Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][C@H:14]1[CH2:28][O:27][C:17]2[CH:18]=[CH:19][C:20]3[C:21](=[O:26])[CH:22]=[CH:23][O:24][C:25]=3[C:16]=2[O:15]1.O>N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][CH:14]2[CH2:28][O:27][C:17]3[CH:18]=[CH:19][C:20]4[C:21](=[O:26])[CH:22]=[CH:23][O:24][C:25]=4[C:16]=3[O:15]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1ccoc2c3c(ccc12)OC[C@H](CO)O3
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4c(=O)ccoc4c3O2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
p-Toluenesulfonyl chloride (0.60 g, 3.15 mmole) was added to solution of (2S)-2-(hydroxymethyl)-2,3-dihydro-7H-[1,4]dioxino[2,3-h]chromen-7-one (0.41 g, 1.75 mmole) in 50 mL of pyridine. The solution was stirred at room temperature overnight under nitrogen. Water was added to quench the excess tosyl chloride and the solvent was removed in vacuum and replaced with methylene chloride. The solution was washed with 2N aqueous HCl, with saturated aqueous sodium bicarbonate, and with saturated brine, and dried over magnesium sulfate. Filtration, evaporation in vacuum and column chromatography on silica gel with 3% methanol/methylene chloride as eluant gave 0.36 g (54%) of the (R)-enantiomer of the title compound as a yellow solid, m.p. 190-191° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24](N(OC)C)=[O:25])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH:9]=2)=[CH:6][N:7]=1>C1COCC1>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=2)[C:14]([NH:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])=[N:4][C:3]=1[CH:24]=[O:25]
Reactant: CON(C)C(=O)c1nc(-c2cccc(C(=O)NCc3ccccc3)c2)cnc1N
Solvent: C1CCOC1
Product: Nc1ncc(-c2cccc(C(=O)NCc3ccccc3)c2)nc1C=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
A solution of 3-amino-6-{3-[(benzylamino)carbonyl]phenyl}-N-methoxy-N-methylpyrazine-2-carboxamide (2.5 g, 6.4 mmol) in THF (20 mL) was cooled to 0° C. Under N2 lithium aluminum hydride (0.364g, 9.58 mmol) was added and the reaction was stirred at 0° C. for 1 h. The mixture was then quenched with H2O at 0° C. Removal of solids via filtration, concentration of the filtrate and dissolution of the solid residue in H2O followed by washing 3× with dichloromethane gave the product (1.90 g, 89% yield) with sufficient purity to be used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:12](Cl)(=[O:14])=[O:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([S:12]([NH:19][CH:16]2[CH2:18][CH2:17]2)(=[O:14])=[O:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: NC1CC1
Reactant: O=S(=O)(Cl)c1cc(Br)cc(C(F)(F)F)c1
Solvent: ClCCl
Product: O=S(=O)(NC1CC1)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Bromo-5-(trifluoromethyl)benzenesulfonyl chloride (0.2 g, 0.62 mmol) is added to a solution of cyclopropylamine (0.09 μl, 1.3 mmol) in DCM (5 ml), and the resulting solution is stirred at room temperature overnight. The reaction mixture is diluted with DCM (2×10 ml), washed with 0.1M HCl (5 ml), sat. aq. NaHCO3 (5 ml), dried (MgSO4) and concentrated in vacuo to yield the title compound. 1H NMR (400 MHz, d6-DMSO) δ 8.37 (1H, s), 8.23 (1H, s), 8.06 (1H, s), 2.21-2.17 (1H, m), 0.55-0.50 (2H, m) 0.40-0.36 (2H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@H:10]([NH:12][C:13]2[C:22]3[C:17](=[C:18]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO>[NH2:1][C:4]1[CH:5]=[C:6]([C@H:10]([NH:12][C:13]2[C:22]3[C:17](=[C:18]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1
Reactant: C[C@@H](Nc1ncnc2c(C(N)=O)cccc12)c1cccc([N+](=O)[O-])c1
Solvent: CO
Product: C[C@@H](Nc1ncnc2c(C(N)=O)cccc12)c1cccc(N)c1
Reaction time: 3 h

