hexane, and the product precipitated. The crude mixture was collected by filtration (washed with hexane and ether). This mixture (78 g) was re-dissolved in pyridine (468 mL) (Note: the other solvent for re-crystallization is acetic acid, and the ratio of crude product to acetic acid is 1:6 based on weight), and kept at reflux for about 30 min. After cooling to rt, the desired product was collected by filtration (washed with ether). The solid was air dried overnight to give 35 g (46%) of 7-chloro-4-hydroxy-2-quinolinecarboxylic acid methyl ester. LC-MS: 237 (M++1). 1H NMR (DMSO-d6): 63.98 (s, 3H), 6.6 (s, 1), 7.38 (d, 1H), 7.96 (s, 1H), 8.04 (d, 1), 12.1 (s, 1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14][NH2:15])[CH2:11][N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[CH:22]=1)([O-:3])=[O:2].O=[C:24]([CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[C:25]([OH:27])=[O:26]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:14][N:15]=[C:24]([C:25]([OH:27])=[O:26])[CH2:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:11][N:10]=[C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[CH:22]=1)([O-:3])=[O:2]
Reactant: NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Reactant: O=C(O)C(=O)CCCN1CCCCC1
Product: O=C(O)C(CCCN1CCCCC1)=NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 13, 7-nitro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine can be stirred with 2-oxo-5-piperidinopentanoic acid at room temperature to give 7-nitro-2-[(1-carboxy-4-piperidinobutylidene)-hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:15][NH:14][C:13](=S)[C@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1.[NH2:25][CH2:26][CH:27]([C:29]1([C:32]([F:35])([F:34])[F:33])[CH2:31][CH2:30]1)[OH:28]>C(O)C.[Hg](Cl)Cl>[C:20]([O:19][C:18](=[O:24])[NH:17][C@@H:12]1[CH2:11][CH2:10][C@@H:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH2:15][NH:14]/[C:13]/1=[N:25]\[CH2:26][CH:27]([OH:28])[C:29]1([C:32]([F:34])([F:35])[F:33])[CH2:31][CH2:30]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: NCC(O)C1(C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S
Agent: Cl[Hg]Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN/C1=N\CC(O)C1(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Mercury(II) chloride (149 mg, 0.547 mmol) was added to a solution of tert-butyl [(3R,6S)-6-(2,3-difluorophenyl)-2-thioxoazepan-3-yl]carbamate (150 mg, 0.421 mmol, described in Intermediate 7), and 2-amino-1-[1-(trifluoromethyl)cyclopropyl]ethanol (569 mg, 3.367 mmol) in ethanol (5 mL) at 60° C. After 10 min, the reaction was allowed to cool to ambient temperature. The mixture was filtered and concentrated under reduced pressure. Saturated aqueous NaHCO3 was added and the mixture was extracted with CH2Cl2 (3×). The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound. MS: m/z=492 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH:18][NH2:19])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:23][CH2:24][C:25](OC(=O)CCl)=O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:25]([CH2:24][Cl:23])=[N:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Reactant: O=C(CCl)OC(=O)CCl
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3nnc(CCl)o3)c2[C@@H]2CCN12
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.3 %

