Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:7][CH2:6][N:5]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[C:4]2=[N:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:27]1[CH2:30][CH2:29][CH2:28]1.[OH-].[Na+]>CS(C)=O.C1COCC1.C(OCC)(=O)C>[CH:27]1([O:18][C:15]2[CH:16]=[CH:17][C:12]([C:11]3[C:4]4=[N:3][S:2](=[O:1])(=[O:19])[CH2:7][CH2:6][N:5]4[CH:8]=[CH:9][CH:10]=3)=[CH:13][CH:14]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: BrC1CCC1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(OC4CCC4)cc3)C2=N1
Temperature: 130 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
A mixture of 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (300 mg), potassium carbonate (390 mg) and bromocyclobutane (191 mg) in DMSO (5 mL) was stirred at 130° C. for 1 hr. Bromocyclobutane (100 mg) was added, and the mixture was stirred at room temperature overnight. 0.5N Aqueous sodium hydroxide solution, ethyl acetate and THF were added and the mixture was extracted. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was separated by HPLC (C18, mobile phase: water/acetonitrile (0.1% TFA containing system)). To the obtained fraction was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from acetonitrile, THF and diisopropyl ether to give the title compound (71.9 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14](OC(C)(C)C)=O)[C@H:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:10]=1.ClCCl.FC(F)(F)C(O)=O.[CH:37]([S:39]([CH3:42])(=[O:41])=[O:40])=C>C(O)C.O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([CH2:14][CH2:37][S:39]([CH3:42])(=[O:41])=[O:40])[C@H:11]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:10]=1
Reactant: C=CS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CS(=O)(=O)CCN1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl (2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxylate (5-5, 100 mg, 0.280 mmol, 1 equiv) in a 4:1 mixture of dichloromethane and trifluoroacetic acid (20 mL) was stirred for 30 min, then concentrated. The residue was partitioned between saturated aqueous sodium bicarbonate solution and ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and were concentrated. A solution of the residue and methyl vinyl sulfone (0.025 mL, 0.28 mmol, 1.0 equiv) in a 1:1 mixture of dioxane and ethanol (5 mL) was stirred at 23° C. for 16 h. Additional methyl vinyl sulfone (0.025 mL, 0.28 mmol, 1.0 equiv) was added and stirring was continued for 4 h. The reaction mixture was concentrated and the residue was purified by flash column chromatography (hexanes initially, grading to 50% EtOAc in hexanes) to give (2S)-4-(2,5-difluorophenyl)-1-[2-(methylsulfonyl)ethyl]-2-phenyl-2,5-dihydro-1H-pyrrole (37-1) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.38-7.28 (m, 5H), 7.09-6.89 (m, 3H), 6.28 (br s, 1H), 4.69 (td, 1H, J=4.9, 1.8 Hz), 4.34 (dd, 1H, J=12.5, 4.9 Hz), 3.84 (ddd, 1H, J=13.0, 4.8, 1.7 Hz), 3.36-3.02 (m, 4H), 2.79 (s, 3H). LRMS m/z (M+H) 364.3 found, 364.1 required.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>C1COCC1>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:9][CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1cncc(Br)c1
Reactant: O=C(CBr)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(COCc1cncc(Br)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
(5-Bromo-pyridin-3-yl)-methanol (25.0 g, 0.13 mol) is added to a solution of NaH (6.45 g, 0.27 mol) in THF (500 ml) at 0° C. and stirred at room temperature for 30 min. Benzyl bromoacetate (34.4 g, 0.15 mol) is added to this solution at 0° C. and stirred at room temperature overnight. The mixture is quenched with water and diluted with DCM. The organic layer is dried over Na2SO4 and concentrated in vacuo. The product is chromatographed on silica gel to give (5-bromo-pyridin-3-ylmethoxy)-acetic acid benzyl ester (10 g).
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[CH3:30][O:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([OH:36])=O>>[CH3:30][O:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:36]
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: COc1ccccc1C(=O)O
Agent: Cl
Product: COc1ccccc1C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 2-methoxybenzoic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(2-methoxybenzoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 498 (M-H)-.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([NH:19][CH2:20][CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([O:26][C:27](=[O:35])[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27](=[O:35])[CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][N:19]([C:10]1[CH:9]=[N:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:11]=1)[CH2:20][CH3:21])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)COCCCCBr
Reactant: CCNc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Product: CCN(CCCCOCC(=O)OC(C)(C)C)c1cnc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
In the same manner as in Example 22, except that 5,6-diphenyl-2-(ethylamino)pyrazine was used in place of 5,6-diphenyl-2-(methylamino)pyrazine and 2-(4-bromobutyloxy)acetic acid tert-butyl ester was used in place of 2-(4-bromobutyloxy)acetic acid methyl ester, the desired compound was prepared as a pale yellow oily substance.
Reaction SMILES: [CH3:1][CH:2]([CH:21]([N+:29]([O-])=O)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH:4][C:5](=[O:13])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OCC)(=O)C.[Pd]>[CH3:1][CH:2]([CH:21]([NH2:29])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:3]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[NH:4][C:5](=[O:13])[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C(C(=O)OC(C)(C)C)[N+](=O)[O-])[C@H](NC(=O)Nc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C(N)C(=O)OC(C)(C)C)[C@H](NC(=O)Nc1ccccc1)C(=O)OC(C)(C)C

