Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[O:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=2)[CH2:19][N:20]2[C:21](=[O:30])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]2=[O:29])=[O:15])[O:10][C:11]=1[CH3:12]
Reactant: Cc1oc(C(=O)O)cc1-c1c(Cl)cnn1C
Reactant: N[C@@H](Cc1cccc(C(F)(F)F)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(C(=O)N[C@@H](Cc2cccc(C(F)(F)F)c2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (230 mg, 0.90 mmol) [prepared according to the procedure of Example 184], 2-{(2S)-2-amino-3-[3-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (348 mg, 0.90 mmol) [prepared according to the procedure of Preparation 6, except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-(trifluoromethyl)-L-phenylalanine (4.98 g, 15.0 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (502 mg, 1.07 mmol) in chloroform (8.5 mL). DIEA (790 μL, 4.52 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (247 mg, 0.43 mmol, 48%): LC-MS (ES) m/z=571 (M+H)+.
Reaction SMILES: [CH:1]([OH:6])=[CH:2][C:3](=[CH2:5])[CH3:4].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.C(N(CC)CC)C>C(Cl)Cl.CS(O)(=O)=O>[CH3:5][C:3](=[CH2:4])[CH2:2][CH2:1][O:6][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1
Reactant: C1=COCCC1
Reactant: C=C(C)C=CO
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)CCOC1CCCCO1
Yield: 100.5 %

Procedure:
To isoprenyl alcohol (80.0 g, 929 mmol) in CH2Cl2 (500 ml) at 0° C. was added one drop of methanesulfonic acid. To this solution was added 2,3-dihydropyran (100 ml, 1.10 mol) dropwise over 3 h. After the addition was complete triethylamine (5 ml) was added and the resulting mixture was filtered through a thin pad of SiO2 and concentrated to afford 159 g (100%) of 2-(3-methyl-3-butenyloxy)tetrahydropyran as a colorless liquid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[CH3:27][O:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:32]2[CH:33]=[N:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2cncc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c2)cn1

Procedure:
By carrying out the operation analogously to example 1, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to preparation IX and 6-methoxy-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=72%).
Reaction SMILES: N[C:2]1[C:3]([F:18])=[C:4]([C:9]2[C:10]([C:16]#[N:17])=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])[C:5]([F:8])=[CH:6][CH:7]=1.N([O-])=O.[Na+].[BrH:23]>O1CCOCC1.O.[Cu]Br>[Br:23][C:2]1[C:3]([F:18])=[C:4]([C:9]2[C:10]([C:16]#[N:17])=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: N#Cc1cccc(F)c1-c1c(F)ccc(N)c1F
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cccc(F)c1-c1c(F)ccc(Br)c1F
Temperature: -5 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
To a solution of 3′-amino-6,2′,6′-trifluorobiphenyl-2-carbonitrile (0.5136 g, 2.07 mmol) in hot 1,4dioxane (1 ml) was added 48% aqueous hydrobromic acid (7 ml) and the mixture was cooled to −5° C. before adding dropwise a solution of sodium nitrite (0.1657 g, 2.40 mmol) in water (0.5 ml) over 5 min so that the temperature did not rise above −4° C. The resulting mixture was stirred at −5 to 2° C. for 2 h before adding a cooled (5° C.) solution of copper(I) bromide (0.4452 g, 3.10 mmol) in 48% hydrobromic acid (3 ml). The mixture was stirred for 5 min then heated to 46° C. over 1 h. The mixture was cooled to ambient temperature, diluted with water (50 ml) and extracted with diethyl ether (2×30 ml). The combined organic extracts were washed with 10% aqueous ammonia (25 ml), then saturated aqueous NaCl (20 ml), dried (MgSO4), and evaporated in vacuo. Purification by chromatography (silica gel, 20% EtOAc/isohexane) gave 0.3790 g (59%) of 3′-bromo-6,2′,6′-trifluorobiphenyl-2-carbonitrile as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:26])[C@@H:5]([N:10]1[CH2:14][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[CH2:23])[C:17]=2[F:24])=[CH:12][C:11]1=[O:25])[CH2:6][CH:7]([CH3:9])[CH3:8])C.O.[OH-].[Li+]>O1CCCC1>[F:24][C:17]1[C:18]([CH:22]=[CH2:23])=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][C:13]1[CH2:14][N:10]([C@@H:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[C:4]([OH:26])=[O:3])[C:11](=[O:25])[CH:12]=1
Reactant: C=Cc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)OCC)C2)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Temperature: 20 °C
Reaction time: 2 h
Yield: 105 %