Procedure:
4.4 g (13.8 mmol) of (S)-8-chloro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]-imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid hydrazide were stirred at room temperature overnight in 30 ml of N,N-dimethylformamide with 2.65 g (15.5 mmol) of chloroacetic anhydride. After evaporating the solvent the residue was stirred at room temperature for 48 hours with 20 ml of a 10% solution of phosphorus pentoxide in methanesulphonic acid. The reaction mixture was treated with ice, made alkaline with conc. sodium hydroxide solution and extracted four times with methylene chloride. By drying the organic phase over magnesium sulfate and evaporating the solvent there were obtained 3.39 g (60%) of (S)-8-chloro-1-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of m.p. 185°-189°.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.C(=O)([O-])O.[Na+].C(O)C.[C:18]([NH:26][C:27]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[CH:36][C:28]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[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.C1(C)C=CC=CC=1.O>[C:18]([NH:26][C:27]1[CH:39]=[C:38]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=2)[CH:37]=[CH:36][C:28]=1[C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1NC(=O)c1ccccc1
Reactant: Oc1ccc(Br)cc1Cl
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(-c2ccc(O)c(Cl)c2)cc1NC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
0.15 g of 4-bromo-2-chlorophenol, 0.18 g of sodium hydrogen carbonate, 0.6 mL of ethanol, 0.3 mL of water and 42 mg of tetrakis(triphenylphosphine) palladium(0) were added to 2.1 mL of toluene solution containing 0.37 g of tert-butyl 2-(benzamido)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate at room temperature, and the resulting mixture was heated to reflux for 4 hours. Toluene and a saturated sodium hydrogen carbonate aqueous solution were added after the reaction mixture was cooled to room temperature. The organic layer was separated and ethyl acetate was added after washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Hexane was added to the obtained residue and a solid substance was separated by filtration to obtain tert-butyl 2-(benzamido)-4-(3-chloro-4-hydroxyphenyl)benzoate.
Reaction SMILES: [Br:1][CH2:2][C:3](=O)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Cl:12])=O.C(OCC)(=O)C.[N+:20]([C:23]1[C:24]([NH2:30])=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21]>>[Br:1][CH2:2][C:3]1[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[Cl:12])=[N:30][C:24]2[C:25](=[CH:26][CH:27]=[CH:28][C:23]=2[N+:20]([O-:22])=[O:21])[N:29]=1
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: O=C(CBr)C(=O)c1ccccc1Cl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc2nc(CBr)c(-c3ccccc3Cl)nc12
Temperature: 25 °C

Procedure:
To a solution of 3-bromo-1-(2-chlorophenyl)propane-1,2-dione (Prepared in Example 81, 4.2971 g, 16.4325 mmol) in ethyl acetate (109.55 mL, 16.433 mmol) was added 3-nitro-1,2-phenylenediamine (2.5165 g, 16.433 mmol) at room temperature and the resulting red mixture was stirred at room temperature. After 26 h of stirring at room temperature, the mixture was concentrated under reduced pressure to give 2-(bromomethyl)-3-(2-chlorophenyl)-5-nitroquinoxaline including its regioisomer as a red syrup: LC-MS (ESI) m/z 378.0 and 379.9 [M+H]+. The crude product as a red syrup was carried on crude without purification for the next step.
Reaction SMILES: C(S([N:7]=[CH:8][CH2:9][CH2:10][C:11]([O:13]C)=O)=O)(C)(C)C.[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1I)[CH3:16].NC(C1C(OC)=CC=CC=1OC)CCC(OC)=O.COC1C=CC=C(OC)C=1C1NC(=O)CC1>>[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:8]1[NH:7][C:11](=[O:13])[CH2:10][CH2:9]1)[CH3:16]
Reactant: CCOc1ccccc1I
Reactant: COC(=O)CCC=NS(=O)C(C)(C)C
Agent: COC(=O)CCC(N)c1c(OC)cccc1OC
Agent: COc1cccc(OC)c1C1CCC(=O)N1
Product: CCOc1ccccc1C1CCC(=O)N1

Procedure:
Synthesized from methyl 4-((tert-butylsulfinyl)imino)butanoate and commercially available 1-ethoxy-2-iodobenzene according to the procedures described for the preparations of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate and 5-(2,6-dimethoxyphenyl)pyrrolidin-2-one. The target product 5-(2-ethoxyphenyl)pyrrolidin-2-one was obtained as a colorless solid after purification by FC (heptane/AcOEt=7/3 to 3/7). LC-MS (conditions D): tR=0.81 min.; [M+H]+: 205.99 g/mol.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([C:18](OC)=[O:19])=[CH:14][C:13]3=[O:22])=[CH:8]2)=[N:3]1.[H-].C([Al+]CC(C)C)C(C)C.CO.O>ClCCl>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][C:13]3=[O:22])=[CH:8]2)=[N:3]1
Reactant: COC(=O)c1ccn(-c2ccc3nn(C)c(C)c3c2)c(=O)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Cc1c2cc(-n3ccc(CO)cc3=O)ccc2nn1C
Reaction time: 2 h
Yield: 54 %

