Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.[OH:20][CH2:21][CH2:22][N:23]1[C:28](=[O:29])[CH2:27][CH2:26][CH:25]([N:30]2[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:40])[C:24]1=[O:41]>C(O)(C(F)(F)F)=O.C(Cl)Cl.C(Cl)Cl>[NH2:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11].[OH:20][CH2:21][CH2:22][N:23]1[C:28](=[O:29])[CH2:27][CH2:26][CH:25]([N:30]2[C:31](=[O:40])[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38]2=[O:39])[C:24]1=[O:41]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
2-(1-(2-hydroxyethyl)-2,6-dioxopiperidin-3-yl)isoindolin-1,3-dione (S)-2-(tert-butoxycarbonylamino)-3-phenylpropanoate (100 mg) was dissolved in 25% TFA/DCM (10 mL) and stirred on a magnetic stirrer at room temperature. The mixture was allowed to react for 4 hrs. DCM and most of TFA were removed by rotary evaporation in vacuo. The foam obtained was dissolved in DCM (50 mL). The mixture was washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and filtered. 52 mg of a solid was obtained after drying in vacuo. 1H NMR (CDCl3, ppm) δ 7.80-7.90 (m, 2H), 7.70-7.80 (m, 2H), 7.10-7.35 (m, 5H), 4.95-5.12 (m, 1H), 4.35-4.45 (m, 1H), 4.15-4.25 (m, 2H), 4.00-4.15 (m, 1H), 3.65-3.72 (m, 1H), 2.95-3.10 (m, 2H), 2.75-2.90 (m, 3H), 2.12-2.20 (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][CH2:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[N:14]=2)[CH2:4][NH:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:30]1([C:27]2[CH:26]=[CH:25][C:24]([NH:23][C:15]3[N:14]=[C:13]([CH2:12][CH2:11][C:9]4[CH:8]=[CH:7][CH:6]=[C:5]5[C:10]=4[C:2](=[O:1])[NH:3][CH2:4]5)[C:18]([C:19]([F:20])([F:21])[F:22])=[CH:17][N:16]=3)=[CH:29][CH:28]=2)[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cccc5c4C(=O)NC5)n3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2cccc(CCc3nc(Nc4ccc(N5CCNCC5)cc4)ncc3C(F)(F)F)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
tert-Butyl 4-(4-((4-(2-(3-oxoisoindolin-4-yl)ethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I63) (0.080 g, 0.137 mmol) was dissolved in DCM (5 mL) under an atmosphere of nitrogen. Trifluoroacetic acid (0.210 mL, 2.75 mmol) was added to the solution and the reaction was stirred at room temperature for 1 hour and then at 35° C. for another 30 minutes. More trifluoroacetic acid (0.100 mL) was added and the reaction was further stirred at 35° C. for another 30 minutes. Volatiles were removed in vacuo then EtOAc (70 mL) and 2 M aq. NaOH (70 mL) were added to the residue and the layers were separated. The aqueous layer was extracted with EtOAc (2×70 mL), the combined organics were washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo to give an oily solid which was taken up in DCM (˜10 mL) and concentrated in vacuo. The process was repeated twice after which the sample was further dried on high-vacuum to give the title compound (15) (0.050 g, 75% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 9.94 (s, 1H), 8.56 (s, 1H), 8.48 (s, 1H), 7.59-7.52 (m, 2H), 7.47-7.36 (m, 2H), 7.23-7.11 (m, 1H), 6.87 (d, J=9.0 Hz, 2H), 4.31 (s, 2H), 3.56 (t, J=7.6 Hz, 2H), 3.11 (t, J=7.4 Hz, 2H), 3.01-2.95 (m, 4H), 2.86-2.79 (m, 4H). LCMS Method A: rt 4.40 min; m/z 483.8 [M+H]+.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[N:12]1([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]1.O>ClCCl>[CH:14]12[O:6][CH:15]1[CH2:16][CH2:17][N:12]([C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[CH2:13]2
Reactant: O=C(OCc1ccccc1)N1CC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC2OC2C1
Reaction time: 18 h
Yield: 78.7 %

Procedure:
3-Chlorobenzoperoxoic acid (16.79 g, 97 mmol) was added portionwise under an atmosphere of nitrogen to a stirred solution of benzyl 5,6-dihydropyridine-1(2H)-carboxylate (15.1 g, 69.5 mmol) (available, for example, from Fluorochem) in anhydrous dichloromethane (DCM) (100 mL) cooled using an ice bath. The resulting mixture was allowed to reach rt and stirred for 18 h. Water (100 mL) was added to the reaction mixture and the layers were partitioned. The organic layer was added dropwise to a stirred 5% aqueous solution of NaS2O5 (200 mL). At the end of the addition, the mixture was stirred for a further 1 h, then the layers were separated and the aqueous layer was back extracted with DCM (50 mL×2). The organics were combined and washed with 5% aqueous K2CO3 solution (100 mL×3), followed by brine (100 mL). At this stage peroxide test showed there was still 25 mg/mL peroxide in the organic layer. The organics were therefore added to a stirred solution of 5% NaS2O5(aq) (200 mL) and the resultant biphasic mixture stirred for 1 h. Peroxide test now showed <0.5 mg/mL peroxide. The layers were separated and aqueous layer washed with further DCM (2×50 mL). The combined organics were then dried (Na2SO4). and concentrated in vacuo to afford the crude product as a pale-gold oil. The crude product was purified by silica gel chromatography, (340 g Si), eluting with 30→80% EtOAc/cyclohexane. The appropriate fractions were combined and concentrated in vacuo to afford the title compound as a colourless oil—benzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (12.75 g, 54.7 mmol, 79% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].Cl.[CH3:15][O:16][NH2:17]>>[CH3:15][O:16][N:17]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=1)[C:10]([OH:12])=[O:11]
Reactant: CON
Reactant: O=C(O)C(=O)c1ccc(O)c(Cl)c1
Agent: Cl
Product: CON=C(C(=O)O)c1ccc(O)c(Cl)c1

Procedure:
2-(3-Chloro-4-hydroxyphenyl)glyoxylic acid (6.45 g.) and O-methylhydroxylamine hydrochloride (2.74 g.) were reacted according to a similar manner to that of Preparation 5-(3)(a) to give oil of 2-methoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (a mixture of syn and anti isomers) (7 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:11]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH:34]([CH3:36])[CH3:35]>CN(C=O)C.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:33][CH:34]([CH3:36])[CH3:35])[C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:11]1
Reactant: O=C(Nc1ccn(Cc2c(O)cccc2Cl)n1)c1c(F)cccc1F
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)COc1cccc(Cl)c1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.3 %

Procedure:
To a solution of N-{1-[(2-chloro-6-hydroxyphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide (for as preparation see Intermediate 11)(37 mg, 0.102 mmol) in DMF (1 ml) was added potassium carbonate (18 mg, 0.13 mmol) and then 1-bromo-2-methylpropane (0.014 ml, 0.132 mmol, Aldrich). The suspension was stirred at ambient temperature overnight. A further amount of potassium carbonate (7 mg, 0.05 mmol) and then 1-bromo-2-methylpropane (0.014 ml, 0.132 mmol, Aldrich) was added to the suspension. The suspension was stirred at ambient temperature for a further 4 h. The suspension was diluted with methanol (0.5 ml) and then filtered through a cotton wool plug. The filtrate was purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid) (Method A). The solvent was evaporated in vacuo to give the title compound as a colourless gum (4 mg); LCMS: (System 1) MH+=420, tRET=3.63 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[C:20]([F:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[C:18]([F:26])=[C:17]([F:27])[C:14]=1[CH2:15]Br>CN(C=O)C>[CH3:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:15][C:14]2[C:17]([F:27])=[C:18]([F:26])[C:19]([C:22]([F:23])([F:25])[F:24])=[C:20]([F:21])[C:13]=2[F:12])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(N)cc1C(=O)O
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Solvent: CN(C)C=O
Product: Cc1ccc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)cc1C(=O)O