Procedure:
To a solution containing (S)-2-[4-(2-fluoro-3-vinyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid ethyl ester (0.400 g, 0.001 mol) in tetrahydrofuran (6 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (0.5N, 3 mL, 0.002 mol). The mixture was stirred at 20° C. for 2 h, and the solvents evaporated. The residue was dissolved in water and washed with diethyl ether, and the diethyl ether layer discarded. The aqueous phase was acidified with dilute hydrochloric acid (pH <2), and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated to afford (S)-2-[4-(2-fluoro-3-vinyl-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.35 g, 95%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][NH2:25])=[CH:19][C:14]=2[C:13](=[O:26])[N:12]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:11][C:10]1=[O:32].[C:33](S(O)(=O)=O)([NH2:35])=[NH:34]>C(=O)(O)[O-].[K+]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][NH:25][C:33]([NH2:35])=[NH:34])=[CH:19][C:14]=2[C:13](=[O:26])[N:12]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:11][C:10]1=[O:32]
Reactant: CN1C(=O)CN(CCC(=O)O)C(=O)c2cc(C#CCCCN)ccc21
Reactant: N=C(N)S(=O)(=O)O
Agent: O=C([O-])O
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)CN(CCC(=O)O)C(=O)c2cc(C#CCCCNC(=N)N)ccc21
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a magnetically stirred solution of 6 mgs of 1-methyl-4-(2-carboxyethyl)-7-(5-amino-1-pentynyl)-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione trifluoracetate (0.017 mmol) in 1.0 mL 10% potassium bicarbonate was added 31.0 mgs of formamidine sulfonic acid (0.25 mmol). After 30 minutes, the reaction mixture was quenched with 0.5 mL acetic acid and concentrated in vacuo. The resulting residue was diluted with 2 mL water and purified by high pressure liquid chromatography, using a 1/2" C-18 reverse-phase column, eluting with a solvent gradient of 10:90 methanol(0.1% trifluoracetic acid)/water (0.1% trifluoracetic acid), time 0 to 10 min, to 50:50 methanol(0.1% trifluoracetic acid)/water (0.1% trifluoracetic acid), time 10 min to 40 min, flow=10 ml/min (Rt= 36.8 min, un detection 254 nm) to yield 4.5 mgs (67%) 1-methyl-4-(2-carboxyethyl)-7-(5-guanidino-1-pentynyl)-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione trifluoracetate. HRMS (FAB) molecular ion m/z=386.1823 (cald. C19H24N5O4, 386.1829). 1H NMR (D2O) 7.60 (1H, d, 4JHH, Ar--H o-CON), 7.51 (1H, dd, 4JHH =2 Hz, 3JHH =8 Hz, Ar--H p-CON), 7.20 (1H, d, 3JHH =8 Hz, Ar--H m-CON), 4.05 (1H, d, 2JHH =14 Hz, NCHHCO), 3.92 (1H, m, NCHHCH2), 3.72 (1H, d, 2JHH =14 Hz, NCHHCO), 3.40 (1H, m, NCHHCH2), 3.23-3.15 (5H, NCH3, H2NC(=NH2)NHCH2), 2.58 (2H, m, CH2CO2), 2.38 (2H, t, 3JHH=7 Hz, CHCCH2), 1.76 (2H, p, 3JHH =7 Hz, CH2CH2CH2).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])[N:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)CCC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:14][C:9]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:3]=2)[C:12]([CH3:13])=[CH:11][CH:10]=1
Reactant: Cc1ccc(C)n1-c1cccc(Cl)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1-c1cccc(-c2ccccc2)n1
Yield: 88.3 %