Procedure:
To a solution of methyl 1-(2,3-dimethyl-2H-indazol-5-yl)-2-oxo-1,2-dihydropyridine-4-carboxylate (450 mg) in dichloromethane (40 ml) was added diisobutylaluminum hydride (1 M toluene solution, 7.5 ml) at −78° C., and the mixture was stirred at the same temperature for 2 hr. To the reaction mixture were added methanol and water at the same temperature, and the mixture was filtered through celite, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane/methanol) to give the title compound (220 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[CH2:9][NH:10][C:11]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]#[N:21])[CH2:15][CH2:14]2)=[O:12])=[CH:4][CH:3]=1.O.[C:24](=O)(O)[O-:25].[Na+].C=O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:22])[CH:9]([NH:10][C:11]([CH:13]2[CH2:14][CH2:15][N:16]([CH2:19][C:20]#[N:21])[CH2:17][CH2:18]2)=[O:12])[CH2:24][OH:25])=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: N#CCN1CCC(C(=O)NCC(=O)c2ccc(F)cc2)CC1
Agent: C=O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCN1CCC(C(=O)NC(CO)C(=O)c2ccc(F)cc2)CC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 380.7 %

Procedure:
In a 22-l round bottomed flask, suspend 1-cyanomethyl-piperidine-4-carboxylic acid-[2-(4-fluorophenyl)-2-oxoethyl] amide (1.004 kg, 3.31 moles) in absolute ethanol (5.0 l) and process water (2.5 l). To the suspension is added sodium bicarbonate (55.62 g, 0.662 moles) and 37% formaldehyde (400 ml, 4.93 moles), then the suspension is warmed to 40° C. and the reaction followed by HPLC. Upon completion, the reaction is quenched by added ice water (5.0 l) and brine (5.0 l). The reaction is stirred for three hours, then the crystals are collected by vacuum filtration, washed with process water (1.0 l) and dried at ambient temperature and 25 in Hg to give 1-cyanomethyl-piperidine-4-carboxylic acid-[2-(4-fluorophenyl)-1-hydroxymethyl-2-oxoethyl] amide (839 g, 2.52 moles). 1H NMR (400 MHz, d6 DMSO) d 1.52 (m, 2H), 1.67 (t, 2H), 2.12 (t, 2H), 2.23 (m, 1H), 2.77 (m, 2H), 3.38 (s, 1H), 3.65 (m, 1H), 3.68 (s, 2H), 3.75 (m, 1H), 5.15 (m, 1H), 5.25 (m, 1H), 7.16 (t, 2H), 8.06 (q, 2H), 8.40 (d, 1H).
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.C[O-].[Na+].[BH4-].[Na+].Cl>CCO.CO.CCOC(C)=O>[ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:17]2)[OH:11])=[CH:8][CH:9]=1
Reactant: COc1ccc(C(=O)C2CCN(CCc3ccccc3)CC2)cc1
Agent: C[O-]
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(C(O)C2CCN(CCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
A solution of (4-methoxyphenyl)[1-(2-phenylethyl)-4-piperidinyl]-methanone hydrochloride (3.5 g, 9.7 mmol) in absolute EtOH (75 ml) was treated with sodium methoxide (0.53 g, 9.7 mmol) followed by sodium borohydride (1.08 g, 20 mmol) and the mixture stirred for 42 h at room temperature. The reaction mixture was filtered and the filtrate concentrated to a solid residue which was dissolved in absolute Et2O and treated with HCl (9.7 mmol) dissolved in CH3OH/EtOAc (1:3, 8 ml). The resulting precipitate was filtered and recrystallized from CH3OH/Et2O to give alpha-(4-methoxyphenyl)-1-(2-phenylethyl)-4-piperidinemethanol hydrochloride, mp 162.5°-164° C.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:42]1[N:47]=[C:46]2[N:48]([C:51]3[CH:52]=[C:53]([CH:56]=[CH:57][CH:58]=3)[C:54]#[N:55])[CH:49]=[N:50][C:45]2=[CH:44][CH:43]=1.[F:59][C:60]1[CH:61]=[C:62]([CH:66]2[CH2:70][CH2:69][CH2:68][NH:67]2)[CH:63]=[CH:64][CH:65]=1>O1CCOCC1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[F:59][C:60]1[CH:61]=[C:62]([CH:66]2[CH2:70][CH2:69][CH2:68][N:67]2[C:42]2[N:47]=[C:46]3[N:48]([C:51]4[CH:52]=[C:53]([CH:56]=[CH:57][CH:58]=4)[C:54]#[N:55])[CH:49]=[N:50][C:45]3=[CH:44][CH:43]=2)[CH:63]=[CH:64][CH:65]=1
Reactant: N#Cc1cccc(-n2cnc3ccc(Cl)nc32)c1
Reactant: Fc1cccc(C2CCCN2)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Product: N#Cc1cccc(-n2cnc3ccc(N4CCCC4c4cccc(F)c4)nc32)c1
Temperature: 100 °C

