Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[CH2:12][CH2:11][C:10]2=[O:15])=[CH:5][CH:4]=1>O1CCCC1>[OH:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[CH2:12][CH2:11][C:10]2=[O:15])=[CH:5][CH:4]=1
Reactant: COc1ccc(N2C(=O)CCC2=O)cn1
Solvent: C1CCOC1
Product: O=C1CCC(=O)N1c1ccc(O)nc1
Temperature: 180 °C
Yield: 15 %

Procedure:
1-(6-Methoxy-pyridin-3-yl)-pyrrolidine-2,5-dione was dissolved in tetrahydrofuran and HCl-gas was bubbled into the solution for 5 minutes. The solvent was evaporated in vacuo and the residue was heated for 10 minutes at 180° C. in a pre-heated kugelrohr oven. After cooling to room temperature the residue was purified by flash column chromatography (SiO2), yielding the title compound (285 mg, 15% yield over two steps).
Reaction SMILES: [F:1][C:2]1[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:19]([F:25])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11](O)=[O:12])[C:7](=[O:18])[CH:6]=1.[CH3:26][C:27]1([CH3:39])[O:31][C@H:30]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH2:38])=[N:34]2)[CH2:29][O:28]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:26][C:27]1([CH3:39])[O:31][C@H:30]([CH2:32][N:33]2[CH:37]=[CH:36][C:35]([NH:38][C:11](=[O:12])[C@@H:10]([N:8]3[CH2:9][C:5]([O:4][C:3]4[C:19]([F:25])=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:2]=4[F:1])=[CH:6][C:7]3=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:34]2)[CH2:29][O:28]1
Reactant: COc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)c1F
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(F)c(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H]4COC(C)(C)O4)n3)C2)c1F
Temperature: 0 °C
Yield: 64.5 %

Procedure:
To a solution of (S)-2-[4-(2,6-difluoro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.200 g, 0.56 mmol) in N,N-dimethylformamide (7 mL) was added 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-ylamine (prepared as in Example 49, 0.139 g, 0.70 mmol) and benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (0.374 g, 0.85 mmol). The mixture was stirred at 0° C. and N,N-diisopropylethylamine (0.193 g, 1.49 mmol) was added. The mixture was stirred at room temperature overnight and the solvents were evaporated. The residue was treated with ethyl acetate and ammonium chloride solution, and the organic layer separated. The organic layer was washed with brine and dried over sodium sulfate. The solvents were evaporated and the residue was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g, 50% to 90% ethyl acetate/hexanes) which afforded (S)-2-[4-(2,6-difluoro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (0.193 g, 64%) as a pale brown solid: HR-ES-MS m/z calculated for C26H32F2N4O6 [M+H]+ 535.2363, observed 535.2363, 1H NMR (300 MHz, DMSO-d6) δ ppm 1.00 0.90 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 1.25 (s, 3H), 1.30 (s, 3 H), 1.36-1.50 (m, 1H), 1.50-1.65 (m, 1H), 1.69-1.84 (m, 1H), 3.73 (dd, J=8.4, 5.7 Hz, 1H), 3.87 (s, 3H), 4.00 (dd, J=8.4, 6.5 Hz, 1H), 4.11 (t, J=5.4 Hz, 2H), 4.27 (d, J=18.7 Hz, 1H), 4.35 (t, J=5.7 Hz, 1H), 4.62 (d, J=18.7 Hz, 1H), 4.88 (dd, J=10.6, 4.8 Hz, 1H), 5.06 (s, 1H), 6.43 (d, J=2.1 Hz, 1H), 7.18 (td, J=9.3, 5.1 Hz, 1H), 7.30 (td, J=9.5, 1.8 Hz, 1H), 7.60 (d, J=2.1 Hz, 1H), 10.82 (s, 1H).
Reaction SMILES: [C:1]([C@H:5]([C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[OH:8])[OH:6])([O:3][CH3:4])=[O:2].[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]1[O:8][C@H:7]([C:9]([O:11][CH3:12])=[O:10])[C@@H:5]([C:1]([O:3][CH3:4])=[O:2])[O:6]1
Reactant: COC(=O)[C@@H](O)[C@H](O)C(=O)OC
Reactant: O=Cc1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@H]1OC(c2ccccc2Cl)O[C@@H]1C(=O)OC
Yield: 60.3 %