Procedure:
2-Chloro-6-(2,5-dimethyl-pyrrol-1-yl)-pyridine (0.097 g, 0.47 mmol) prepared as described in Example 8a was reacted for 24 h with tributyl-phenyl-stannane (0.185 mL, 0.564 mmol) under nitrogen in toluene at 75° C. in the presence of 2 mole % tetrakis(triphenylphosphine) palladium(0). The volatiles were subsequently removed under reduced pressure to yield the crude product, which was purified by flash chromatography on silica gel to give the title compound (0.103 g, 88%).
Reaction SMILES: [OH-].[Na+].Cl.[NH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8]1=[O:16].[C:17](OC(=O)C)(=[O:19])[CH3:18].Cl>O.O1CCOCC1>[O:16]=[C:8]1[N:7]([CH2:6][CH2:5][NH:4][C:17](=[O:19])[CH3:18])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9]1
Reactant: NCCn1c(=O)[nH]c2ccccc21
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)NCCn1c(=O)[nH]c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled solution of NaOH (0.41 g, 10 mmoles) in water (5 ml) were simultaneously added 1-(2-aminoethyl)-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (0.7 g, 3.3 mmoles) and a solution of acetic anhydride (0.37 ml, 3.9 mmoles) in dioxane (10 ml). The reaction mixture was stirred for 2 hours at room temperature and then taken to dryness. The residue was dissolved in water, adjusted to pH 4 with 10% aqueous HCl, and extracted with CHCl3. The organic layer was taken to dryness and from the crude residue 0.35 g of the title compound was obtained after crystallization from diethyl ether. M.p. 153° C.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:8]2[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[CH:10]([C:18]3[C:27]([OH:28])=[CH:26][C:21]4[O:22][CH2:23][CH2:24][O:25][C:20]=4[CH:19]=3)[C:9]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:36]1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(C3C=C(C)C(OC)=CC=3O)C2=O)C=CC=CC=1>>[C:30]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[C:12]([F:17])[CH:13]=[CH:14][CH:15]=3)[C:10]3([C:18]4[C:27](=[CH:26][C:21]5[O:22][CH2:23][CH2:24][O:25][C:20]=5[CH:19]=4)[O:28][CH2:36]3)[C:9]2=[O:29])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1cc(O)c(C2C(=O)N(C(c3ccccc3)c3ccccc3)c3ccccc32)cc1C
Reactant: O=C1C(c2cc3c(cc2O)OCCO3)c2c(F)cccc2N1C(c1ccccc1)c1ccccc1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(F)c2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 2 and making non-critical variations using 1-(diphenylmethyl)-4-fluoro-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one to replace 1-(diphenylmethyl)-3-(2-hydroxy-4-methoxy-5-methylphenyl)-1,3-dihydro-2H-indol-2-one, 1′-(diphenylmethyl)-4′-fluoro-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (83%) as a colorless solid: mp 196-198° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.46-7.26 (m, 10H), 7.19 (ddd, J=8.2, 8.2, 6.1 Hz, 1H), 6.89 (s, 1H), 6.83 (dd, J=8.9, 8.9 Hz, 1H), 6.50 (s, 1H), 6.46 (d, J=8.0 Hz, 1H), 6.09 (s, 1H), 4.83 (q, J=9.6 Hz, 2H), 4.14 (dd, J=5.3, 3.2 Hz, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.3, 157.9 (d, 1JC-F=247 Hz), 144.3, 143.8 (d, 3JC-F=8.4 Hz), 137.2 (d, 3JC-F=13.6 Hz), 130.5 (d, 3JC-F=8.6 Hz), 128.1, 127.8 (d, 3JC-F=9.0 Hz), 119.2, 117.3 (d, 2JC-F=19.0 Hz), 110.4, 110.0 (d, 2JC-F=19.7 Hz), 107.8 (d, 4JC-F=2.8 Hz), 98.7, 77.5, 64.1, 63.5, 58.6, 55.8 (d, 4JC-F=2.8 Hz); MS (ES+) m/z 480.0 (M+1),
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[S:11](Cl)(=[O:13])=[O:12].[F:15][C:16]([F:30])([F:29])[CH:17]([NH2:28])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[S:11]([NH:28][CH:17]([CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[C:16]([F:15])([F:29])[F:30])(=[O:13])=[O:12]
Reactant: COc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cc(Cl)cc(Cl)c1S(=O)(=O)NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.4 %

