Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([C:36]([F:39])([F:38])[F:37])=[N:22][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[N:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([C:36]([F:39])([F:37])[F:38])=[N:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:28][CH:27]=3)=[N:24][CH:25]=2)=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C(F)(F)F)n2)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)cc3)nc2C(F)(F)F)cc1C

Procedure:
In analogy to the procedures described in example 101A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 107D]) to give 2-methyl-2-{2-methyl-4-[4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-propionic acid ethyl ester, which was subsequently saponified in analogy to the procedure described in example 101B] to yield the title compound as off-white powder of mp. 149–151° C., dec.
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[C:21]([Cl:22])=[CH:20][C:19]([S:23]([N:26]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=3[O:42][CH3:43])[C:27]3[CH:32]=[CH:31][N:30]=[CH:29][N:28]=3)(=[O:25])=[O:24])=[C:18]([F:44])[CH:17]=2)[C@@H:11]([C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:22][C:21]1[C:16]([O:15][C@H:12]2[CH2:13][CH2:14][C@@H:9]([OH:8])[CH2:10][C@@H:11]2[C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)=[CH:17][C:18]([F:44])=[C:19]([S:23]([N:26]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=2[O:42][CH3:43])[C:27]2[CH:32]=[CH:31][N:30]=[CH:29][N:28]=2)(=[O:25])=[O:24])[CH:20]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CC[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CC[C@@H](O)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Yield: 69 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 120c by using the 4-{[(1S,2R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (262 mg, 0.351 mmol) prepared in Example 165b, tetrabutyl ammonium fluoride (1.0 M solution in THF; 0.702 mL, 0.702 mmol) and THF (5.0 mL), to yield the title compound (153 mg, 69%) as a colorless amorphous solid.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=O.Br.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][NH:25][CH2:24]2.C(N=C=NCCCN(C)C)C>ClCCl>[O:17]=[C:15]([N:25]1[CH2:24][C:23]2[C:27](=[CH:28][CH:29]=[C:21]([C:20]([F:19])([F:31])[F:30])[CH:22]=2)[CH2:26]1)[CH2:14][N:3]1[CH2:4][CH2:5][CH2:6][CH:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1=[O:1]
Reactant: FC(F)(F)c1ccc2c(c1)CNC2
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
Agent: Br
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)C1=O)N1Cc2ccc(C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-(2-oxo-3-phenylpiperidin-1-yl)acetic acid (0.137 g, 0.587 mmol; Example 91D) and 5-(trifluoromethyl)isoindoline hydrogen bromide (0.173 g, 0.646 mmol) in dichloromethane (0.5 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.156 mL, 0.881 mmol) and the reaction was stirred at room temperature overnight. The reaction was loaded directly onto a SF15-12 column (Analogix®) and the product eluted using a gradient of 50% ethyl acetate/hexanes to 100% ethyl acetate over 15 minutes (Flow=30 mL/minute) to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 7.66-7.11 (m, 8H), 4.96 (s, 2H), 4.89 (s, 2H), 4.44 (dd, J=2.6, 15.6, 1H), 4.08 (dt, J=2.3, 6.8, 1H), 3.80-3.65 (m, 2H), 3.59 (dt, J=4.0, 5.6, 1H), 2.39-2.16 (m, 1H), 2.16-1.78 (m, 3H).
Reaction SMILES: Cl[Si](C)(C)C.Br[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[F:15][C:16]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=[O:19]>C1COCC1.[Zn]>[F:15][C:16]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]([OH:19])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: COc1cccc(C=O)c1F
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: COc1cccc(C(O)CC(=O)OC(C)(C)C)c1F
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 58.1 %