Procedure:
A suspension of 4-{[(1R)-1-(3-nitrophenyl)ethyl]amino}quinazoline-8-carboxamide (1.50 g, 4.45 mmol) in methanol (125 mL) was shaken for 3 h in a
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8]Br)[C:3]([O:5][CH3:6])=[O:4].[CH3:10][C:11]1([CH3:18])[CH2:16][CH:15]([NH2:17])[CH2:14][CH2:13][O:12]1>>[CH3:10][C:11]1([CH3:18])[CH2:16][CH:15]([N:17]2[CH2:8][CH2:7][CH:2]2[C:3]([O:5][CH3:6])=[O:4])[CH2:14][CH2:13][O:12]1
Reactant: CC1(C)CC(N)CCO1
Reactant: COC(=O)C(Br)CCBr
Product: COC(=O)C1CCN1C1CCOC(C)(C)C1
Yield: 33 %

Procedure:
The reaction of methyl 2,4-dibromobutanoate 17 with 2,2-dimethyltetrahydro-2H-pyran-4-amine 18H yielded methyl 1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)azetidine-2-carboxylate as a light brown solid (33%). MS ISP (m/e): 228.3 (100) [(M+H)]+.
Reaction SMILES: I[C:2]1[C:7]([NH2:8])=[C:6]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[CH:4][N:3]=1.[CH2:16]([OH:21])[CH:17]=[CH:18][C:19]#[CH:20]>C(#N)C.C(N(CC)CC)C.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.[Cu]I>[NH2:8][C:7]1[C:2]([C:20]#[C:19]/[CH:18]=[CH:17]/[CH2:16][OH:21])=[N:3][CH:4]=[N:5][C:6]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1c(I)ncnc1Oc1ccccc1
Reactant: C#CC=CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1c(C#C/C=C/CO)ncnc1Oc1ccccc1
Yield: 59.9 %

Procedure:
4-Iodo-6-phenoxypyrimidin-5-amine (3.5 g) was dissolved in a mixed solvent of acetonitrile (185 mL)/triethylamine (136 mL), and 2-penten-4-yn-1-ol (1.1 g), trans-dichlorobis(triphenylphosphine)palladium(II) (392 mg) and copper(I) iodide (127 mg) were sequentially added. The title compound (1.79 g) was obtained as a powder by the reaction in the same manner as in Example 9 (iv).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:11][C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[C@@H:5]([C:12](=[O:14])[CH3:13])[C:4]([CH3:15])=[CH:3]1.[C:16](OC(=O)C)(=[O:18])[CH3:17].C([O-])(=O)C.[Na+]>[OH-].[Na+]>[C:16]([O:1][C@H:2]1[CH:3]=[C:4]([CH3:15])[C@H:5]([C:12](=[O:14])[CH3:13])[C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:11]1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[C@H]1C(C)=C[C@H](O)CC12CCCC2
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)O[C@H]1C=C(C)[C@H](C(C)=O)C2(CCCC2)C1
Temperature: 80 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
A mixture of 8:92 cis/trans-1-(9-hydroxy-7-methylspiro[4.5]dec-7-en-6-yl)ethanone (4.2 g, 20.2 mmol) was treated with acetic anhydride (4 ml, 42.3 mmol) and sodium acetate (1.65 g, 20.2 mmol). The resulting mixture was stirred at 80° C. for 1 h, poured into cold 2N aqueous NaOH (50 ml), and extracted twice with MTBE (40 ml). The combined organic phases were washed with water (40 ml), with a saturated aqueous solution of NaCl (40 ml), dried (MgSO4), and concentrated. FC (300 g SiO2, hexane/MTBE 8:1) of the crude product (4.82 g) gave 8:92 cis/trans-10-acetyl-9-methylspiro[4.5]dec-8-en-7-yl acetate (4.1 g, 82%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([NH:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([F:13])=[CH:8][C:7]=1[F:14])=[O:4].[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([NH:28][C:29]([NH:1][C@@H:2]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]([NH:5][C:6]2[C:7]([F:14])=[CH:8][C:9]([F:13])=[CH:10][C:11]=2[F:12])=[O:4])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C=Nc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1c(F)cc(F)cc1F
Product: O=C(Nc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)Nc1c(F)cc(F)cc1F

