Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:13][CH2:12][O:11][C:10]1=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:15]>CO>[Si:1]([O:8][C@@H:9]([CH2:13][CH2:12][OH:11])[C:10]([NH2:15])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(C)(C)[Si](C)(C)OC1CCOC1=O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H](CCO)C(N)=O
Reaction time: 48 h

Procedure:
To a solution of 3-(tert-butyldimethylsilyloxy)dihydrofuran-2(3H)-one (11 g, 49 mmol) in methanol was added 7 N ammonia in methanol (20 mL, 140 mmol). The reaction was stirred in a sealed tube for 2 days. The solvent was removed in vacuo to yield (S)-2-(tert-butyldimethylsilyloxy)-4-hydroxybutanamide (4.85 g, 20.8 mmol) as a white solid. [M+H] calc'd for C10H23NO3Si, 234; found, 234.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.S(Cl)([Cl:15])=O.CN(C)C=O.CO>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][C:9]([Cl:15])=[O:10])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1cc(Br)ccc1F
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Cl)Cc1cc(Br)ccc1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 105 %

Procedure:
To a mixture of commercially available 5-bromo-2-fluorophenylacetic acid (compound B1A, [CAS No. 883514-21-4], 6.42 g, 26 mmol) in toluene (52 ml) and thionyl chloride (SOCl2) (4.721 ml, 40 mmol) at 23° C. was added a drop of N,N-dimethylformamide (DMF) and the mixture was stirred at 80° C. for 4 hours (reaction checked by HPLC with product+MeOH). All volatiles were removed by rotary evaporation and the residue was dried in high vacuum to give the title compound as a colorless liquid (7.01 g, 105%), which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:10][C@@H:9]2[CH3:29])=[O:7])=[CH:4][CH:3]=1.[CH2:32]([CH:34]([CH2:37][CH3:38])[CH:35]=O)[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[CH2:32]([CH:34]([CH2:37][CH3:38])[CH2:35][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([N:18]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:19](=[O:22])[CH2:20][CH3:21])[CH2:10][C@@H:9]2[CH3:29])=[O:7])=[CH:30][CH:31]=1)[CH3:33]
Reactant: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N)cc2)c2ccccc21
Reactant: CCC(C=O)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(NCC(CC)CC)cc2)c2ccccc21
Temperature: 25 °C
Yield: 83 %

Procedure:
(±)-Cis-N-{1-[4-(2-ethyl-butylamino)-benzoyl]-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl}-N-phenyl-propionamide was prepared from (±)-cis-N-[1-(4-amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide. To a solution of (±)-cis-N-[1-(4-Amino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-N-phenyl-propionamide (75 mg, 0.145 mmol) in dichloromethane (3 mL) was added 2-ethylbutyraldehyde (26 uL, 0.2 mmol) in one portion. The mixture was stirred at room temperature for a 0.5 h before a solution of sodium triacetoxyborohydride (74 mg, 0.348 mmol) 1 ml DCM was added slowly. A single drop of acetic acid was added and the reaction was allowed to stir at room temperature over night. Excess reagent was quenched by the addition of saturated aqueous sodium bicarbonate. The resulting mixture was extracted three times with 20 mL dichloromethane. The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Crude product was purified by HPLC to afford the title compound (60 mg, 83%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][C:7]([CH:9]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[O:8])[CH:4]=[CH2:5].Br[CH2:26][CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1.O>CN(C=O)C>[CH2:3]([O:6][C:7]([C:9]([CH2:26][CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[O:8])[CH:4]=[CH2:5]
Reactant: C=CCOC(=O)C(CCCCC(=O)OCC)C(=O)OCC=C
Reactant: N#Cc1ccc(CCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)C(CCCCC(=O)OCC)(CCc1ccc(C#N)cc1)C(=O)OCC=C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6.37 g (159.27 mmol; 60% pure) of sodium hydride are added in portions to a solution of 45.23 g (144.79 mmol) of 1-allyl 7-ethyl 2-allyloxycarbonylheptanedioate in 250 ml of DMF at 0° C. The reaction solution is then allowed to reach room temperature and is stirred for 30 min. The reaction solution is then cooled to 0° C. and, after addition of 36.50 g (173.75 mmol) of 4-(2-bromoethyl)benzonitrile in 250 ml DMF, stirred at this temperature for 30 min. The mixture is then stirred at room temperature overnight. Water is added dropwise to the reaction mixture and, after extraction three times with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness in vacuo. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1→4:1→1:1). 17.85 g (40.43 mol, 28% of theory) of a colorless solid are obtained.
Reaction SMILES: Br[C:2]1[C:6]2[C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:5]=2[S:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:6]3[C:7](=[O:11])[NH:8][CH2:9][CH2:10][C:5]=3[S:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=C1NCCc2scc(Br)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1NCCc2scc(-c3ccc(F)cc3)c21
Yield: 93.8 %