Procedure:
To a suspension of zinc (0.848 g, 12.98 mmol) in dry THF (10 mL), was added chlorotrimethylsilane (0.829 mL, 6.49 mmol). After 10 min, tert-butyl 2-bromoacetate (0.959 mL, 6.49 mmol) was added and the reaction mixture was heated at 50° C. for 10 min. The reaction mixture was then cooled to 0° C. under argon. To the cooled solution was then added 2-fluoro-3-methoxybenzaldehyde (1 g, 6.49 mmol) in THF (3 mL) and the reaction was allowed to warm to rt overnight. The reaction mixture after overnight stirring was quenched with 5% NaHCO3 solution, filtered off the solids and rinsed with EtOAc. The organic layer was washed with water followed by brine and dried over MgSO4 to yield the crude product. The crude product was then purified using silica gel chromatography to yield the desired product (1.02 g, 58%) as clear oil. MS (ESI) m/z: 215.1 (M-tBu)+.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)([C:14](OC)=[O:15])[C:10](OC)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Li+].Cl.B>C(OCC)(=O)C.O.O1CCCC1.CCOCC>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)([CH2:10][OH:11])[CH2:14][OH:15])=[CH:28][CH:29]=1)([O-:3])=[O:2]
Reactant: COC(=O)C(Cc1ccc([N+](=O)[O-])cc1)(Cc1ccc([N+](=O)[O-])cc1)C(=O)OC
Agent: B
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(CC(CO)(CO)Cc2ccc([N+](=O)[O-])cc2)cc1
Yield: 100 %

Procedure:
About 2 mole of 1-bromomethyl)-4-nitrobenze and about 1 mole of dimethyl malonate were mixed with excess methyl ethyl ketone (MEK) which was mixed with potassium carbonate at a temperature of about 50° C. for about 3 hours. After adding excess water at temperature of about 25° C., the above materials were precipitated to obtain about 1 mole of dimethyl 2,2-bis(4-nitrobenzyl)malonate. About 1 mole of dimethyl 2,2-bis(4-nitrobenzyl)malonate was mixed with water and tetrahydrofurane (THF) which was mixed with lithium hydroxide, and dimethyl 2,2-bis(4-nitrobenzyl)malonate at a temperature of about 25° C. for about 22 hours. After adding about 1 N of hydrochloric acid at a temperature of about 25° C., excess water and ether were added to extract about 1 mole of 2,2-bis(4-nitrobenzyl)maloic acid. THF and borane were added to about 1 mole of 2,2-bis(4-nitrobenzyl)maloic acid and THF, borane at a temperature of about 25° C. for about 20 hours. After adding excess water and ethyl acetate, about 1 mole of 2,2-bis(4-nitrobenzyl)propane-1,3-diol was obtained. Formaldehyde was added to about 1 mole of 2,2-bis(4-nitrobenzyl)propane-1,3-diol, and 2,2-bis(4-nitrobenzyl)propane-1,3-diol at a temperature of about 80° C. for about 30 minutes. Hydrogen bromide was added to, and 2,2-bis(4-nitrobenzyl)propane-1,3-diol, formaldehyde, and hydrogen bromide were reacted at a temperature of about 25° C. for about 3 hours to obtain about 1 mole of 2,2-bis((bromomethoxy)methyl)-1,3-bis(4-nitrophenyl)propane. After adding triphenylphosphine and carbon dichloride to 2,2-bis((bromomethoxy)methyl)-1,3-bis(4-nitrophenyl)propane at a temperature of about 23° C. for about 2 hours, about 1 mole of 4-formylphenyl 4-(4,4,4-trifluorobutoxy)benzoate was mixed with excess sodium hydride and THF at a temperature of about 23° C. for about 18 hours. Then, zinc chloride and carbon dichloride are added at a temperature of about 40° C. for about 16 hours to obtain about 1 mole of the compound represented by Chemical Formula 6.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[C:9]([C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)(=[O:11])[CH3:10]>>[Cl:1][C:2]1[N:7]=[C:6]([C:16]2[CH:17]=[C:12]([C:9](=[O:11])[CH3:10])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(=O)c1cccc(B(O)O)c1
Product: CC(=O)c1cccc(-c2ccnc(Cl)n2)c1