Procedure:
Following the procedure of Example 58 only using the product of Example 50 and phenylisocyanate, the title compound was obtained, mp 225°-233° C.
Reaction SMILES: [N+](=[CH:3]P(=O)(OC)OC)=[N-].CC(C)([O-])C.[K+].[C:16]([O:20][C:21]([NH:23][C@@H:24]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:25]=O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[C:28]1([CH2:27][C@H:24]([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:19])([CH3:18])[CH3:17])[C:25]#[CH:3])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)Cc1ccccc1
Reactant: COP(=O)(C=[N+]=[N-])OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C#C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -35 °C
Reaction time: 0.25 h
Yield: 36.7 %

Procedure:
To a solution of dimethyl diazomethylphosphonate (0.60 g, 4.0 mmol) (prepared as described by Brown, D. et al., J. Org. Chem. 1996, 61(7), 2540-1 which is hereby incorporated by reference in its entirety and for all purposes as if specifically set forth herein) in 20 mL of THF at −78° C. was added potassium tert-butoxide (4.0 mL, 4.0 mmol). The mixture was stirred for 15 minutes and (S)-(−)-2-(tert-butoxycarbonylamino)-3-phenylpropanal (0.50 g, 2.0 mmol) (commercially available from 3B Scientific Corporation Product List (Order Number 3B3-015684)), was added in 2 mL of THF. The mixture was stirred for 10 minutes and then warmed to −35° C. and stirred for 1 hour. The reaction was then quenched with 10 mL of aqueous NH4Cl and stirred for 15 minutes. The biphasic mixture was diluted with 10 mL of water and partitioned in a separatory funnel. The aqueous portion was then extracted three times with 10 mL of EtOAc. The combined organic layers were washed with 25 mL of brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (2.5% to 20% EtOAc/hexanes) afforded (S)-tert-butyl 1-phenylbut-3-yn-2-ylcarbamate (0.18 g, 37% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.40-7.23 (m, 5H), 4.81-4.75 (m, 1H), 4.40-4.29 (m, 2H), 3.16 (dd, J=5.3 Hz, 14.2 Hz, 1H), 3.03 (dd, J=9.2 Hz, 5.1 Hz, 1H), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[CH:5][C:6]2[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[N:11][CH2:10][C:9](=[O:21])[NH:8][C:7]=2[CH:22]=1.[CH2:31](I)[CH2:32][CH3:33]>>[CH3:1][O:2][C:3]1[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[CH:5][C:6]2[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])=[N:11][CH2:10][C:9](=[O:21])[N:8]([CH2:31][CH2:32][CH3:33])[C:7]=2[CH:22]=1
Reactant: COc1ccccc1-c1cc2c(cc1OC)NC(=O)CN=C2c1cccc(C#N)c1
Reactant: CCCI
Product: CCCN1C(=O)CN=C(c2cccc(C#N)c2)c2cc(-c3ccccc3OC)c(OC)cc21
Yield: 89 %

Procedure:
Prepared from 3-[8-methoxy-7-(2-methoxy-phenyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl]-benzonitrile Example 10 using the same method described for Example 35 using propyl iodide instead of hexyl bromine. The title compound (99 mg) was obtained as a white solid, yield=89%.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:9])[CH2:6][CH2:7][CH3:8].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:5](=[O:9])[CH2:6][CH2:7][CH3:8])=[CH:14][CH:13]=1
Reactant: CCCC(=O)Cl
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.2 %