Procedure:
In step 1-4, tris(dibenzylideneacetone) dipalladium (0) (10.8 mg, 0.012 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (22 mg, 0.047 mmol) and cesium carbonate (77 mg, 0.24 mmol) were added consecutively into a solution of 3-(5-chloro-3H-imidazo[4,5-b]pyridin-3-yl)benzonitrile (30 mg, 0.12 mmol) and 2-(3-fluorophenyl)pyrrolidine (29 mg, 0.18 mmol) in 1,4-dioxane. The mixture was degased under house vacuum, and charged with nitrogen and heated for 18 hours at 100° C. The reaction mixtures was purified using HPLC to afford 3-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)-3H-imidazo[4,5-b]pyridin-3-yl)benzonitrile (1-4) as a white solid. 1H NMR methanol-d4 δ (ppm) 8.86 (s, 1H), 8.28 (s, 1H), 7.98 (m, 1H), 7.89 (d, 1H), 7.78 (d, 1H), 7.63 (t, 1H), 7.33 (m, 1H), 7.09 (dm, 1H), 6.93 (m, 2H), 6.70 (d, 1H), 5.18 (d, 1H), 3.94 (m, 1H), 3.68 (m, 1H), 2.48 (m, 1H), 2.11 (m, 2), 1.97 (m, 1H); m/z 384 (M+1).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:21][C:22]([NH:24][C@@H:25]1[CH2:39][C:38]2=[CH:40][CH:41]=[C:35]([CH:36]=[CH:37]2)[NH:34][C:33](=[O:42])[CH2:32][CH2:31][O:30][CH2:29][C@H:28]([CH:43]([CH3:45])[CH3:44])[NH:27][C:26]1=[O:46])=[O:23])[C:14]([O:16]C(C)(C)C)=[O:15])=O)(C)(C)C.O.C([SiH](C(C)C)C(C)C)(C)C>C(O)(C(F)(F)F)=O>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]([NH:21][C:22]([NH:24][C@@H:25]1[CH2:39][C:38]2=[CH:37][CH:36]=[C:35]([CH:41]=[CH:40]2)[NH:34][C:33](=[O:42])[CH2:32][CH2:31][O:30][CH2:29][C@H:28]([CH:43]([CH3:44])[CH3:45])[NH:27][C:26]1=[O:46])=[O:23])[C:14]([OH:16])=[O:15]
Reactant: CC(C)[C@H]1COCCC(=O)Nc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)N1
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H]1COCCC(=O)Nc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](CCCCN)C(=O)O)C(=O)N1
Yield: 33.9 %

Procedure:
20.0 mg (0.03 mmol) of tert-butyl(S)-6-tert-butoxycarbonylamino-2-[3-((8S,11R)-8-isopropyl-3,10-dioxo-6-oxa-2,9-diazabicyclo[11.2.2]heptadeca-1(16),13(17),14-trien-11-yl)ureido]hexanoate were stirred in a mixture of 0.95 ml of TFA, 25 μl of water and 25 μl of triisopropylsilane at room temp. for 2 h. After the reaction was complete, the mixture was concentrated in vacuo and codistilled with toluene several times. The crude product obtained in this way was purified by preparative HPLC (acetonitrile/water+addition of 0.1% TFA). 5 mg of the title compound were obtained in this way as trifluoroacetate in the form of a colorless amorphous material.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:13][C:14]#[N:15].[Cl-].[NH4+]>CN(C)C=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:13][C:14]#[N:15])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: N#CCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: N#CCOc1ccc(C=O)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 39.7 %

Procedure:
4-Hydroxybenzaldehyde (244 mg, 2.00 mmol) in N,N-dimethylformamide (5 mL) was mixed with sodium hydride (60 wt % dispersion in liquid paraffin, 120 mg, 3.00 mmol) and chloroacetonitrile (189 μL, 3.00 mmol) under cooling with ice and then stirred at 50° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and mixed with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with 1M aqueous sodium hydroxide, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a brown oil (128 mg, yield 40%).