Procedure:
2,4 dichloropyrimidine was coupled with 3-acetylphenylboronic acid following procedure A. LC-MS showed the product had the expected M+H+ of 234.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O1CCOCC1>[CH3:21][C:19]1[CH:18]=[CH:17][N:16]=[C:15]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Si:2]([CH3:13])([CH3:12])[CH3:1])[CH:4]=2)[CH:20]=1
Reactant: C[Si](C)(C)c1cccc(B(O)O)c1
Reactant: Cc1ccnc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1ccnc(-c2cccc([Si](C)(C)C)c2)c1

Procedure:
15.0 g (0.0773 mol) of 3-trimethylsilyl-phenylboronic acid, 11.96 g (0.0695 mol) of 2-bromo-4-methyl-pyridine, 30.21 g (0.0927 mol) of cesium carbonate, 0.71 g (0.000776 mol) of tris(dibenzylideneacetone) dipalladium (0), 0.38 g (0.00188 mol) of tri-tert-butyl-phosphane and 100 ml of dioxane were stirred at room temperature for 12 hr. The reaction mixture was filtered and the solvent was removed under 1 mm vacuum. The resulting mixture was purified by distillation in vacuum. Yield of 4-methyl-2-(3-trimethylsilanyl-phenyl)-pyridine was 8.18 g (48.75%) as a colorless liquid with b.p. 89-90° C./0.02. 1H NMR (CD2Cl2) 0.30 (s, 9H, Me3Si), 2.32 (s, 3H, Me) 7.00-8.55 (m, 7H, arom-H). Anal. Found: C, 74.65; H, 7.94; N, 5.88.
Reaction SMILES: [H-].[Na+].C(NC(C)C)(C)C.[C:10]([OH:15])(=[O:14])[CH:11]([CH3:13])[CH3:12].C([Li])CCC.CCCCCC.Cl[CH2:28][C:29]1[S:30][CH:31]=[CH:32][CH:33]=1>O.C1COCC1>[CH3:12][C:11]([CH3:13])([CH2:28][C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)[C:10]([OH:15])=[O:14]
Reactant: CC(C)C(=O)O
Reactant: ClCc1cccs1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(Cc1cccs1)C(=O)O
Reaction time: 0.25 h

Procedure:
A mixture of 57% oil emulsion of sodium hydride (3.14 g., 0.074 mole), THF (68 ml.) and diisopropylamine (6.87 g., 0.068 mole) was placed under N2. Isobutyric acid (5.98 g., 0.068 mole) was added dropwise. The mixture was heated at reflux for 15 min. to complete formation of the salt. After cooling at 0°, a solution of 1.6 molar n-butyllithium in hexane (42 ml., 0.068 mole) was added in small portions while holding the temperature below 10°. The resulting turbid solution was kept at 0° for 15 min. and then warmed to 30°-35° for 30 min. After again cooling to 0°, 2-chloromethylthiophene (9 g., 0.068 mole) was added dropwise over 15-20 min. while holding temperature between 0° and 5°. The mixture was kept at 0° for 30 min., in the range of 30°-35° for 1 hr. and was then cooled to 15°. Water (90 ml.) was added dropwise and the aqueous layer was separated. The organic phase was washed with a mixture of water (50 ml.) and Et2O (75 ml.). The aqueous extracts were combined, washed with Et2O and then acidified with conc. HCl. The oily product was extracted with Et2O and the combined ET2O extracts were dried over MgSO4. Evaporation of the Et2O in vacuo gave 11.4 g. (91%) of product of sufficient purity to be used for conversion into (IVa). The NMR spectrum is consistent with the assigned structure.
Reaction SMILES: N[C:2]1[C:3]([CH3:11])=[CH:4][C:5]([C:9]#[N:10])=[N:6][C:7]=1[CH3:8].[BrH:12].BrBr.N([O-])=O.[Na+].[OH-].[Na+]>>[Br:12][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([C:9]#[N:10])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cc(C#N)nc(C)c1N
Reactant: Br
Agent: BrBr
Agent: O=N[O-]
Agent: [Na+]
Product: Cc1cc(C#N)nc(C)c1Br
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5-amino-4,6-dimethylpicolinonitrile (390 mg) was added to aqueous hydrogen bromide (2.9 mL). Bromine (164 μl) and sodium nitrite (467 mg) were added to the solution at 0° C. The solution was warmed to room temperature and stirred for four hours. A 5 N aqueous sodium hydroxide solution was added to the reaction mixture, followed by separation with ethyl acetate. The organic layer was washed with brine and then dried using magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 0% to 30%) to give the title compound (300 mg).
Reaction SMILES: C[O:2][CH2:3][C:4]1[S:8][N:7]=[N:6][C:5]=1[C:9]([O:11][CH3:12])=[O:10].BrBr>C(Cl)(Cl)(Cl)Cl>[CH:3]([C:4]1[S:8][N:7]=[N:6][C:5]=1[C:9]([O:11][CH3:12])=[O:10])=[O:2]
Reactant: COCc1snnc1C(=O)OC
Agent: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nnsc1C=O
Yield: 71.3 %