Procedure:
Aluminum chloride (139 g, 1.04 mol) was added to a solution of butyryl chloride (55.45 g, 0.520 mol, Aldrich) in dichloromethane (500 ml) stirring under a nitrogen atmosphere at 25° C. A solution of fluorobenzene (50.1 g, 0.521 mol, Aldrich) in dichloromethane was added and stirring was continued for 18 h. The reaction solution was poured over ice and extracted with dichloromethane (3×400 ml) . The combined dichloromethane extractions were washed with deionized water (2×250 ml), 1.0N hydrochloric acid (500 ml), saturated sodium bicarbonate solution (2×500 ml) and deionized water (4×250 ml),concentrated by spin evaporation in vacuo. This material was combined with material from a similar preparation (using 0.26 mol of fluorobenzene) for distillation. Distillation at reduced pressure gave 69.27 g (53%) of 4'-fluorobutyrophenone as a pale yellow liquid which later partially crystallized, b.p. 108°-112° C. at 30 millitorr: NMR (DMSO-d6): d 8.03 (q, 2H, J=9.0 Hz and 5.6 Hz), 7.31 (t, 2H, J=8.9 Hz), 2.97 (t, 2H, J=7.0 Hz), 1.65-1.55 (m, 2H), 0.91 (t, 3H, J=7.3 Hz).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][O:10][N:11]=[C:12]1[C:16](=[O:17])[C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[O:13]1>CO>[OH:7][CH2:8][CH2:9][O:10][N:11]=[C:12]1[C:16](=[O:17])[C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[O:13]1
Reactant: O=C1C(=NOCCOC2CCCCO2)Oc2ccccc21
Solvent: CO
Product: O=C1C(=NOCCO)Oc2ccccc21
Yield: 81.6 %

Procedure:
2.07 g (0.01 mol) of benzofuran-2,3-dione2-{O-[2-(tetrahydropyran-2-yloxy)-ethyl]oxime} (XIV-2) are dissolved in 12 ml of methanol and stirred at room temperature with 100 mg of acidic ion exchanger resin for 16 hours. 40 ml of methanol are added to the reaction mixture which is then warned until the crystals have dissolved. The acidic ion exchanger resin is filtered off, the filtrate is concentrated and the residue is recrystallized from 10 ml of toluene. 1.69 g (81.5% of theory) of crystalline benzofuran-2,3-dione2-[O-(2-hydroxy-ethyl)-oxime] (VII-1) of melting point 110-111° C. are obtained.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@H:5]([NH2:11])[CH2:4]2.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1/[CH:17]=[CH:18]/[C:19](O)=[O:20]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@H:5]([NH:11][C:19](=[O:20])/[CH:18]=[CH:17]/[C:13]1[O:12][CH:16]=[CH:15][CH:14]=1)[CH2:4]2
Reactant: O=C(O)/C=C/c1ccco1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(/C=C/c1ccco1)N[C@@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (S)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(2-furyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent, followed by recrystallization from ethyl acetate/hexane; MS (ES+) 247 (MH+).
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][C@H:13]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:56]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:57][C:58](O)=[O:59]>CN(C=O)C>[C:1]([N:11]1[CH2:15][CH2:14][C@H:13]([N:16]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:58](=[O:59])[CH2:57][NH:56][C:61]([O:63][C:64]([CH3:66])([CH3:65])[CH3:67])=[O:62])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: O=C(OCc1ccccc1)N1CC[C@H](NC2CCCCC2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC(=O)N(C1CCCCC1)[C@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.7 %

Procedure:
To a solution of (3S)-1-Cbz-3-{cyclohexylamino}pyrrolidine (3.0 g, 10.0 mmol), prepared in Intermediate 2, in DMF (30 mL) were added DIPEA (3.50 mL, 20.0 mmol), HBTU (4.88 g, 13 mmol), BOC-Gly (1.92 g, 11 mmol). After the mixture was stirred at rt for 4 h, the solvent was removed in vacuo, and the residue was diluted with an aqueous NaHCO3. The organic material was extracted with EtOAc, and the organic extracts were washed with 1N HCl, dried over MgSO4, concentrated in vacuo. The residue was purified by column chomatography (EtOAc/Hex=1/3) to give the title compound (4.63 g, 92.0%).
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14]2)=[O:12])=[CH:6][C:5]=1[Cl:41].[OH-].[Na+]>CO>[Cl:41][C:5]1[CH:6]=[C:7]([NH:10][C:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14]2)=[O:12])[CH:8]=[CH:9][C:4]=1[C:3]([OH:42])=[O:2]
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)c(Cl)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 55 °C
Reaction time: 1 h