Procedure:
In this example 50.0 g (0.28 mole) of dimethyl D-tartrate and 39.5 g (0.28 mole) of 2-chlorobenzaldehyde were refluxed for 48 hours in 500 ml of toluene in the presence of 0.2 g of p-toluenesulfonic acid. Water was azeotroped off with the aid of a Dean-Stark trap. The reaction mixture was concentrated by evaporation under reduced pressure to afford 50.8 g (60% yield) of the title compound as a solid which was washed with hexane and ether.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[C:9](OCC)(=[O:14])[CH2:10][C:11]([CH3:13])=O>C(O)(=O)C>[CH3:13][C:11]1[NH:2][N:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[C:9](=[O:14])[CH:10]=1
Reactant: NNc1ccccn1
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(=O)n(-c2ccccn2)[nH]1

Procedure:
A solution of 2-hydrazinopyridine (1.35 g; 0.012 mol.) and ethyl acetoacetate (1.60 mL; 0.012 mol.) in glacial acetic acid (50.0 mL) was stirred and heated at 100° for 24 h.
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH:16]=O)[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3].Cl.[NH2:19][OH:20].O.O.O.C([O-])(=O)C.[Na+]>C(#N)C.O>[CH2:1]([N:4]([CH2:15][CH:16]=[N:19][OH:20])[C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(CC=O)C(=O)OCc1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: C=CCN(CC=NO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
A solution of benzyl N-allyl-N-(2-oxoethyl)carbamate (25 g, 107 mmol) in acetonitrile (150 mL) is treated with hydroxylamine hydrochloride (9.68 g, 139 mmol) and a solution of sodium acetate trihydrate (16 g, 117.9 mmol) in water (75 mL). The mixture is stirred at room temperature overnight. The acetonitrile is evaporated and the aqueous solution is extracted with ethyl acetate. The organic layer is separated, dried over magnesium sulfate, and concentrated under vacuum to give the title compound (24 g, 90%). ES/MS (m/e): 249 (M+H).
Reaction SMILES: C([Li])CCC.CCCCCC.C([N-]C(C)C)(C)C.[Li+].[Cl:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[CH2:27][CH3:28].[F:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[C:37](=[O:44])[CH2:38][N:39]1[CH:43]=[N:42][CH:41]=[N:40]1>C1COCC1>[Cl:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][C:26]=1[CH:27]([CH3:28])[C:37]([C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[F:29])([OH:44])[CH2:38][N:39]1[CH:43]=[N:42][CH:41]=[N:40]1
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1F
Reactant: CCc1ccncc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(c1ccncc1Cl)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: -20 °C

Procedure:
To a solution of diiscpropylamine (1.01 g, 10 mmol) in dry THF (60 ml) at -60° C. and under a nitrogen atmosphere was added dropwise a 1.6M solution of n-butyllithium in hexane (6.25 ml, 10 mmol). The mixture was allowed to warm to -20° C. then recooled to -70° C. and to the resulting solution of lithium diisopropylamide (LDA) (10 mmol) at -70° C. was added dropwise 3-chloro-4-ethylpyridine (see D. L. Comins et al, Heterocycles, 22, 339 (1984)) (1.41 g, 10 mmol). The resulting mixture was stirred at this temperature for 15 minutes after which time a solution of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (2.23 g, 10 mmol) in THF (15 ml) was added. This mixture was allowed to warm to room temperature over a 30 minute period and the reaction was quenched by the addition of water (30 ml) and extracted with ethyl acetate (3×60 ml). The combined organic extracts were dried over magnesium sulphate, filtered, concentrated under reduced pressure and the title compound isolated by "flash" chromatography on silica eluting with ethyl acetate. The product was recrystallised from ethyl acetate (yield=0.46 g), m.p. 182°-184° C. Found: C,55.76; H,4.15; N,15.23; C17 H15ClF2N4O requires: C,55.98; H,4.14; N,15.36%.
Reaction SMILES: COC([CH:5]1[CH:9]([CH:10]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:8][O:7][C:6]1=[O:25])=O.[Cl-].[Li+].Cl>CN(C)P(=O)(N(C)C)N(C)C>[C:19]1([S:18][CH:10]([CH:9]2[CH2:8][O:7][C:6](=[O:25])[CH2:5]2)/[CH:11]=[CH:12]/[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCCCC/C=C/C(Sc1ccccc1)C1COC(=O)C1C(=O)OC
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCC/C=C/C(Sc1ccccc1)C1COC(=O)C1
Temperature: 100 °C