Procedure:
A solution of di t-butyl 3-methyl-4-nitrophenylcarbamoyl-L-glutamate (4.7 g) in ethyl acetate (125 ml) was hydrogenated over 30% Pd/C (0.5 g). The mixture obtained was then filtered through CELITE (a purified and calcined diatomaceous earth-particle size 20-45 um obtainable inter alia from Fluka Chemicals Ltd) and evaporated to a dark solid. This solid was chromatographed on silica eluted using ethyl acetate:hexane (1.1) to give di t-butyl 3-methyl-4-aminophenylcarbamoyl-L-glutamate as in oil yield=3.71 g 83%. NMR: 7.98(s)1H; 6.9(m)2H; 6.52(d)1H; 6.15(d)1H; 4.53(s)2H; 4.15(m)1H; 2.25(m)2H; 2.04(s)3H; 1.8(m)2H; 1.45(d)18H.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([O:23]CC5C=CC=CC=5)=[CH:19][CH:18]=4)[N:14]=[C:7]3[C:8](=[O:13])[CH2:9]2)[CH:4]=[N:3]1.[H][H]>[Pd].CO>[CH3:1][C:2]1([CH3:31])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=4)[N:14]=[C:7]3[C:8](=[O:13])[CH2:9]2)[CH:4]=[N:3]1
Reactant: [H][H]
Reactant: CC1(C)N=CC2=C3N=C(c4ccc(OCc5ccccc5)cc4)N=C3C(=O)CC2C1=O
Agent: [Pd]
Solvent: CO
Product: CC1(C)N=CC2=C3N=C(c4ccc(O)cc4)N=C3C(=O)CC2C1=O

Procedure:
A mixture consisting of 2.3 gm of 7,7-dimethyl-2-(4-benzyloxy-phenyl)-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione, 200 ml of methanol and 0.5 gm of 10% palladium-on-charcoal was hydrogenated at 50° C. at a hydrogen pressure of 5 atmospheres for 4 hours. The catalyst was then filtered off, the filtrate was evaporated to 50 ml and the precipitated crystals were suction-filtered off.
Reaction SMILES: [CH3:1][O:2][P:3]([Cl:5])Cl.C[Si](C)(C)[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[Cl:5][P:3]([O:2][CH3:1])[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: COP(Cl)Cl
Reactant: C[Si](C)(C)N1CCCC1
Solvent: ClCCl
Product: COP(Cl)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of methyldichlorophosphite (10.0 g, 75.24 mmol, 7.1 mL) in CH2Cl2 (50 mL) was added dropwise 1-(trimethylsilyl)pyrrolidine (13.1 mL, 10.8 g, 75.2 mmol) at 0° C. The resulting mixture was stirred for 2 h at room temperature. The solvent was removed under reduced pressure to give a colorless oil (11.97 g, 95%) as a product. 31P NMR (CDCl3) δ 182.3.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[NH:15][CH2:14][CH2:13][N:12]=2)[CH:2]=1.[CH:22](I)([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:22]([N:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:11]([C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[N:12][CH2:13][CH2:14]1)([CH3:24])[CH3:23]
Reactant: CC(C)I
Reactant: c1ccc2c(c1)NCCN=C2c1cnc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N1CCN=C(c2cnc3ccccc3c2)c2ccccc21
Temperature: 100 °C
Reaction time: 48 h
Yield: 8.6 %