Procedure:
Using analogous reaction conditions and workup as described in Example 3, step 5, 3-bromo-6,7-dihydro-5H-thieno[3,2-c]pyridin-4-one (I-15b: 300 mg, 1.293 mmol) was reacted with (4-fluoro-phenyl)-dihydroxy-borane (217.11 mg, 1.55 mmol), Pd(PPh3)4 (149.4 mg, 0.1293 mmol), toluene (20 mL) and water (3 mL) to afford the crude product. Purification by column chromatography on silica gel (2% methanol in CHCl3) afforded 300 mg of the product (47.02% yield).
Reaction SMILES: [OH-].[K+].[C:3]1([CH:9]=[CH:10][C:11](=O)[CH:12]([OH:26])[CH2:13][C:14](=[O:25])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.O.C(O)(=O)C(O)=O>C(Cl)(Cl)Cl>[OH:26][CH:12]1[CH2:13][C:14](=[O:25])[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[C:11]1[CH:10]=[CH:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)CCCCCCCC(=O)CC(O)C(=O)C=Cc1ccccc1
Agent: O=C(O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=O
Reaction time: 4 h

Procedure:
To 3000 parts by volume of an aqueous solution containing 6.7 parts of potassium hydroxide is added, with stirring at 21°-23° over a period of about 21/4 hours, a solution of 10.4 parts of 14-phenyl-9,12-dioxo- 11-hydroxytetradec-13-enoic acid in 187 parts of chloroform. After completion of the addition, the reaction mixture is stirred for an additional 2 hours, then is made acidic by adding 10 parts of oxalic acid dihydrate. The acidic mixture is extracted with chloroform and the organic layer is washed with dilute aqueous sodium chloride, then dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The resulting residue is recrystallized first from benzene, then from chloroform-ether to yield 3-hydroxy-5-oxo-2 -styrylcyclopent-1eneheptanoic acid, which displays a melting point at about 118°. This compound displays an ultraviolet absorption maximum at about 325 millimicrons with a molecular extinction coefficient of about 36,400 and is further characterized by the following structural formula ##SPC3##
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.[H-].[Na+].[I-].[Na+].[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][O:8][C:3]1[CH:4]=[CH:5][C:6]([NH2:7])=[CH:1][CH:2]=1
Reactant: Nc1ccc(O)cc1
Reactant: CN(C)CCCCl
Agent: O=C([O-])[O-]
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CN(C)CCCOc1ccc(N)cc1
Temperature: 70 °C

