Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12](/[C:15](=[C:20](\[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)/[C:21]([O:23][CH3:24])=[O:22])/[C:16]([O:18][CH3:19])=[O:17])[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:40][CH2:41][NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([O:44][C:43]([NH:42][CH2:41][CH2:40][O:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25]/[C:20](=[C:15](\[C@H:12]2[CH2:13][CH2:14][C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][CH2:11]2)/[C:16]([O:18][CH3:19])=[O:17])/[C:21]([O:23][CH3:24])=[O:22])=[CH:31][CH:30]=1)=[O:49])([CH3:48])([CH3:47])[CH3:46]
Reactant: COC(=O)/C(Cc1ccc(O)cc1)=C(\C(=O)OC)[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)/C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)=C(\C(=O)OC)[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 19 h

Procedure:
A suspension of dimethyl 2-(cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-3-(4-hydroxybenzyl)maleate (35 mg, 0.075 mmol) and cesium carbonate (27 mg, 0.083 mmol) in DMF (1.2 ml) was cooled to 0° C., a solution of tert-butyl (2-bromoethyl)carbamate (20 mg, 0.091 mmol) in DMF (0.5 ml) was added dropwise, and the mixture was stirred at room temperature for 19 hr. The reaction mixture was diluted with water and was extracted with ethyl acetate, the organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate, and the filtrate was removed by distillation under reduced pressure. The residue was chromatographed on silica gel column (hexane:ethyl acetate=8:2) to give the title compound as an oil (20 mg, yield 43%).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14]CC)[C:5]1[N:6]=[CH:7][NH:8][C:9]=1[C:10](OC)=[O:11])C.C(O)(=O)C>O>[CH:10]([C:9]1[N:8]=[CH:7][NH:6][C:5]=1[C:4]([O:3][CH3:1])=[O:14])=[O:11]
Reactant: CCOC(OCC)c1nc[nH]c1C(=O)OC
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1[nH]cnc1C=O
Reaction time: 6 h

Procedure:
To a solution of Intermediate 1B (5.65 g, 24.75 mmol) in water (12 mL) was added acetic acid (49 mL, 0.86 mol). The resulting mixture was stirred under nitrogen for 6 hours. The reaction mixture was azeotroped with toluene and dried under vacuum to give the desired aldehyde, Intermediate 1C in quantitative yield as a white solid, which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:38]([NH:42][C:43]([C@@H:45]1[CH2:50][NH:49][CH2:48][CH2:47][NH:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>>[C:38]([NH:42][C:43]([C@@H:45]1[CH2:50][N:49]([C:32]([N:12]2[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][C:7]=2[O:35][CH2:36][CH3:37])=[O:33])[CH2:48][CH2:47][NH:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(C)(C)NC(=O)[C@@H]1CNCCN1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN[C@H](C(=O)NC(C)(C)C)C1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with (S)-piperazine-2-carboxylic acid tert-butylamide (Wako) to give the title compound. HR-MS (ES, m/z) calculated for C38H49Cl2N6O3 [(M+H)+] 707.3238, observed 707.3239.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C@H:12]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)=[O:20])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)C.[OH-].[Li+].O>CC#N>[F:30][C:29]([F:31])([F:32])[O:28][C:25]1[CH:24]=[CH:23][C:22]([NH:21][C:19](=[O:20])[NH:18][C@@H:15]2[CH2:16][CH2:17][C@H:12]([O:11][C:8]3[CH:7]=[CH:6][C:5]([C:4]([OH:33])=[O:3])=[CH:10][CH:9]=3)[CH2:13][CH2:14]2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1ccc(O[C@H]2CC[C@@H](NC(=O)Nc3ccc(OC(F)(F)F)cc3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)N[C@H]1CC[C@@H](Oc2ccc(C(=O)O)cc2)CC1
Reaction time: 8 h
Yield: 912.4 %