Procedure:
Methyl 5-(methoxymethyl)-1,2,3-thiadiazole-4-carboxylate (4.18 g, 0.022 mol) was dissolved in carbon tetrachloride (60 mL). To the solution was added bromine (4.18 g, 0.026 mol) and the solution was refluxed upon irradiation with long wavelength UV light (100 watts) for 3 h. The volatiles were evaporated in vacuo and the crude material purified by flash chromatography to give the desired product (2.70 g, 71%) as a viscous oil. 1H NMR (400 MHz, CDCl3): δ 10.67 (s, 1H), 4.15 (s, 3H). MF═C5H4N2O3S; LCMS calculated for C5H5N2O3S(M+H)+: m/z=173.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2C3C(=CC=C(I)C=3)N=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][C:28]12[CH2:35][O:34][C:31]([C:36]3[O:40][C:39]([Sn](CCCC)(CCCC)CCCC)=[CH:38][CH:37]=3)([O:32][CH2:33]1)[O:30][CH2:29]2>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[N:17]=[CH:18][C:13]3[C:12](=[CH:11][CH:10]=[C:9]([C:39]4[O:40][C:36]([C:31]56[O:30][CH2:29][C:28]([CH3:27])([CH2:33][O:32]5)[CH2:35][O:34]6)=[CH:37][CH:38]=4)[CH:14]=3)[N:15]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C23OCC(C)(CO2)CO3)o1
Reactant: Ic1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC12COC(c3ccc(-c4ccc5nc(Nc6ccc(OCc7ccccc7)cc6)ncc5c4)o3)(OC1)OC2
Yield: 131.4 %

Procedure:
(4-Benzyloxy-phenyl)-(6-iodoquinazolin-4-yl)-amine (0.925 g, 2.04 mmol), 5-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)-2-[tri(n-butyl)stannyl]furan (2.00 g, 4.1 mmol) and bis(triphenylphosphine)palladium (II) chloride (catalytic) were reacted in dry dioxane (25 ml) according to Procedure B. Purification by silica gel chromatography and eluting with 100% EtOAc gave the title compound as a yellow solid (0.700 g, 1.34 mmol, 66%); δH [2H6]DMSO 10.0 (1H, s), 8.75 (1H, s), 8.48 (1H, s), 8.12 (1H, d), 7.79 (1H, d), 7.66 (2H, d), 7.30-7.52 (5H, m), 7.03-7.12 (3H, m), 6.64 (1H, d), 5.14 (2H, s), 4.06 (6H, s), 0.85 (3H, s).
Reaction SMILES: FC1C=CC=CC=1N[N:9]1[C:18]2[C:13](=[C:14]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[C:15]([F:19])=[CH:16][CH:17]=2)[C:12](=[O:27])[N:11]([O:28]CC2C=CC=CC=2)[C:10]1=[O:36]>[Pd]>[F:19][C:15]1[CH:16]=[CH:17][CH:18]=[CH:13][C:14]=1[N:9]1[C:18]2[C:17](=[CH:16][C:15]([F:19])=[C:14]([N:20]3[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]3)[CH:13]=2)[C:12](=[O:27])[N:11]([OH:28])[C:10]1=[O:36]
Reactant: CN1CCN(c2c(F)ccc3c2c(=O)n(OCc2ccccc2)c(=O)n3Nc2ccccc2F)CC1
Agent: [Pd]
Product: CN1CCN(c2cc3c(cc2F)c(=O)n(O)c(=O)n3-c2ccccc2F)CC1
Yield: 200.3 %