Procedure:
To a solution of 50 mg (0.18 mmol) of 2,4-dichloro-6-methoxybenzenesulfonyl chloride in 4 mL of pyridine was added 42 mg (0.19 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethylamine. The mixture stirred for 6 hours at room temperature and was then diluted with 10 mL of ethyl acetate and washed with four 30 mL portions of 10% acetic acid, two 30 mL portions of saturated aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, decanted and concentrated in vacuo. The crude material was purified by filtering through a pad of silica eluting with ether. The material from the pad was dissolved in ether, and precipitated by slow evaporation which afforded 50 mg (57%) of the title compound as a bright yellow powder. MS: m/z 467 (M+1).
Reaction SMILES: C(O[C:6]([N:8]([CH2:17][C:18]#[C:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[O:27][CH2:28][C@@H:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:30]=2)[CH:21]=1)[O:9]C(OC(C)(C)C)=O)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+].C[Si]([N:53]=C=O)(C)C>ClCCl>[C:31]1([C@@H:29]2[CH2:28][O:27][C:26]([C:22]3[CH:21]=[C:20]([C:19]#[C:18][CH2:17][N:8]([OH:9])[C:6]([NH2:53])=[O:7])[CH:25]=[CH:24][CH:23]=3)=[N:30]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)ON(CC#Cc1cccc(C2=N[C@H](c3ccccc3)CO2)c1)C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)N=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)N(O)CC#Cc1cccc(C2=N[C@H](c3ccccc3)CO2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a solution of N,O-di(tert-butoxycarbonyl)-[3-[3-(4,5-dihydro-4(R)-phenyl-oxazol-2-yl)phenyl]-2-propyn-1-yl]hydroxylamine (1.99 g, 4 mmol) in dichloromethane (30 ml) cooled to 0° C. was slowly added trifluoroacetic acid (10 ml). The reaction mixture was allowed to warm to room temperature, stirred an additional 30 min., and then poured into a saturated aqueous NaHCO3 solution (100 ml). The mixture was extracted with dichloromethane (3×30 ml) and the organic phase washed with brine (20 ml), dried (MgSO4) and evaporated. The resulting residue was dissolved in tetrahydrofuran (20 ml) and trimethylsilyl isocyanate (0.84 ml, 6.3 mmol) added. After stirring for 10 min. precipitation of product occurred. Methanol (1 ml) was added and solvent was removed by evaporation. The resulting solids were recrystallized from ethyl acetate to afford the title compound (0.98 g, 72 %) as white solids.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:16])([C:13]([NH2:15])=[O:14])[C:10]([NH2:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([O:16][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[Cl:17])([C:10]([NH2:12])=[O:11])[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C(O)(C(N)=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: NC(=O)C(OC(=O)c1ccccc1Cl)(C(N)=O)c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 33.1 %

Procedure:
26.3 g of 3,4-dichlorophenylhydroxymalonic acid diamide were dissolved in 50 ml of pyridine, and 17.1 g of o-chlorobenzoyl chloride were added at below 30° C. After one hour, the mixture was stirred into cold 1NCl, the precipitate was taken up in ethyl acetate, the mixture was extracted by shaking and the extract was worked up. 26.5 g of crude product remained, and were recrystallised from 400 ml of ethanol. 13 g of pure 3,4-dichlorophenyl-(2-chlorobenzoyloxy)-malonic acid diamide of melting point 220° C. were obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].Cl.N1C=CC=CC=1.[F:23][C:24]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:25]=1[NH2:26]>C(OCCO)C>[Cl:31][C:29]1[CH:28]=[CH:27][C:25]([NH:26][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])=[C:24]([F:23])[CH:30]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cccc2c(Nc3ccc(Cl)cc3F)c(C#N)cnc12
Temperature: 100 °C
Yield: 87.7 %

Procedure:
Using an analogous procedure to that described in Example 274. A reaction mixture of 328.0 mg (1.5 mmol) of 4-chloro-8-methoxy -3-quinolinecarbonitrile, 173.3 mg (1.5 mmol) of pyridine hydrochloride and 240.0 mg (1.7 mmol) of 2-fluoro-4-chloroaniline in 15 mL of 2-ethoxyethanol was heated at 100° C. for 2 hr. After the work up, 431.3 mg (87.9%) of the product was obtained as an off white solid, m.p. 127° C. (dec.), mass spectrum (electrospray, m/e): M+H 327.8, 329.9.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][OH:13].[N+:14]([O-])([OH:16])=[O:15].CCO>C(O)(=O)C>[OH:1][C:2]1[C:9]([N+:14]([O-:16])=[O:15])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][OH:13]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccc(O)c(OCCO)c1
Solvent: CC(=O)O
Solvent: CCO
Product: O=Cc1cc(OCCO)c(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 88.7 %

Procedure:
To the solution of 4-hydroxy-3-(2-hydroxyethoxy)benzaldehyde in acetic acid (5 mL) was added 65% nitric acid (34.6 mg, 0.55 mmol) at 0° C., and the mixture was stirred at 0° C. 4 hours. The reaction mixture was poured into ice water followed by a standard aqueous/EtOH workup. Isolated 110 mg, yield 88.7% of Intermediate 10.
Reaction SMILES: Cl[CH2:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.ClCCCN1CCC(C2C=CC=CC=2)CC1.C1(C2CCN([CH2:43][CH2:44][N:45]3[C:49](=[O:50])[C:48]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=4)[NH:47][C:46]3=[O:63])CC2)C=CC=CC=1.C1(C2(C3C=CC=CN=3)NC(=O)NC2=O)C=CC=CC=1>>[C:9]1([CH:6]2[CH2:7][CH2:8][N:3]([CH2:2][CH2:43][CH2:44][N:45]3[C:49](=[O:50])[C:48]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=4)[NH:47][C:46]3=[O:63])[CH2:4][CH2:5]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1NC(c2ccccc2)(c2ccccn2)C(=O)N1CCN1CCC(c2ccccc2)CC1
Reactant: ClCN1CCC(c2ccccc2)CC1
Agent: ClCCCN1CCC(c2ccccc2)CC1
Agent: O=C1NC(=O)C(c2ccccc2)(c2ccccn2)N1
Product: O=C1NC(c2ccccc2)(c2ccccn2)C(=O)N1CCCN1CCC(c2ccccc2)CC1