Procedure:
A stirred solution of 65.4g (0.60 mole) of p-aminophenol in 250 ml of dimethylformamide is treated portion-wise with 28.6g (0.60 mole) of 50% sodium hydride. The temperature is maintained below 35° C during the addition, warmed to 70° C then cooled to 25° C. The mixture is treated with 5g of sodium iodide and 476 ml of a 1.89 N toluene solution of 3-dimethylaminopropyl chloride, then heated at 100°-105° C for 3 hours. The cooled mixture is poured over 500 ml of ice and extracted with 300 ml of ether (2 times). The combined solvent fractions are shaken in a separatory funnel with 150 ml of 6 N hydrochloric acid. The basic product is obtained by treating the aqueous fraction with 200g of potassium carbonate (ether extraction). After drying, the solvent is evaporated and the residue fractionated to give 25.1g of an oil, boiling point 128°-135° C/0.2 mm of Hg. (Continuation of the distillation yields 21.9g of di-alkylated material, boiling point 135°-158° C/0.2 mm of Hg).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:9](=[O:12])[NH:10][N:11]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.CO>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:8]2[C:7](=[O:20])[C:6]([C:4]([OH:5])=[O:3])=[N:11][NH:10][C:9]2=[O:12])=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1n[nH]c(=O)n(-c2ccc(F)cc2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1n[nH]c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
4-(4-Fluoro-phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid ethyl ester (300 mg, 1 mmol) in THF (3 mL) and MeOH (7 mL) was added 5M NaOH (2 mL, 2 mmol). The mixture was stirred at rt for 1h and was concentrated. Water was added and the mixture was extracted with ether. The aq. layer was made acidic with HCl at 0° C. and was extracted with EtOAc and concentrated. LCMS m/z=274 (M+Na); 1H NMR (DMSO) δ: 13.03 (s, 1H), 7.35-7.30 (m, 4H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:47][O:48][C:49](=[O:63])[C@H:50]([NH:53][CH2:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=1)[CH2:51][CH3:52]>CN(C=O)C.O>[CH3:47][O:48][C:49](=[O:63])[C@H:50]([N:53]([C:11](=[O:13])[C@@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:10])[CH2:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=1)[CH2:51][CH3:52]
Reactant: CC[C@@H](NCc1ccc(OC)cc1)C(=O)OC
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC[C@H](C(=O)OC)N(Cc1ccc(OC)cc1)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To a solution of 3.99 g of Boc-L-alanine in 50 ml of DMF were added 12.02 g of HATU, 4.3 ml of Hünig's base and 5.00 g (R)-2-(4-Methoxy-benzylamino)-butyric acid methyl ester. The reation was stirred overnight, and 6.01 g of HATU and 2.1 ml of Hünig's base were added, and the reaction was stirred for 24 h at r.t. and then for 4 h at 50° C. The reaction was poured unto water, the layers were separated and the aqueous phase was extracted with EtOAc twice. The combined organic layers wer washed with 10% aqueous citric acid twice, dried over Na2SO4, fitrered and concentrated in vacuo. The residue was purified by flash chromatography (silica, heptane/EtOAc) to obtain 7.60 g (88%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:22]3([OH:32])[CH2:31][CH2:30][C:25]4(OCC[O:26]4)[CH2:24][CH2:23]3)[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[OH-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:22]3([OH:32])[CH2:31][CH2:30][C:25](=[O:26])[CH2:24][CH2:23]3)[O:12][C:13]=2[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc(C3(O)CCC4(CC3)OCCO4)oc2-c2ccc(OC)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(C3(O)CCC(=O)CC3)oc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
To a solution of 8-(4,5-bis(4-methoxyphenyl)oxazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (Reference Example 92) (781 mg, 1.78 mmol) in tetrahydrofuran (4.5 mL), 6 M hydrochloric acid (9.0 mL) was added at 0° C., and the obtained solution was stirred at room temperature for 2 hours. The reaction solution was cooled to 0° C., and alkalified by addition of 10% aqueous sodium hydroxide solution and saturated sodium bicarbonate solution. The resulting solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by recrystallization (ethyl acetate/n-hexane) to obtain the title compound (445 mg, 1.13 mmol, 63%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[C:14]([O:18][C:19]([N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:31][CH2:32][O:33][C:34]3[CH:35]=[C:36]4[C:40](=[CH:41][CH:42]=3)[NH:39][CH:38]=[CH:37]4)[N:29]=2)[CH2:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([CH2:31][CH2:32][O:33][C:34]3[CH:35]=[C:36]4[C:40](=[CH:41][CH:42]=3)[N:39]([C:5]([C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=3)=[CH:4][C:3]([O:2][CH3:1])=[O:13])[CH:38]=[CH:37]4)[N:29]=2)[CH2:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Reactant: COC(=O)C#Cc1ccc(F)cc1
Product: COC(=O)C=C(c1ccc(F)cc1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 73 %

Procedure:
The title compound was synthesized from (4-fluoro-phenyl)-propynoic acid methyl ester and 7-[2-(1H-Indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 17, step (a), in 73% yield as an E/Z isomeric mixture. 1H NMR (CDCl3) [E/Z mixture] δ 7.43 (m, 1H), 7.30 (m, 2H), 7.00–7.20 (m, 3), 6.94 (m, 1H), 6.50–6.90 (m, 3H), 6.12 (s, 1H), 4.36 (m, 2H), 3.75 (m, 2H), 3.7 and 3.6 (s, 3H), 3.20 (m, 2H), 2.75 (m, 2H), 1.90 (m, 2H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI) calculated for C33H35FN3O5 572.3 (M+H); found 472.3 (M-Boc+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][C:11]=1[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C:20]1=O.O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][C:11]=1[N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1ccc(F)c(-c2ccc(C(=O)O)cc2N2CCCCC2=O)c1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)c(-c2ccc(C(=O)O)cc2N2CCCCC2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 69.4 %