Yield: 26.2 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 5-amino-2-methylbenzoic acid (2.06 g 15.0 mmole), DMF (60 ml), TEA (4 ml), and 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl bromide (5.52 ml, 17.7 mmole), 1.50 g (27.0% yield) of 2-methyl-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([CH3:15])=[CH:7][C:6]=1[Si:16](Cl)([CH3:18])[CH3:17])[CH:2]=[CH2:3].[CH3:20][CH:21]1[S:25][C:24]2=[C:26]([Li])[C:27]3[S:28][C:29]([CH3:32])=[CH:30][C:31]=3[C:23]2=[CH:22]1>C1(C)C=CC=CC=1.O1CCCC1>[CH2:1]([O:4][C:5]1[C:10]([C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:9][C:8]([CH3:15])=[CH:7][C:6]=1[Si:16]([C:26]1[C:27]2[S:28][C:29]([CH3:32])=[CH:30][C:31]=2[C:23]2[C:24]=1[S:25][CH:21]([CH3:20])[CH:22]=2)([CH3:17])[CH3:18])[CH:2]=[CH2:3]
Reactant: [Li]C1=C2SC(C)C=C2c2cc(C)sc21
Reactant: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)C1=C2SC(C)C=C2c2cc(C)sc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of (2-allyloxy-3-tert-buyl-5-methylphenyl)chlorodimethylsilane (0.71 g, 2.40 mmol) in toluene (4 mL) was added dropwise to a solution of (2,5-dimethylcyclopenta[1,2-b:4,3-b′]dithiophen-7-yl)lithium (0.51 g, 2.40 mmol) in tetrahydrofuran (10 mL) at −78° C. The resulting reaction mixture was warmed to room temperature and stirred for 5 hours. After the solvent was distilled off under reduced pressure, hexane was added and the mixture was filtered to remove insoluble substances. The filtrate was concentrated under reduced pressure to quantitatively obtain (2-allyloxy-3-tert-butyl-5-methylphenyl)(2,5-dimethylcyclopenta[1,2-b:4,3-b′]dithiophen-7-yl)dimethylsilane.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]([F:16])([F:15])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[CH3:17][O:18][C:19]([C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=1)=[O:20].[OH-].[Na+]>N1C=CC=CC=1>[F:5][C:6]([F:16])([F:15])/[C:7](=[N:27]\[C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][N:24]=1)[C:19]([O:18][CH3:17])=[O:20])/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccnc(N)c1
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccnc(/N=C(/c2ccccc2)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
Thionyl chloride (2.2 ml) was added at 0° C. to a pyridine (4.8 ml) solution of 2,2,2-trifluoro-1-phenylethanone (5.1 g) and 2-aminopyridine-4-carboxylic acid methyl ester (4.5 g). The temperature of the reaction solution was increased to room temperature, and the reaction solution was then stirred for 1 hour. Thereafter, the reaction solution was poured into a 1 N sodium hydroxide aqueous solution, and the mixed solution was then extracted with ethyl acetate. Organic layers were gathered, and the gathered organic layer was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel:eluent; heptane:ethyl acetate=2:1-1:1), so as to obtain the title compound (2.5 g) in the form of a yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]=[CH:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:29][CH:28]=2)[C:12](N2[C@H](CC3C=CC=CC=3)COC2=O)=[O:13])=[CH:6][CH:5]=1.[OH:40]O.[Li+].[OH-]>C1COCC1.O>[CH3:1][O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C@@H:11]([C:12]([OH:13])=[O:40])[C:27]2[CH:32]=[CH:31][C:30]([CH:33]=[CH:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:29][CH:28]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CC(C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccc(C=CC(C)(C)C)cc2)cc1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C[C@@H](C(=O)O)c2ccc(C=CC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 134.8 %

Procedure:
To a stirred solution of the (R)-diastereomer of 4-{3-(4-(R)-Benzyl-2-oxo-oxazolidin-3-yl)-2-[4-(3,3-dimethyl-but-1-enyl)-phenyl)-3-oxo-propyl}-benzoic acid methyl ester (0.43 g, 0.81 mmol) in THF/H2O (20 mL) (3:1) at room temperature were added H2O2 (2.2 mL, 8.1 mmol 35% in H2O) followed by LiOH (40 mg, 1.63 mmol). The reaction mixture was stirred for 3 h, at room temperature, quenched with (0.1 N HCl). The reaction mixture was extracted with ethyl acetate (100 mL) and dried over MgSO4, filtered and concentrated under reduced pressure to afford corresponding acid. The crude product was purified by column chromatography on silica gel, eluting with CH2Cl2/MeOH 2%-15% to afford the title compound (0.4 g, 100%).