Procedure:
2,3-Dihydro-5-(3-quinolinyl)-1H-1,4-benzodiazepine (0.12 g, 0.44 mmol) was dissolved in 5 mL of dimethyl formamide, and added with isopropyl iodide (0.11 g, 0.65 mmol) and potassium carbonate (0.10 g, 0.72 mmol), followed by stirring at 100° C. for 48 hours. Isopropyl iodide (0.22 g, 1.29 mmol) and potassium carbonate (0.20 g, 1.45 mmol) were added to the resulting reaction solution, followed by stirring at 100° C. for 14 hours. The resulting reaction solution was cooled to room temperature, and cold water was poured into the reaction solution, followed by extracting with ethyl acetate. The organic layer was washed with brine, followed by drying magnesium sulfate. The solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:ethyl acetate=7:3) to obtain the target compound (0.012 g, yield: 8.7%).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([CH:9]3[CH2:16][CH2:15][CH2:14][CH2:13][C:10]43[CH2:12][CH2:11]4)[C:5]=2[C:17](O)=[O:18])[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([CH:9]3[CH2:16][CH2:15][CH2:14][CH2:13][C:10]43[CH2:12][CH2:11]4)[C:5]=2[CH2:17][OH:18])[CH2:3][CH2:2]1
Reactant: O=C(O)c1c(C2CCCCC23CC3)noc1C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1c(C2CCCCC23CC3)noc1C1CC1

Procedure:
(5-Cyclopropyl-3-(spiro[2.5]octan-4-yl)isoxazol-4-yl)methanol (I-11L) was prepared by reaction of 5-cyclopropyl-3-(spiro[2.5]octan-4-yl)isoxazole-4-carboxylic acid and LiAlH4 following the same protocol as described for I-6F. MS m/z 248.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][F:13])[C:8](=[O:14])[CH2:7]2.[N+:15]([O-])([OH:17])=[O:16]>>[F:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=[O:16])[CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][F:13])[C:8](=[O:14])[CH2:7]2
Reactant: O=[N+]([O-])O
Reactant: O=C1Cc2cccc(F)c2N1CCF
Product: O=C1Cc2cc([N+](=O)[O-])cc(F)c2N1CCF
Temperature: 25 °C
Reaction time: 24 h

Procedure:
7-Fluoro-1-(2-fluoro-ethyl)-1,3-dihydro-indol-2-one (0.880 g, 0.0119 mol) is added portionwise to 70% nitric acid (8 ml) at −10° C. After the addition is complete, the reaction is allowed to warm to room temperature and then stirred for 24 hours. The mixture is diluted with ice water and the resulting precipitate filtered, washed with water, and dried under vacuum to give the title compound as a light brown solid. HPLC r.t. 4.65 min; MS for C10H8F2N2O3 m/z 243.3 (M+H)+.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[CH:13]=[CH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9][C:8]=2[CH:18]=1)#N.[OH2:19]>CCOCC>[CH:6]1[C:7]2[CH:13]=[CH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9][C:8]=2[CH:18]=[C:4]([CH:2]=[O:19])[CH:5]=1
Reactant: O
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1C=C2
Agent: Cl
Solvent: CCOCC
Product: O=Cc1ccc2c(c1)Sc1ccccc1C=C2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Saturate a suspension of anhydrous stannous chloride (378 mg; 2 mmole) in 7.5 ml dry ether with hydrogen chloride at a temperature of 0°-5° C., and add 235 mg (1 mmole) of 3-cyano-dibenzo[b,f]thiepin. Stir for one hour at 0° C. and allow to warm to room temperature (25° C.). Continue stirring at room temperature for approximately 48 hours. Add 5 ml of water and 1 ml 2N hydrochloric acid, and extract with a mixture of 5 ml ether and 5 ml ethyl acetate. When the hydrolysis of the chloro stannate is complete, evidenced by the disappearance of solids from the solution, separate the organic layer containing the product, wash with water/sodium chloride solution, and after drying, evaporate the solution to produce a dark oil which solidifies when triturated with hexane. The title product is obtained when the above solid material is crystallized from acetonitrile, m.p. 114.5°-115.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15](C=C[CH:21]=2)[C:16](O)=O)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:24]1CCCCC1>>[CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][NH:24][CH2:21]2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1CCNCC1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(C(=O)O)c2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(CC2CCCNC2)=C(C)C1=O
Yield: 37 %

Procedure:
3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)benzoic acid (85 mg, 0.27 mmol) obtained in Example 41 and piperidine (0.036 ml, 0.41 mmol) were used, and a method similar to that described in Example 42 was employed to obtain the title compound (40 mg, 0.10 mmol, yield 37%).
Reaction SMILES: [C:1]([C:3]1[C:4]([O:14][CH3:15])=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:2].[ClH:16].NCC1C=C(C=C(OC)C=1)C(OC)=O>>[ClH:16].[NH2:2][CH2:1][C:3]1[C:4]([O:14][CH3:15])=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1cccc(C#N)c1OC
Agent: COC(=O)c1cc(CN)cc(OC)c1
Agent: Cl
Product: CCOC(=O)c1cccc(CN)c1OC