Procedure:
To a cooled solution of 67.20B (0.4401 g, 1.282 mmol) in dry THF (8 mL) at 0° C. was added borane THF complex, 1.0 M in THF (2.5 mL, 2.5 mmol) dropwise. Upon complete addition, the reaction was maintained at 0° C. and monitored by TLC and LCMS. After 3 hours, water was added to quench the reaction, and the resulting solution was extracted three times with EtOAc. The organic extractions were combined and washed successively with saturated aqueous sodium bicarbonate, water, and then brine. After drying over anhydrous magnesium sulfate, filtration, and concentration, the residue was purified with silica gel flash chromatography (0-25% MeOH in DCM) to afford 67.20C as an oil (292.9 mg, 69% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.85 (2H, m), 7.36 (1H, d, J=7.8 Hz), 7.11 (2H, m), 6.86 (1H, dt, J=8.9, 3.6 Hz), 3.83 (3H, s), 2.85 (4H, m), 1.46 (6H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].CCN=C=NCCCN(C)C.Cl.[CH3:23][NH:24][O:25][CH3:26].Cl>C(Cl)Cl.O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([N:24]([O:25][CH3:26])[CH3:23])=[O:6]
Reactant: O=C(O)c1cccc(F)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of 3-fluorobenzoic acid (30 g, 214.1 mmol) in DCM (300 mL) were added EDC.HCl (45 g, 235 mmol) and N,O-dimethylhydroxylamine.HCl (23 g, 235 mmol) at 0° C. under N2. The reaction mixture was stirred at rt for 3 h, then diluted with water (1000 mL) and extracted with DCM (3×200 mL). The organics were washed with brine, dried over Na2SO4, and concentrated to obtain the 3-fluoro-N-methoxy-N-methylbenzamide (24 g, 61%). (183.91 [M+H]) 1H NMR: (400 MHz, CDCl3) δ: 3.38 (s, 3H), 3.57 (s, 3H), 7.14-7.19 (m, 1H), 7.37-7.43 (m, 2H), 7.48-7.50 (d, J=7.6, 1H).
Reaction SMILES: O[CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.S(Cl)([Cl:18])=O.O>CN(C)P(=O)(N(C)C)N(C)C>[Cl:18][CH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: COC(=O)C(C)Oc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(C)Oc1ccc(CCl)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
12 gm (0.058 mol) of methyl 2-(4-hydroxymethyl-phenoxy)-propionate were dissolved in 60 ml of hexamethylphosphoric acid triamide, the solution was cooled to -10° C., and 4.4 ml (0.06 mol) of thionyl chloride were added dropwise thereto. The resulting mixture was stirred for 30 minutes at 0° C. and then for one hour at 10° C., and subsequently poured into water. The aqueous mixture was extracted with ether, and the extract solution was washed with water, sodium bicarbonate solution and again with water, and dried. The ether was subsequently removed in vacuo at room temperature, leaving methyl 2-(4-chloromethyl-phenoxy)-propionate as a residue.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]([O:23][CH3:24])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH:25][C:26]1[C:29]([CH3:31])([CH3:30])[C:28](=O)[CH:27]=1>C(Cl)Cl>[CH3:30][C:29]1([CH3:31])[C:28]([NH:1][C@@H:2]([CH2:8][C:9]2[CH:10]=[C:11]([O:23][CH3:24])[C:12]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[C:13]([O:15][CH3:16])[CH:14]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:27][C:26]1=[O:25]
Reactant: CC1(C)C(=O)C=C1O
Reactant: CCOC(=O)[C@@H](N)Cc1cc(OC)c(-c2ccccc2)c(OC)c1
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1cc(OC)c(-c2ccccc2)c(OC)c1)NC1=CC(=O)C1(C)C