Procedure:
60 mg (0.17 mmol) of 3-methoxycarbonyl-4-(1-phenylthio-trans-2-octenyl)-oxolane-2-one was dissolved in 2 ml of hexamethyl phosphoric triamide in an argon atmosphere, and 36 mg (0.85 mmol) of lithium chloride was added to the solution followed by heating at a temperature of 100° C. for 5 hours with stirring. The reaction mixture was then allowed to cool to room temperature and decomposed with dilute hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The mixture was filtered and the filtrated was concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to obtain 4-(1-phenylthio-trans-2-octenyl)-oxolane-2-one.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:11]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)([CH3:13])[CH3:12]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:18][C:17]1[CH:19]=[CH:20][C:14]([CH:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CC(C)c1ccc(N)cc1
Product: CC(C)c1ccc(Nc2nc3ccccc3[nH]2)cc1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 4-isopropylaniline by Procedure A. The product was isolated upon basic work-up and recrystallized from acetonitrile to give the title compound as the free base (white solid, mp 179-180° C.). MS(ES+) m/z 252 ([M+1]+, 100).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]3[C:15]([N:16]4[CH2:20][CH2:19][NH:18][C:17]4=[O:21])=[N:14][N:13]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][O:23]4)[C:10]3=[CH:11][N:12]=2)[CH:2]=1.[H-].[Na+].[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][CH:40]([CH2:43]Br)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>CN(C)C=O>[O:21]=[C:17]1[N:16]([C:15]2[C:9]3[C:10](=[CH:11][N:12]=[C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:8]=3)[N:13]([CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[N:14]=2)[CH2:20][CH2:19][N:18]1[CH2:43][CH:40]1[CH2:41][CH2:42][N:37]([C:35]([O:34][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:36])[CH2:38][CH2:39]1
Reactant: O=C1NCCN1c1nn(C2CCCCO2)c2cnc(-c3cccnc3)cc12
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(c3nn(C4CCCCO4)c4cnc(-c5cccnc5)cc34)C2=O)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)imidazolidin-2-one (0.120 g, 0.329 mmol) dissolved in N,N-Dimethylformamide (3.43 mL) and cooled to 0° C. was added NaH in Oil (6:4, Sodium hydride:Mineral Oil, 26.3 mg). The reaction mixture was stirred at RT for 30 mins then cooled to 0° C. 4-bromomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.183 g, 0.659 mmol) was added. The reaction was stirred at RT for 18 hr. The mixture was quenched with H2O then extracted with EtOAc. The organic layers was dried, filtered, and concentrated to give tert-butyl 4-((2-oxo-3-(5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)imidazolidin-1-yl)methyl)piperidine-1-carboxylate which was dissolved in 4.0 M of Hydrogen chloride in 1,4-Dioxane (6.00 mL) and 1,4-Dioxane (3.00 mL, 38.4 mmol;) was stirred at RT 18 h. The reaction was concentrated and submitted for rHPLC purification to give 296 (11.6 mg, 9.3% yield). ESI MS m/z=378.2 (M+1). 1H NMR (400 MHz, DMSO) δ 9.17 (s, 1H), 9.03 (s, 1H), 8.78 (s, 1H), 8.55 (d, J=4.7 Hz, 1H), 8.30 (d, J=8.0 Hz, 1H), 7.50 (dd, J=8.0, 4.7 Hz, 1H), 4.03-3.93 (m, 2H), 3.65-3.56 (m, 2H), 3.11 (d, J=7.2 Hz, 2H), 2.92 (d, J=12.0 Hz, 2H), 2.42 (d, J=10.9 Hz, 1H), 1.79-1.67 (m, 1H), 1.59 (d, J=11.8 Hz, 2H), 1.05 (dd, J=21.5, 9.9 Hz, 2H)
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([O:13][CH3:14])=[O:12])[CH2:3][CH2:2]1.[C:15](Cl)(=[O:19])[C:16](Cl)=[O:17]>O1CCCC1>[O:17]=[C:16]1[C:9]2=[C:10]3[C:5](=[CH:6][CH:7]=[CH:8]2)[CH:4]([C:11]([O:13][CH3:14])=[O:12])[CH2:3][CH2:2][N:1]3[C:15]1=[O:19]
Reactant: COC(=O)C1CCNc2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)C1CCN2C(=O)C(=O)c3cccc1c32
Reaction time: 8 h
Yield: 83.3 %