Procedure:
rac 4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-chloro-benzoic acid methyl ester (54 mg) was dissolved in MeOH (10 mL) with help of slight heating. To the stirred solution was added NaOH (1N, 2 mL) and the mixture was stirred for 1 hrs at 55° C. The solvent was removed and the residue was treated with 1 N HCl to make the mixture acidic. The white suspension was extracted with EtOAc (3×10 mL) and the extracts combined and dried with sodium sulfate. The solvent was removed and the residue was freeze dried to give a white powder. 40 mg.
Reaction SMILES: C([O:8][C:9]1[CH:24]=[C:23]([B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)[CH:22]=[CH:21][C:10]=1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])C1C=CC=CC=1.CO>[C].[Pd].O1CCCC1>[OH:8][C:9]1[CH:24]=[C:23]([B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)[CH:22]=[CH:21][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CC1(C)OB(c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)OC1(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)OB(c2ccc(C(=O)O)c(O)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.4 %

Procedure:
To a mixture of benzyl 2-benzyloxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.24 g), methanol (6 mL) and tetrahydrofuran (6 mL) was added 10% palladium-carbon (0.05 g) at room temperature under an atmosphere of argon. The mixture was stirred at room temperature for 3 hrs under an atmosphere of hydrogen. The catalyst was removed by filtration, and the solvent was evaporated under reduced pressure to afford the title compound (0.146 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH2:21]O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[CH2:21][N:27]2[C:23](=[O:33])[C:24]3=[CH:32][CH:31]=[CH:30][CH:29]=[C:25]3[C:26]2=[O:28])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(c1ccccc1)c1cc(F)ccc1-n1ccnc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(c1ccccc1)c1cc(F)ccc1-n1ccnc1CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in Example 17, 5-fluoro-2-[2-(hydroxymethyl)imidazol-1-yl]benzophenone is treated with phthalimide and triphenylphosphine and finally with diethyl azodicarboxylate to give 5-fluoro-2-[2-(phthalimidomethyl)imidazol-1-yl]benzophenone.
Reaction SMILES: BrC(C)C([C:5]1[CH:15]=[CH:14][C:8]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:7][CH:6]=1)=O.C(#N)C.[ClH:20]>CC(=O)CC>[ClH:20].[CH3:13][S:10]([NH:9][C:8]1[CH:7]=[CH:6][CH:5]=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: CC(Br)C(=O)c1ccc(NS(C)(=O)=O)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCC(C)=O
Product: CS(=O)(=O)Nc1ccccc1

Procedure:
A mixture of 4'-(2-bromopropionyl)methanesulfonanilide (15.3 g., 0.05 mole) and α,60 -dimethylphenethylamine (16.42 g., 0.11 mole) in 200 ml. of acetonitrile is refluxed for a period of 16 hr. The product is isolated by concentrating the reaction mixture under reduced pressure, dissolving the residue in chloroform which is then washed with water, dried over magnesium sulfate, filtered through diatomaceous earth and concentrated to provide an oily residue of the crude product free base. The residue is taken up in butanone, acidified with ethanolic hydrogen chloride and the insoluble hydrochloride salt product collected, washed with butanone and dried. Crystallization of the hydrochloride salt from methanol-isopropyl alcohol and drying at high vacuum affords analytically pure 4'-[N-α,α-DIMETHYLPHENETHYL)-ALANYL]METHANESULFONANILIDE HYDROCHLORIDE, m.p. 236.0°-237.0°C. (dec.).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[OH-].[Na+].O=[C:10]([CH3:18])[CH2:11][CH2:12][C:13](OCC)=[O:14]>O>[O:5]=[C:4]1[CH2:3][N:2]2[C:13](=[O:14])[CH2:12][CH2:11][C:10]2([CH3:18])[NH:6]1
Reactant: CCOC(=O)CCC(C)=O
Reactant: NCC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC12CCC(=O)N1CC(=O)N2
Yield: 21 %