Procedure:
Ethyl 3-(aminomethyl)-2-methoxybenzoate hydrochloride was prepared from ethyl 3-cyano-2-methoxybenzoate in an analogous manner to Intermediate 2.
Reaction SMILES: [CH2:1]1CCC(N=C=NC2CCCCC2)C[CH2:2]1.[C:16]([CH2:19][CH2:20][CH2:21][C:22]([N:24]1[CH2:28][C@@H:27]([P:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:26]([P:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:25]1)=O)(O)=O>CN(C1C=CN=CC=1)C.ClCCl>[CH2:28]1[N:24]([CH2:22][C:21]2[CH:2]=[CH:1][CH:16]=[CH:19][CH:20]=2)[CH2:25][C@@H:26]([P:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:27]1[P:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)CCCC(=O)N1C[C@@H](P(c2ccccc2)c2ccccc2)[C@H](P(c2ccccc2)c2ccccc2)C1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: c1ccc(CN2C[C@@H](P(c3ccccc3)c3ccccc3)[C@H](P(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 369.9 %

Procedure:
Preparation of polyester-supported DUGPHOS ligand. DCC (40 mg, 0.194 mmol) was added to a mixture of the above OH-terminating polyester (Mw=4200, 0.390 g, ~0.186 mmol OH), (3R, 4R)-N-(4-carboxybutanoyl)-3,4-bis(diphenylphosphanyl)pyrrolidine (120 mg, 0.223 mmol), and DMAP (5 mg, 0.041 mmol) in dichloromethane (20 mL). The reaction mixture was stirred for 12 h at ambient temperature and the urea precipitate was removed by filtration. Methanol was then slowly added to the resulting filtrate under stirring, and the precipitated polyester-supported DEGPHOS ligand was then isolated by filtration, and washed with cold methanol and dried in vacuo to give 380 mg polymeric DEGPHOS ligand (96% theoretical yield): ##STR16## The analytical data for this new material are as follows:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:6]([NH:7][C:8](=[O:44])/[C:9](=[N:23]\[O:24][C:25]2([C:28]([O:30][CH:31]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:29])[CH2:27][CH2:26]2)/[C:10]2[N:11]=[C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[S:13][CH:14]=2)[C:5](=[O:45])[NH:4]1.O=[CH:47][CH2:48][NH:49][C:50](=[O:66])[O:51][CH2:52][CH:53]1[C:65]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:59]2[C:54]1=[CH:55][CH:56]=[CH:57][CH:58]=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:55]1[C:54]2[CH:53]([CH2:52][O:51][C:50]([NH:49][CH2:48][CH2:47][NH:1][CH2:2][C@@H:3]3[C@H:6]([NH:7][C:8](=[O:44])/[C:9](=[N:23]\[O:24][C:25]4([C:28]([O:30][CH:31]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[O:29])[CH2:27][CH2:26]4)/[C:10]4[N:11]=[C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[S:13][CH:14]=4)[C:5](=[O:45])[NH:4]3)=[O:66])[C:65]3[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=3)[C:59]=2[CH:58]=[CH:57][CH:56]=1
Reactant: O=CCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2CN)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2CNCCNC(=O)OCC2c3ccccc3-c3ccccc32)cs1
Reaction time: 12 h
Yield: 57.5 %