Procedure:
A solution of methyl 1,2,3,4-tetrahydroquinoline-4-carboxylate (51.0 g) in tetrahydrofuran (THF, 200 ml) was heated under refluxing and a solution of oxalyl chloride (30 ml) in dry THF was added thereto. The mixture was refluxed for 4 hours, then cooled and concentrated. The residue was dissolved in carbon disulfide (800 ml) and aluminum chloride (66.7 g) was added portionwise. The mixture was refluxed for 4 hours, and then allowed to stand overnight. The solvent was eliminated by decantation and to the residue was added ice-water (1 litter). The mixture was extracted with chloroform. The chloroform layer was washed well with water, dried over anhydrous sodium sulfate and concentrated to give the title compound (55.15 g, 83.3%) which was recrystallized from acetonitrile to dark red crystals, mp 135° C.-136° C.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH2:19]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)[CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[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>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:26]4[CH:27]=[CH:28][C:23]([CH2:19][CH2:20][CH2:21][CH3:22])=[CH:24][CH:25]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CCCCc1ccc(B(O)O)cc1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCCCc1ccc(-c2ccc3c(c2)CC[C@H]2N(C)C(=O)CC[C@]32C)cc1
Yield: 76.6 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 4-n-butylphenylboronic acid (139 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 180 mg (77%) of the title compound as a white solid. mp 102°-108°. FDMS: m/e=361. α[D]589 =+68.70 (c=1.05, chloroform).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:38])[C@@H:11]([N:17]1[C:21](=[O:22])[C@@H:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][O:32]C(C)(C)C)=[CH:25][CH:24]=2)[NH:19][C:18]1=[O:37])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14].C[Si](I)(C)C.CO>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:38])[C@@H:11]([N:17]1[C:21](=[O:22])[C@@H:20]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][OH:32])=[CH:27][CH:28]=2)[NH:19][C:18]1=[O:37])[CH2:12][C:13]([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)C[C@@H](C(=O)Nc1ccc(I)cc1F)N1C(=O)N[C@H](c2ccc(OCCOC(C)(C)C)cc2)C1=O
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)C[C@@H](C(=O)Nc1ccc(I)cc1F)N1C(=O)N[C@H](c2ccc(OCCO)cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of (S)-2-{(R)-4-[4-(2-tert-butoxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-4,4-dimethyl-pentanoic acid (2-fluoro-4-iodo-phenyl)-amide (295 mg, 0.46 mmol) in dichloromethane (3 mL) at 0° C. under an atmosphere of dry argon was slowly added a solution of trimethylsilyl iodide (183 uL, 1.3 mmol) in dichloromethane (1 mL). The reaction mixture stirred at ambient temperature for 2 hours. Methanol (0.5 mL) was added to quench the reaction. The reaction mixture extracted with dichloromethane and the organic layer was washed sequentially with saturated aqueous sodium carbonate, 5% aqueous sodium thiosulfate, brine, then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography over silica gel gradient eluted from 100% hexane up to 50% ethyl acetate/50% hexane over 30 minutes. Concentration of the product containing fractions gave (S)-2-{(R)-4-[4-(2-hydroxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-4,4-dimethyl-pentanoic acid (2-fluoro-4-iodo-phenyl)-amide as a white solid (126 mg, 47%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.[H-].[Na+].[Br:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1F>CN(C=O)C>[Br:13][C:14]1[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[CH:16][C:15]=1[N:4]1[CH2:5][CH2:6][O:1][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]1=2
Reactant: c1ccc2c(c1)NCCO2
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(N2CCOc3ccccc32)c(Br)c1
Reaction time: 0.25 h