Procedure:
To a solution of 19b (0.1 g, 0.21 mmol) in 5 mL of CH3CN was added lithium hydroxide (15.4 mg, 0.64 mmol) followed by 2 mL of water at room temperature. The reaction mixture was stirred overnight. The solvent was evaporated in vacuo and washed with EtOAc. The aqueous layer was acidified with 1N HCl to give white precipitates. The resulting white solids were collected by suction filtration and washed with water. The crude product was recrystallized from MeOH to give the titled compound (0.84 g, 90%) as a white solid. mp 210-212° C. 1H NMR (DMSO-d6): 12.60 (s, 1H), 8.48 (s, 1H), 7.87 (d, J=8 Hz, 1H), 7.47 (d, J=9 Hz, 1H), 7.21 (d, J=9 Hz, 1H), 7.03 (d, J=8 Hz, 1H), 6.35 (d, J=8 Hz, 1H), 4.66-4.57 (m, 1H), 3.73-3.60 (m, 1H), 1.87-1.50 (m, 1H). 13C NMR (DMSO-d6): □ 167.04, 160.90, 154.36, 141.99, 139.84, 131.48, 122.77, 121.67, 118.57, 115.28, 71.95, 45.66, 27.71, 27.36. MS (ESI) m/z: 439.1 (M+H+). Anal. Calcd for C21H21F3N2O5: C, 57.53; H, 4.83; N, 6.39. Found: C, 57.33; H, 4.81; N, 6.29.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:10][CH:9]1[CH:11]1[CH2:13][CH2:12]1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(C)(C)C.[Na+].C(OCC)(=O)C>C(COC)OC>[CH2:14]([NH:21][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:10][CH:9]1[CH:11]1[CH2:13][CH2:12]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Brc1ccccc1C1CC1C1CC1
Reactant: NCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: c1ccc(CNc2ccccc2C2CC2C2CC2)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 84.5 %

Procedure:
3.7 g of 2-(2-bromophenyl)bicyclopropyl (15.6 mmol, trans/cis ratio of about 3:1), 2.0 g of benzylamine (18.7 mmol), 2.1 g of sodium tert-butanolate (21.8 mmol), 3.5 mg of Pd(II) acetate (0.016 mmol) and 8.6 mg of R(−)-di-tert-butyl-[1-[(S)-2-(dicyclohexylphosphanyl)-ferrocenyl]ethyl]phosphine (0.016 mmol) are dissolved in 30 ml of dimethoxyethane. The reaction mixture is heated to 70° C. and stirred for 24 hours. After cooling, ethyl acetate is added. The organic phase is washed with water. The solvent is removed using a water jet vacuum and the residue is dried. The product is purified by column chromatography on silica gel (eluant:ethyl acetate/hexane 1:15). 3.47 g of benzyl(2-bicyclopropyl-2-yl-phenyl)amine (84% of theory) are obtained in the form of a brown oil (trans/cis ratio of about 3:1).
Reaction SMILES: [Na].[NH:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](OCC)=[O:18]>C(O)C>[C:13]1([C:17]([CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[N:7][CH:6]=3)[NH:2][C:3]2=[O:11])=[O:18])[S:12][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cccs1
Reactant: O=C1Cc2cnccc2N1
Agent: [Na]
Solvent: CCO
Product: O=C1Nc2ccncc2C1C(=O)c1cccs1
Yield: 78.7 %

Procedure:
Pellets of sodium metal (1.15 g, 50 mmol) were added to dry ethanol (30 mL) in a dry round-bottomed flask. When dissolution of the sodium was complete, solid 5-azaoxindole (1.40 mg, 10.4 mmol) was added followed by ethyl 2-thiophenecarboxylate (2.7 mL, 20.1 mmol). The mixture was heated under nitrogen at reflux for 1 hour. At this point, the volume of the mixture was reduced 50% by distillation of ethanol at atmospheric pressure. The mixture was cooled and poured into ice/water. The resulting solution was filtered to remove a small amount of insoluble material which was washed well with water. Upon acidification of the filtrate to pH 7 with 6N HCl solution, the product precipitated. This was collected by filtration, washed with water and dried in the air to yield the title compound as a yellow/brown solid (2.0 g, 83%).
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13].[CH3:16][S:17](Cl)(=[O:19])=[O:18].Cl>N1C=CC=CC=1>[CH3:16][S:17]([O:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]=[C:3]1[C:12]([F:15])([F:14])[F:13])(=[O:19])=[O:18]
Reactant: On1c(C(F)(F)F)nc2ncc(Cl)cc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)On1c(C(F)(F)F)nc2ncc(Cl)cc21
Temperature: 5 °C