Procedure:
Using the General Method 6A, the reaction of 10% Pd/C (0.03 g) with 1-(2-fluorophenylamino)-6-fluoro-3-benzyloxy-(4-methylpiperazin-1-yl)-1H-quinazoline-2,4-dione (Example X-1, 0.09 g, 0.18 mmol) provided 0.07 g of the title compound as a solid, mp 160-162° C.
Reaction SMILES: [Br-:1].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N+:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH3:20])([CH3:19])[C:11]=1[CH3:21])([OH:4])=[O:3].[C:22]1([NH:28][CH:29]=NC2C=CC=CC=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO.ClCCl>C(O)(=O)C>[Br-:1].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N+:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH3:20])([CH3:19])[C:11]=1[CH:21]=[CH:29][NH:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([OH:4])=[O:3]
Reactant: CC1=[N+](CCCCCC(=O)O)c2ccccc2C1(C)C
Reactant: C(=Nc1ccccc1)Nc1ccccc1
Agent: [Br-]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1(C)C(C=CNc2ccccc2)=[N+](CCCCCC(=O)O)c2ccccc21
Reaction time: 2.5 h

Procedure:
1-(5-carboxypentyl)-2,3,3-trimethylindolium bromide (1.77 g, 5 mmol) and N,N′-diphenylformamidine (1.96 g, 10 mmol) were mixed in acetic acid (15 m); the resulting mixture was then heated at reflux. The reaction was monitored by UV/VIS spectroscopy (methanol solution, product absorbance λmax 398 nm) and TLC (silica. Methanol, 20: dichloromethane, 80; product runs as a yellow streak, Rf 0.1-0.25). After 2.5 hrs the orange-red solution was then left to cool over 16 hrs, then the solvent was removed under reduced pressure. The residue was purified by flash chromatography (silica. 5-20% methanol/dichloromethane) to give the title compound [1.3] as a yellow-orange foam after drying, 1.5 g (66%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:21][CH:22]=O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Na]>ClCCCl>[CH2:32]([NH:39][CH2:22][CH2:21][C@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[CH2:19][O:18][Si:1]([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: NCc1ccccc1
Agent: [Na]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCNCc1ccccc1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.4 %

Procedure:
To (S)-tert-butyl (1-((tert-butyldiphenylsilyl)oxy)-4-oxobutan-2-yl)carbamate (14.93 g, 33.8 mmol) in DCE (100 mL) at 0° C. was added benzylamine (3.69 mL, 33.8 mmol) and sodium triacetoxyhydroborate (8.60 g, 40.6 mmol) sequentially. After stirring at rt 18 h, it was quenched by addition of saturated NaHCO3 (aq, 300 mL) and stirred for an additional 30 min. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified via silica gel chromatography (EtOAc-Heptane) to afford the title compound (8 g, 44%). LCMS: Rt=1.08 min, m/z=533.2 (M+1) Method 2m_acidic.
Reaction SMILES: O.[OH-].[Li+:3].C[O:5][C:6]([C:8]1[CH:12]=[C:11]([C:13]2[N:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]([C:19]2[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[N:9]=1)=[O:7]>CO>[Li+:3].[CH3:26][O:25][C:22]1[N:21]=[CH:20][C:19]([N:10]2[C:11]([C:13]3[N:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:12][C:8]([C:6]([O-:7])=[O:5])=[N:9]2)=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc(-c2cccnn2)n(-c2ccc(OC)nc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-n2nc(C(=O)[O-])cc2-c2cccnn2)cn1