Procedure:
To a flask under nitrogen, 3,4-dihydro-2H-benzo[b][1,4]oxazine (Tyger Scientific Inc., Ewing, N.J., 0.457 mL, 3.70 mmol) was dissolved in DMF (18.50 mL) and at room temperature, NaH (60% dispersion in mineral oil) (0.326 g, 8.14 mmol) was added, and the reaction was stirred for 15 minutes. 2-Bromo-1-fluoro-4-(trifluoromethyl)benzene (Alfa Aesar, Ward Hill, Mass., 0.790 mL, 5.55 mmol) was then added, and the reaction was stirred overnight at room temperature until complete conversion to the desired product. The reaction was then quenched with saturated aqueous ammonium chloride solution, and extracted with EtOAc (×2). The combined organics were washed with brine, dried over sodium sulfate, and concentrated to give material, which was purified via silica gel MPLC (Biotage Isolera One; PuriFlash HP, 15μ, 25 g (Biotage, Uppsala, Sweden)), eluting with 0 to 100% ethyl acetate in heptanes. Fractions containing clean product were collected and concentrated under a vacuum to yield 1.73 g of 4-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (INTERMEDIATE B) as an orange oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.62-3.69 (m, 2H) 4.28 (t, J=4.21 Hz, 2H) 6.30 (dd, J=7.87, 1.71 Hz, 1 H) 6.71 (dtd, J=18.67, 7.42, 7.42, 1.71 Hz, 2H) 6.85 (dd, J=7.78, 1.81 Hz, 1 H) 7.59 (d, J=8.41 Hz, 1 H) 7.81 (dd, J=8.41, 1.56 Hz, 1 H) 8.13 (d, J=1.66 Hz, 1 H). m/z (ESI) 357.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]([CH3:13])([CH3:12])[CH:10]=O)=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[CH3:32][NH:33][CH3:34].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]([CH3:13])([CH3:12])[CH2:10][N:33]([CH3:34])[CH3:32])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CC(C)(C=O)Oc1ccc(Cl)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C)CC(C)(C)Oc1ccc(Cl)nc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a large capacity microwave tube containing 2-(6-chloropyridin-3-yloxy)-2-methylpropanal (354 mg, 1.77 mmol) and sodium triacetoxyborohydride (940 mg, 4.43 mmol) in dry dichloromethane (4 ml) was added glacial acetic acid (0.81 ml, 14.2 mmol) followed by a 2 M solution of dimethylamine (14.2 ml, 28.4 mmol, in tetrahydrofuran). The tube was capped and heated to 50° C. (oil bath) with vigorous stirring for 16 hours. The mixture was cooled to ambient and the contents poured into a separatory funnel containing an aqueous solution of saturated sodium bicarbonate (30 ml). Dichloromethane (30 ml) was added and the mixture was shaken. The contents were filtered through a plug of celite, washing well with dichloromethane. The filtrate was collected and washed with a brine solution (40 ml). The dichloromethane phase was collected and the aqueous phase was back extracted with methylene chloride (2×40 mL). The organic phases were combined, dried over magnesium sulfate, filtered and stripped. The material was purified by preparative thin layer chromatography (2 plates), eluting with 1.8% methanol/dichloromethane. The plates were then re-developed with 2.6% methanol/dichloromethane, and the product band was collected which provided the desired as a light yellow mobile oil, which slowly solidified on standing (255 mg). (M+H)+=229 m/e.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([CH2:13][CH3:14])[C:11](=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:13]([N:12]1[C:11](=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:2][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1)[CH3:14]
Reactant: CCn1c(CCl)nc2ccccc2c1=O
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCn1c(COc2ccc(C=O)cc2)nc2ccccc2c1=O
Yield: 87.6 %

Procedure:
The title compound (4.24 g, 88%) was prepared from 2-chloromethyl-3-ethyl-4-oxo-3,4-dihydroquinazoline (3.5 g, 15.7 mmol) and 4-hydroxybenzaldehyde (2.10 g, 17.21 mmol) in the presence of K2CO3 (2.38 g, 17.26 mmol) as base by a similar procedure to that described in preparation 13.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:16][O:17][C:18](=[O:23])[CH2:19][CH2:20][CH2:21]Br>>[CH3:16][O:17][C:18](=[O:23])[CH2:19][CH2:20][CH2:21][N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: COC(=O)CCCBr
Product: COC(=O)CCCN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 52.5 %

Procedure:
The title compound (1.56 g, 52.6%) was synthesized from 1-(4-nitro-phenyl)-piperazine (2 g, 9.66 mmol) and 4-bromo-butyric acid methyl ester (1.75 g, 9.83 mmol) by the procedure described in step 1 of Example 1 MS (ESI) m/z 264 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.86 (m, 2H), 2.39 (m, 4H), 2.58 (t, J=5.2 Hz, 4H), 3.41 (t, J=5.2, 4H), 3.68 (s, 3H), 6.81 (m, 2H), 8.12 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:10]=2[C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[CH2:6][O:5][CH2:4]1.C(N(CC)CC)C.[C:36](Cl)(=[O:41])[O:37][CH:38]([CH3:40])[CH3:39].COC1C(OC)=CC=C(C2C=CC=C3C=2CCC3=O)C=1OCC1(CNC(=O)C)COC1>ClCCl>[CH:38]([O:37][C:36](=[O:41])[NH:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:10]([C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH2:21][CH2:22][C:23]4=[O:28])=[CH:11][CH:12]=[C:13]([O:17][CH3:18])[C:14]=2[O:15][CH3:16])[CH2:4][O:5][CH2:6]1)([CH3:40])[CH3:39]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)COC2)c1OC
Reactant: CC(C)OC(=O)Cl
Agent: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CNC(C)=O)COC2)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CNC(=O)OC(C)C)COC2)c1OC

Procedure:
To a stirring solution of 4-[2-(3-Aminomethyl-oxetan-3-ylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 191) (150 mg, 0.3916 mmol) in dichloromethane (15 mL), were added triethylamine (118 mg, 1.174 mmol) and isopropyl carbonochloridate (95 mg, 0.783 mmol) and the resultant reaction mixture was subjected to the conditions used in the preparation of Compound 192 to afford the title compound as a solid.