Procedure:
1-Hydroxy-6-chloro-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine (5 grams) in 15 milliliters of pyridine was cooled to 5° C. with stirring and methylsulfonyl chloride (5 milliliters) was added in 1-milliliter portions, maintaining the temperature at about 5° C. After the addition was completed, the reaction mixture was stirred for two hours at 5°-10° C., then poured into 30 grams of ice and 20 milliliters of concentrated hydrochloric acid. The desired 1-(methylsulfonyloxy)-6-chloro-2-(trifluoromethyl)-1H-imidazo(4,5-b)pyridine product precipitated and was separated by filtration and washed with water. The washed product was taken up in diethyl ether with a trace of acetone, dried over magnesium sulfate and the solvent evaporated under vacuum. The product so obtained melted at 136.7° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:18](OCC)(OCC)(OCC)[CH2:19][CH3:20]>C(OCC)(=O)C.CCOCC>[CH3:15][C:14]([CH3:17])([OH:16])[CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:18]1[CH2:19][CH3:20]
Reactant: CCOC(CC)(OCC)OCC
Reactant: CC(C)(O)CNc1c(N)cnc2ccccc12
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Yield: 84.2 %

Procedure:
A mixture containing 15.4 g (0.067 mol) of 1-[(3-amino-4-quinolinyl)amino]-2-methyl-2-propanol (U.S. Pat. No. 4,689,338 example 189) and 14.5 mL (0.07 mol) of triethyl orthopropionate was heated at about 165° C. for about 2 hours. The resulting solid was slurried in a mixture of ethyl acetate and ether, collected and dried to provide 15.2 g of a solid. This material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.Cl[C:22]1[CH:23]=[C:24]2[N:31](C(OC(C)(C)C)=O)[C:30]([CH3:40])([CH3:39])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1)[CH2:19][O:20][C:22]1[CH:23]=[C:24]2[NH:31][C:30]([CH3:40])([CH3:39])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1
Reactant: CC(C)(C)OC(=O)N1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1ccc(Oc2cncc(C(F)(F)F)c2)c(F)c1
Product: CC1(C)Cn2c(cc(OCc3ccc(Oc4cncc(C(F)(F)F)c4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and tert-butyl 7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CC(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2ccc(O)cc2C1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc2c(c1)C[C@H](NC(=O)OC(C)(C)C)CC2
Yield: 33.5 %

Procedure:
A solution of 10.8 g of (R)-2-tert-butoxycarbonylamino-7-hydroxytetraline (a) in 300 ml of acetone, is heated at reflux under stirring for 6 hours in the presence of 12.4 g of powdered anhydrous potassium carbonate and 15.1 g of ethyl bromoacetate. After filtration, acetone is evaporated under reduce pressure and the residue is taken up with ethyl ether. The solution so obtained is washed with water, dried over sodium sulfate and evaporated to dryness. The residue is taken up with ethyl ether and crystallized from isopropyl ether. Thus, 4.8 g of (R)-2-tert-butoxycarbonylamino-7-carbethoxymethoxytetraline are obtained; m.p. 113°-115° C., /alpha/=+57.97° (methanol, c=1%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2Cl.[CH3:17][N:18]([CH2:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:15])[CH2:13][CH3:14])=[C:5]2[NH:25][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:18]([CH3:19])[CH3:17])=[CH:27][CH:26]=1
Reactant: CCC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CN(C)Cc1ccc(N)cc1
Product: CCC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN(C)C)cc1
Yield: 85.9 %