Procedure:
The title compound was prepared in a similar manner to that of the compound of Example 41 from ethyl (2S)-2-amino-3-(2,6-dimethoxy[1,1′-biphenyl]-4-yl)propanoate (1.5 g, 4.5 mol), and 3-hydroxy-4,4-dimethyl-2-cyclobutenone (0.5 g, 4.5 mmol) in DCM (11 ml) as a white foam (1.8 g, 93%). δH (300 MHz, DMSO d6) 8.68 (1H, d, J 8.6 Hz), 7.22-7.37 (3H, m), 7.18 (2H, d, J 8.3 Hz), 6.78 (2H, d, J 8.4 Hz), 4.46 (11H, s), 4.32 (1H, m), 4.21 (2H, q, J 7.1 Hz), 3.69 (6H, s), 3.24 (1H, dd, J 13.8, 5.9 Hz), 3.09 (1H, dd, J 13.8, 9.1 Hz), 1.24 (3H, t, J 7.1 Hz), 1.16 (3H, s), 1.08 (3H, s); m/z (ES+, 70V) 424 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C([O-])([O-])=O.[Na+].[Na+].[N+:16]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)([O-:18])=[O:17]>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=2)=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: O=Cc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(-c2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 49.9 %

Procedure:
To a sealable flask containing a mixture of 3-bromobenzaldehyde (1.8 mL, 15 mmol) and Na2CO3 (1.6 g, 15 mmol) in anhydrous DMF (20 mL) and water (10 mL), were added 4-nitrophenylboronic acid (2.5 g, 15 mmol) then palladium(II) acetate (0.17 g, 0.75 mmol). Argon was bubbled through the mixture before the flask was sealed and the mixture stirred at room temperature. After 4 days, the reaction mixture was partitioned between ethyl acetate and brine before the entire mixture was filtered through a pad of Celite®. The aqueous and organic layers, of the filtrate, were separated and the aqueous layer was extracted twice more with EtOAc. All of the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel flash chromatography (ISCO CombiFlash Companion system, 120 g, RediSep normal phase silica flash column, eluting with 10-50% EtOAc in hexane) afforded the desired compound (1.7 g, 47%) as an off-white solid. 1H NMR (CDCl3) δ 10.05 (s, 1H), 8.31-8.25 (m, 2H), 8.10-8.06 (m, 1H), 7.93-7.81 (m, 2H), 7.77-7.70 (m, 2H), 7.63 (t, J=7.7 Hz, 1H). MS (ESI): 228.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH:15]2[O:16][CH2:17][CH2:18][CH2:19][C@@H:20]([CH2:21]O)[N:14]2[C:13](=[O:24])[C@@H:12]1[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O.Cl.[CH2:39]1[C:41]2([CH2:46][CH2:45][NH:44][CH2:43][C@H:42]2[OH:47])[CH2:40]1.CCN(CC)CC.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CC1(C)N([O])C(C)(C)CCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH:15]2[O:16][CH2:17][CH2:18][CH2:19][C@@H:20]([CH2:21][N:44]3[CH2:45][CH2:46][C:41]4([CH2:39][CH2:40]4)[C@H:42]([OH:47])[CH2:43]3)[N:14]2[C:13](=[O:24])[C@@H:12]1[CH3:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1C(=O)N2C(CN1C(=O)OCc1ccccc1)OCCC[C@H]2CO
Reactant: O[C@@H]1CNCCC12CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: C[C@H]1C(=O)N2C(CN1C(=O)OCc1ccccc1)OCCC[C@H]2CN1CCC2(CC2)[C@H](O)C1
Temperature: 0 °C
Yield: 52.8 %

Procedure:
2,2,6,6-Tetramethylpiperidine-1-oxyl radical (0.05 mg, 0.3 μmol) was added at room temperature to a suspension of (3S,5S)-5-hydroxymethyl-3-methyl-4-oxo-octahydro-9-oxa-2,4a-diaza-benzocycloheptene-2-carboxylic acid benzyl ester (example 23B, 102 mg, 0.29 mmol) and trichloroisocyanuric acid (72 mg, 0.29 mmol) in DCM (1 mL), then after 5 min the mixture was washed with 1 M aq. sodium sulfite solution and brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue [(3S,5S)-5-oxomethyl-3-methyl-4-oxo-octahydro-9-oxa-2,4a-diaza-benzocycloheptene-2-carboxylic acid benzyl ester] was dissolved in DCM (1 mL) and added dropwise at room temperature to a suspension of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (48 mg, 0.29 mmol), Et3N (30 mg, 0.29 mmol), HOAc (35 mg, 0.58 mmol) and sodium triacetoxyborohydride (70 mg, 0.32 mmol) in DCM, then after 16 h the reaction mixture was cooled to 0° C. and partitioned between EtOAc and 1 M aq. sodium carbonate solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; DCM→DCM/MeOH/25% aq. ammonia solution 90:10:0.25) produced the title compound (70 mg, 52%). Light yellow gum, MS: 458.4 (M+H)+.