Procedure:
Analysis -- Calculated for C32H34N4O6 : C, 67.36; H, 6.00; N, 9.82. Found: C, 67.60; H, 6.16; N, 10.01. Substitution of 1-(2-chloroethyl)-4-phenyl-piperidine or 1-(chloromethyl)-4-phenyl-piperidine for 1-(3-chloropropyl)-4-phenyl-piperidine in the above example respectively yields: 3-[2-(4-phenyl-1-piperidyl)ethyl]-5-phenyl-5-(2-pyridyl)-hydantoin and 3-[(4-phenyl)-1-piperidyl)methyl]-5-phenyl-5-(2-pyridyl)-hydantoin.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:22]2[CH2:21][CH2:20][N:19]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:18](=[O:29])[C:17]=2[C:16]([CH3:30])=[C:15]1[C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1.I[CH2:39][CH2:40][CH2:41][C:42]([F:45])([F:44])[F:43].O>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[C:22]2[CH2:21][CH2:20][N:19]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)[C:18](=[O:29])[C:17]=2[C:16]([CH3:30])=[C:15]1[C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:39][CH2:40][CH2:41][C:42]([F:45])([F:44])[F:43])=[CH:35][CH:36]=1
Reactant: FC(F)(F)CCCI
Reactant: Cc1c2c(n(-c3ccccc3Cl)c1-c1ccc(O)cc1)CCN(N1CCCCC1)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c2c(n(-c3ccccc3Cl)c1-c1ccc(OCCCC(F)(F)F)cc1)CCN(N1CCCCC1)C2=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
Potassium carbonate (0.19 g, 1.38 mmol) was added to a solution of 1-(2-chlorophenyl)-2-(4-hydroxyphenyl)-3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridine-4-one, from Ex. 1, Step 8 (0.50 g, 1.15 mmol) in DMF (30 ml) followed by 1-iodo-4,4,4-trifluorobutane (328 mg, 1.38 mmol). The reaction mixture was heated at 80° C. overnight. TLC showed very little conversion to starting material; 656 mg (2 eqv.) 1-iodo-4,4,4-trifluorobutane and 380 mg (2 eqv.) K2CO3 were added and heating continued for one hour. After cooling to rt, water was added and the product extracted with EtOAc (×3). The combined organic extracts were washed with brine (×2), dried (Na2SO4), filtered and concentrated. Flash chromatography (heptane:EtOAc gradient) afforded 250 mg (40%) of the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]1=[S:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cccn(Cc2ccccc2)c1=O
Solvent: Cc1ccccc1
Product: COc1cccn(Cc2ccccc2)c1=S
Temperature: 25 °C
Yield: 134.8 %

Procedure:
A suspension of 141b (0.060 g, 0.28 mmol) and Lawesson's reagent (0.067 g, 0.17 mmol) in toluene (10 mL) was heated to reflux overnight. Reaction mixture was then cooled to room temperature. Toluene was evaporated in vacuo and resulting crude solid was directly loaded on prep-TLC. Elution with CH2Cl2:Acetone:MeOH (5:1:0.2) gave 143b 53 mg (82%) of yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:15]1[CH:20]=[C:19]2[CH:21]=[CH:22][C:23]3[C:28](=O)[O:27][C:25](=[O:26])[C:24]=3[C:18]2=[CH:17][CH:16]=1>>[O:26]=[C:25]1[C:24]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:20][C:19]=3[CH:21]=[CH:22][C:23]=2[C:28](=[O:27])[N:1]1[CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Reactant: O=C1OC(=O)c2c1ccc1ccccc21
Product: CCOC(=O)C(CN1C(=O)c2ccc3ccccc3c2C1=O)C1(C)OCCO1

Procedure:
Ethyl 3-(1,3-dioxo-1,3-dihydro-benzo[e]isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.55 g, 73%) in the same manner as described in the above example 5 (20) from ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.40 g, 1.97 mmol) and 1,2-naphthalic anhydride (0.51 g, 2.56 mmol), and the obtained product was identified with the following NMR data.