Procedure:
To a solution of benzhydryl 1-(((Z)-(2-(((2R,3S)-2-(aminomethyl)-4-oxoazetidin-3-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (199 mg, 0.29 mmol) in DCE (2.9 mL) was added (9H-fluoren-9-yl)methyl (2-oxoethyl)carbamate (84 mg, 0.30 mmol) and sodium triacetoxyborohydride (181 mg, 0.86 mmol). After 12 h, the reaction mixture was quenched with saturated NaHCO3 (aq), diluted with EtOAc, and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 0-100%) to afford the title compound (150 mg, 58%). LCMS: Rt=1.10 min, m/z=900.0 (M+1), Method 2m_acidic. 1H NMR (400 MHz, DMSO-d6): 9.16 (d, J=9.0 Hz, 1H), 8.35 (s, 1H), 7.87 (d, J=7.4 Hz, 2H), 7.66 (d, J=7.4 Hz, 2H), 7.45-7.18 (m, 16H), 6.83 (s, 1H), 5.24-5.17 (m, 1H), 4.28 (d, J=6.7 Hz, 2H), 4.19 (d, J=6.3 Hz, 1H), 3.79-3.67 (m, 1H), 3.03-2.95 (m, 2H), 2.73-2.63 (m, 1H), 1.54-1.37 (m, 13H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][NH:16][C:17]2([C:21]3[S:22][CH:23]=[CH:24][N:25]=3)[CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1.[CH2:28]([Sn:32](Cl)([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH3:31]>O1CCCC1>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH:16][C:17]2([C:21]3[S:22][C:23]([Sn:32]([CH2:33][CH2:34][CH2:35][CH3:36])([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:24][N:25]=3)[CH2:20][CH2:19][CH2:18]2)=[CH:26][CH:27]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COc1ccc(CNC2(c3nccs3)CCC2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(C2(NCc3ccc(OC)cc3)CCC2)s1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A freshly prepared solution of lithium diisopropylamide (12.83 mmol) in anhydrous tetrahydrofuran (15 mL) at −10° C. was added dropwise via cannula over 20 minutes to a −78° C. solution of N-(4-methoxybenzyl)-1-(thiazol-2-yl)cyclobutanamine (1.6 g, 5.83 mmol) (Example 112B) in anhydrous tetrahydrofuran (45 mL). The temperature was maintained below −70° C. during the addition, and after the addition, the reaction was stirred 45 minutes at −78° C. Tributyltin chloride (1.89 mL, 7.00 mmol) was then added dropwise. The cold bath was removed, and the reaction was allowed to warm to ambient temperature over 20 minutes. The reaction was quenched with saturated ammonium chloride, and the product was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 10% to 20% ethyl acetate in hexanes, to provide the title compound. MS ESI(+) m/z 565.1 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[N:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1>CN(C)C=O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[S:5]1[CH:6]=[CH:7][CH:8]=[C:4]1[C:1](=[O:3])[CH:2]=[CH:15][C:12]1[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=1
Reactant: CC(=O)c1cccs1
Reactant: O=Cc1ccncc1
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(C=Cc1ccncc1)c1cccs1
Reaction time: 0.5 h
Yield: 1.1 %

Procedure:
Dissolve anhydrous cobalt(II) acetate (700 mg, 4 mmol) in dimethylformamide (100 mL) . Add 2,2'-dipyridyl (600 mg, 4 mmol) and stir for 30 minutes. Add 2-acetylthiophene (6.3 g, 50 mmol) and 4-pyridinecarboxaldehyde (5 g, 50 mmol) and heat at 80° C. for 18 hours. Evaporate the solvent and purify the resiude by silica gel chromatography (1:1 toluene/ethyl acetate). Recrystallize (ethyl ether/hexane) to yield 120 mg of the title compound; mp 150.5°-152° C.
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[F:13])([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.Br[CH:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23](Cl)=[O:24]>C(#N)C>[Br:12][C:10]1[CH:9]=[CH:8][C:7]([F:13])=[C:6]([C:2]([NH:1][C:23](=[O:24])[CH:22]=[CH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([CH3:5])[CH2:3][OH:4])[CH:11]=1
Reactant: O=C(Cl)C(Br)Cc1ccccc1
Reactant: CC(N)(CO)c1cc(Br)ccc1F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(CO)(NC(=O)C=Cc1ccccc1)c1cc(Br)ccc1F
Temperature: 25 °C
Yield: 10.3 %

Procedure:
A solution of (RS)-2-amino-2-(5-bromo-2-fluoro-phenyl)-propan-1-ol (1.5 g, 6 mmol) and triethylamine (1.01 ml, 7.3 mmol) in acetonitrile (31 ml) was cooled to 0° C. A solution of (RS)-2-bromo-3-phenyl-propionyl chloride (CAS 42762-86-7) (1.637 g, 6.6 mmol) in acetonitrile was added dropwise. After complete addition the reaction mixture was left to warm to room temperature. After 1 hour the reaction mixture was evaporated under reduced pressure and directly purified by chromatography on silica gel using a gradient of heptane and ethyl acetate=100/0 to 50/50 as the eluent. Besides the N-[(RS)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-3-phenyl-acrylamide (0.233 g, 10% of theory), the (2RS)-bromo-N-[(RS)-1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-3-phenyl-propionamide (mixture of diastereoisomers 3:2) was obtained as a white solid (1.985 g, 71.5% of theory). Mass (calculated) C18H18Br2FNO2 [459.156]; (found) [M+H]+=457, [M+2-H]+=459, [M+4-H]+=461.