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)propan-1-one (750 mg, 2.51 mmol) was reacted with 4-(dimethylaminomethyl)aniline (377 mg, 2.51 mmol) to afford the desired product (889 mg, 86%) as a yellow solid. APCI MS m/z 412 [C21H22BrN3O+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([CH:17]3[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([CH:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)N2CCN(c3ccc(Cl)c(Cl)c3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(C1CCCNC1)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl 3-{[4-(3,4-dichlorophenyl)piperazin-1-yl]carbonyl}piperidine-1-carboxylate (1.002 g) in DCM (10 ml) was added TFA (10 ml). The reaction was allowed to stir at ambient temperature for 2 hours. The solvents were removed in vacuo, the residue partitioned between DCM and 2M NaOH, extracted twice and the combined organics dried (Na2SO4), filtered and evaporated to give the product, 1-(3,4-dichlorophenyl)-4-(piperidin-3-ylcarbonyl)piperazine, as a yellow foam (703 mg).
Reaction SMILES: CCOCC.Br[C:7]1[C:20]2[O:19][C:18]3[C:13](=[CH:14][C:15]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:16][C:17]=3Br)[C:12]([CH3:27])([CH3:26])[C:11]=2[CH:10]=[C:9]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:8]=1.[Li]CCCC.[Si:37]([Cl:41])(Cl)([CH3:39])[CH3:38]>CCCCCC>[Cl:41][Si:37]([CH3:39])([CH3:38])[C:7]1[C:20]2[O:19][C:18]3[C:13](=[CH:14][C:15]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:16][C:17]=3[Si:37]([Cl:41])([CH3:39])[CH3:38])[C:12]([CH3:27])([CH3:26])[C:11]=2[CH:10]=[C:9]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:8]=1
Reactant: CC(C)(C)c1cc(Br)c2c(c1)C(C)(C)c1cc(C(C)(C)C)cc(Br)c1O2
Reactant: C[Si](C)(Cl)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)c1cc2c(c([Si](C)(C)Cl)c1)Oc1c(cc(C(C)(C)C)cc1[Si](C)(C)Cl)C2(C)C
Temperature: -65 °C

Procedure:
The reaction outlined in the reaction scheme below is as follows: Et2O (125 mL) and 4,5-dibromo-2,7-di(tert-butyl)-9,9-dimethylxanthene (9.54 g, 19.9 mmol) were combined and cooled to −65° C. A hexane solution of BuLi (19.2 mL, 47.7 mmol) was added dropwise over 5 min and the colorless suspension was allowed to warm to −30° C. over a period of 45 min during which time the starting material dissolved (at about −40° C.). After 15 min at −30° C. the solution was cooled to −80° C. and cold SiMe2Cl2 (20.5 g, 159 mmol) was added in one portion.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([NH:13][CH2:14][C@@H:15]([OH:20])[C:16]([O:18][CH3:19])=[O:17])[CH:3]=1.[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[C:7]2[N:8]([CH3:12])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([N:13]2[CH2:14][C@H:15]([C:16]([O:18][CH3:19])=[O:17])[O:20][C:21]2=[O:22])[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)[C@H](O)CNc1cc(F)c2c(c1)oc(=O)n2C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)[C@H]1CN(c2cc(F)c3c(c2)oc(=O)n3C)C(=O)O1
Temperature: 60 °C
Yield: 95.8 %