Procedure:
To a solution of glycinamide hydrochloride (18.4 g, 0.166 mol) in water (200 ml), adjusted to pH 9.5 with 10% sodium hydroxide (about 60 ml), ethyl 4-oxopentanoate (20 g, 0.139 mol) was added. The solution was refluxed for 24 hours. After cooling the solvent was evaporated under vacuum and the residue was chromatographed over silica gel (dichloromethane-methanol 9:1) to afford 4.5 g (21%) of the title compound, m.p. 187°-189° C. NMR (CDCl3): deltaH =4.17 and 3.53 (ABq, J=16 Hz, 2H, NCH2CO), 1.5 (s, 3H, CH3). MS (E.I., 70 eV, 1.5 mA) m/z=154 (M+), 139 (M--CH3)+, 111 (M--CONH+.
Reaction SMILES: [N:1]([C@H:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14](OC)=[O:15])=[CH:11][CH:12]=2)[O:7][CH2:6][CH2:5]1)=[N+:2]=[N-:3].CC(C[AlH]CC(C)C)C>C1COCC1>[N:1]([C@H:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:14][OH:15])=[CH:11][CH:12]=2)[O:7][CH2:6][CH2:5]1)=[N+:2]=[N-:3]
Reactant: COC(=O)c1ccc2c(c1)OCC[C@H]2N=[N+]=[N-]
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: [N-]=[N+]=N[C@@H]1CCOc2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
(R)-Methyl 4-azido-3,4-dihydro-2H-chromene-7-carboxylate (21.50 mmol, 1.0 eq) in 50 mL THF was cooled to 0° C., and treated with DIBAL (63.0 mmol, 3.0 eq). After 2.5 h, the reaction mixture was quenched by adding 50% saturated K—Na tartrate (60 mL). After stirring 1 h at room temperature, the solution was extracted with DCM (4×50 mL). The organic layers were then washed with water (2×50 mL), dried over MgSO4 and concentrated. The residue was purified using SiO2 chromatography (10→80% EtOAc/Hexanes) to afford the title compound.
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][C:5]=1[C:16]([F:19])([F:18])[F:17].Cl>>[F:17][C:16]([F:19])([F:18])[C:5]1[CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=1[OH:1]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c(C(F)(F)F)c1
Temperature: 60 °C
Yield: 90 %

Procedure:
To a 1000 cm3 flask equipped with a stirrer, dropping funnel, reflux and thermometer 300 g /0.75 mole/ of a 10% by weight NaOH solution are added 81.3 g /0.3 mole/ of 2-chloro-3,5-dinitro-benzotrifluoride of a purity of 95% are added under stirring. The temperature is raised to 60° C. and the reaction mixture is stirred at 60°-65° C. for 4 hours, while the aqueous suspension forms an emulsion. The reaction mixture is then cooled to room temperature /20°-25° C./ under stirring and within 1 hour a 37% hydrochloric acid solution corresponding to 0.82 mole HCl is added in equal portions under vigorous stirring. The precipitated product is filtered, washed with water and dried to constant weight at room temperature. 2-Trifluoromethyl-4,6-dinitro-phenol is obtained /68.1 g., purity: 94%/ Idenfication was carried out by a mass spectrometer connected to a gas chromatograph.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[N:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=1)=[C:11]=[O:12]>ClCCl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11]([NH:10][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)=[O:12])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: Cc1cccc(N=C=O)c1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)Nc2ccc(Br)cc2F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.5 %

Procedure:
A 0° C. solution of 4-bromo-2-fluoroaniline (1 g, 5.26 mmol) in dichloromethane (10 mL) was treated dropwise with 1-isocyanato-3-methylbenzene (0.71 mL, 5.26 mmol), warmed to room temperature, stirred for 18 hours, and filtered. The filter cake was washed with dichloromethane and dried to provide 0.62 g of the desired product. MS (ESI(−)) m/e 321 (M−H)−.