Procedure:
Lithium hydroxide monohydrate (42 mg) was added to the above-obtained 1-(6-methoxy-3-pyridyl)-5-(3-pyridazinyl)pyrazole-3-carboxylic acid methyl ester (309 mg) in methanol (20 mL), and the resultant mixture was refluxed under heat for 18 hours, and then cooled in air. The reaction solvent was removed under reduced pressure, to thereby give the title compound as an amorphous product (322 mg, >100%).
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[CH2:44]([C@@H:51]1[CH2:55][O:54][C:53](=[O:56])[N:52]1[C:57]1[CH:58]=[C:59]([CH:63]=[CH:64][CH:65]=1)[C:60](O)=[O:61])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.[CH:66]12[CH2:72][CH:69]([CH2:70][CH2:71]1)[CH2:68][CH:67]2[NH:73][C:74](=[O:89])[C@H:75]([CH3:88])[CH2:76][C@H:77]([OH:87])[C@@H:78]([NH2:86])[CH2:79][C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1>>[CH2:79]([C@H:78]([NH:86][C:60](=[O:61])[C:59]1[CH:63]=[CH:64][CH:65]=[C:57]([N:52]2[C@H:51]([CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH2:55][O:54][C:53]2=[O:56])[CH:58]=1)[C@@H:77]([OH:87])[CH2:76][C@H:75]([C:74](=[O:89])[NH:73][CH:67]1[CH2:68][CH:69]2[CH2:72][CH:66]1[CH2:71][CH2:70]2)[CH3:88])[C:80]1[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=1
Reactant: O=C(O)c1cccc(N2C(=O)OC[C@H]2Cc2ccccc2)c1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cccc(N2C(=O)OC[C@H]2Cc2ccccc2)c1)C(=O)NC1CC2CCC1C2

Procedure:
Prepared in an analogous manner to E6 from 3-((R)-4-benzyl-2-oxooxazolidin-3-yl)benzoic acid (D21) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[F:13])([O-])=O>[Fe]>[F:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: [Fe]
Product: Nc1cc([N+](=O)[O-])ccc1F

Procedure:
European Patent Application 127,079, Takemoto et al. (1984), discloses a process in which 2,4-dinitrofluorobenzene is selectively reduced using between 2.5 and 4 moles of iron in the presence of acid to produce one mole of 2-fluoro-5-nitroaniline. In one example in which acetic acid was employed and the reaction mixture was refluxed for ten minutes, 2-fluoro-5-nitroaniline was produced in 70% yield, by weight. The weight % ratio of the desired 2-fluoro-5-nitroaniline to the by-product 4-fluoro-3-nitroaniline was 93:7. The use of a noble metal catalyst is not taught by this patent application.
Reaction SMILES: [CH3:1]I.[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8](=[N:24][OH:25])[C:9]1[CH:23]=[CH:22][C:12]([O:13][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1>CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8](=[N:24][O:25][CH3:1])[C:9]1[CH:23]=[CH:22][C:12]([O:13][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(C(=NO)c2cccs2)cc1
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C(=NOC)c2cccs2)cc1

Procedure:
This oily compound, which consists of a mixture of both isomers Z/E, is obtained by reacting methyl iodide with ethyl 2-[4-(2-thienyl-hydroxyiminomethyl)-phenoxy]-2-methyl-propionate dissolved in dimethyl formamide and in the presence of potassium carbonate.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:12])[CH2:3]1.[CH2:14]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17].CC(N1CCCC(C(C)=O)=C1)C>>[CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[N:9]([C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:18]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:12])[CH2:3]1
Reactant: CC1(C)CC(=O)C2=C(C1)NCCC2
Reactant: CCCCc1ccc(C(=O)Cl)cc1
Agent: CC(=O)C1=CN(C(C)C)CCC1
Product: CCCCc1ccc(C(=O)N2CCCC3=C2CC(C)(C)CC3=O)cc1

Procedure:
7,7-Dimethyl-1,2,3,4,7,8-hexahydro-quinoline -5(6H)-one was reacted with 4-butylbenzoyl chloride according to the procedure of Part (b) of Example 1 to give 7,7-dimethyl-1,2,3,4, 7,8-hexahydro-1-(4-butylbenzoyl)-quinoline5(6H)-one (22) as a yellow solid.