Procedure:
A mixture of methyl (2R)-3-[(4-fluoro-3-methyl-2-oxo-2,3-dihydro-6-benzoxazolyl)amino]-2-hydroxypropanoate (Step 8, 0.84 g, 2.96 mmol) and 1,1′-carbonyldiimidazole (0.48 g, 2.96 mmol) in acetonitrile is stirred and heated at 60° C. overnight. The reaction is diluted with ethyl acetate, washed with 2N HCl and saline, and evaporated under reduced pressure. The resulting solid is triturated with methanol to give pure product as a white solid (0.88 g, 96%); MS for C13H11FN2O6 m/z 311 (M+H)+.
Reaction SMILES: [H-].[Na+].[O:3]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:21]([O:23][CH3:24])=[O:22])[C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C1COCC1>[O:3]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([C:21]([O:23][CH3:24])=[O:22])[C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(Oc2ccccc2)cc1
Reactant: CCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCC(C(=O)OC)(C(=O)OC)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To a suspension of NaH (144 mg of 60% in mineral oil washed with hexanes, 86.4 mg, 3.6 mmol) in dry THF (20 mL) was carefully added dimethyl 2-(4-phenoxyphenyl)malonate (900 mg, 3.0 mmol). The resulting mixture was stirred at room temperature for 1 hour and then 1-iodohexane (1.27 g, 0.89 mL, 6.0 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and then heated to reflux overnight . The reaction was cooled to room temperature and quenched with 1N HCl (20 mL) and extracted with ether (2×40 mL). The combined organic extracts were washed with saturated Na2S2O3, water, then brine, dried (Na2SO4), concentrated, and purified by chromatography using a Chromatotron with a silica gel plate (4000 micron) eluted with 13% EtOAc/hexanes to give 950 mg of dimethyl 2-(4-phenoxyphenyl)-2-n-hexylmalonate as a viscous oil. 1H NMR (200 mHz, CDCl3) δ 7.39-6.92 (9H, m), 3.75 (6H, s), 2.10 (2H, t), 1.29 (8H, m), 0.87 (3H, t).
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[C:11]([CH:12]=2)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH2:3][CH2:2]1.[Br:19][C:20]1[O:21][C:22]([CH2:25]Cl)=[CH:23][CH:24]=1>>[Br:19][C:20]1[O:21][C:22]([CH2:25][N:5]2[C:6]3[C:11](=[C:10]([C:13]([F:14])([F:15])[F:16])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH:12]=[C:4]2[CH:1]2[CH2:2][CH2:3]2)=[CH:23][CH:24]=1
Reactant: ClCc1ccc(Br)o1
Reactant: N#Cc1ccc2[nH]c(C3CC3)cc2c1C(F)(F)F
Product: N#Cc1ccc2c(cc(C3CC3)n2Cc2ccc(Br)o2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 4 using 2-cyclopropyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile (Example 165A) and 2-bromo-5-(chloromethyl)furan (Example 310B): MS (ES) m/z 409 (M+1) and 411 (M+1, isotope).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[C:25]([C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][CH:36]([C:39](O)=[O:40])[CH2:35][CH2:34]2)=[N:31][CH:32]=1)#[N:26]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:39]([CH:36]3[CH2:35][CH2:34][N:33]([C:30]4[CH:29]=[CH:28][C:27]([C:25]#[N:26])=[CH:32][N:31]=4)[CH2:38][CH2:37]3)=[O:40])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)nc1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white foam. MS m/e: 562.1 [M]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)O1.O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 13.8 %

Procedure:
In a 50 mL round-bottomed flask, 5-bromo-2-nitropyridine (3.28 g, 16.2 mmol, Eq: 1) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (5 g, 16.2 mmol, Eq: 1.00) were combined with dioxane (80.0 ml) to give a light yellow solution. Cs2CO3 (10.5 g, 32.3 mmol, Eq: 2) and 3 mL H2O were added. The solution was degassed with Ar before bis(triphenylphosphine)palladium(ii) dichloride (1.13 g, 1.62 mmol, Eq: 0.1) was added. The reaction mixture was heated to 80° C. and stirred for 15 h. The reaction mixture was poured into 300 mL H2O and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine and dried over MgSO4. The crude reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 220 g, 10% to 100% EtOAc/Hex gradient) to give a dark brown impure solid. The solid was triturated with Et2O to afford tert-butyl 4-(6-nitropyridin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (685 mg, 69%) as a tan solid. LC/MS-ESI observed [M+H]+ 306.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:6]([S:10]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[C:25]([OH:35])[CH:24]=2)=[CH:16][C:15]=1[O:36][CH3:37])(=[O:12])=[O:11])[CH2:7][CH2:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].O>C(C(C)=O)C>[CH2:6]([S:10]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[C:25]([O:35][CH2:2][CH2:3][CH2:4][CH3:5])[CH:24]=2)=[CH:16][C:15]=1[O:36][CH3:37])(=[O:12])=[O:11])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCS(=O)(=O)Oc1ccc(CCCc2ccc(CCC(=O)OC)c(O)c2)cc1OC
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CCCCOc1cc(CCCc2ccc(OS(=O)(=O)CCCC)c(OC)c2)ccc1CCC(=O)OC
Temperature: 70 °C
Yield: 40 %

Procedure:
ml (0.95 mmol) of iodobutane is added to a solution of 400 mg (0.86 mmol) of methyl 3-(4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-2-hydroxyphenyl)propanoate (prepared according to Example 10i) and 178 mg (1.29 mmol) of potassium carbonate in 10 ml of methyl ethyl ketone, and the reaction mixture is then heated at 70° C. for 18 hours. The reaction is treated by adding 20 ml of water and then extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered and evaporated. The residue is purified by chromatography on a column of silica eluted with a 70/30 heptane/ethyl acetate mixture. 179 mg (40%) of methyl 3-(4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-2-butoxyphenyl)propanoate are obtained in the form of a colorless oil.