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[C:44]([CH3:45])=[CH:43][C:42]([NH:46][C:47](=[O:49])[CH3:48])=[C:41]([S:50]([CH2:53][CH2:54][CH3:55])(=[O:52])=[O:51])[CH:40]=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:40]=[C:41]([S:50]([CH2:53][CH2:54][CH3:55])(=[O:52])=[O:51])[C:42]([NH:46][C:47](=[O:49])[CH3:48])=[CH:43][C:44]=1[CH3:45])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCCS(=O)(=O)c1cc(Br)c(C)cc1NC(C)=O
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CCCS(=O)(=O)c1cc(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c(C)cc1NC(C)=O

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and N-[4-Bromo-5-methyl-2-(propane-1-sulfonyl)-phenyl]-acetamide (Intermediate 230), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:12][CH:11]2[CH2:13][CH:14]=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[OH-:16].[Na+]>CCO.O.[N+]([O-])([O-])=O.[Ag+]>[F:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:12][CH:11]2[CH2:13][C:14]([OH:16])=[O:15])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C2CC2CC=O)cc1F
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C2CC2CC(=O)O)cc1F
Reaction time: 3 h
Yield: 79.6 %

Procedure:
[2-(3-Fluoro-4-methoxy-phenyl)-cyclopropyl]-acetaldehyde (0.088 g, 0.42 mmol) obtained in Step C was dissolved in EtOH (2 mL). AgNO3(0.143 g, 0.84 mmol) dissolved in water (0.26 mL) and NaOH (0.067 g, 1.69 mmol) dissolved in water (0.26 mL) was added thereto in turn, and the mixture was stirred for 3 hours. After the termination of the reaction, the reactant was filtered by using celite to remove solid material, and 1N HCl aqueous solution was added to adjust the pH of the solution to 2. The organic layer obtained by the extraction with EtOAc was separated, dried with MgSO4, and concentrated under reduced pressure to obtain the title compound (0.075 g, 79%).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=O)[N:10]=2)=CC=1.[N:44]1[CH:45]=[N:46][N:47]2[CH2:52][CH2:51][NH:50][CH2:49][C:48]=12>>[N:44]1[CH:45]=[N:46][N:47]2[CH2:52][CH2:51][N:50]([CH2:21][C:20]3[CH:23]=[C:16]([C:11]4[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([NH2:8])[N:10]=4)[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)=[N:18][CH:19]=3)[CH2:49][C:48]=12
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: c1nc2n(n1)CCNC2
Product: COc1ccc(Nc2ncc(CN3CCn4ncnc4C3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was synthesized following an analogous procedure to Example 220 using 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (178 mg, 0.308 mmol) and 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine (GeneTech, Indianapolis, Ind.) (57.4 mg, 0.462 mmol). 1H NMR (400 MHz, CDCl3) δ 11.70 (s, 1H); 8.78 (d, J=2.54 Hz, 1H); 8.36 (d, J=2.74 Hz, 1H); 8.25 (d, J=2.35 Hz, 1H); 8.10 (dd, J=8.80, 2.74 Hz, 1H); 7.87 (s, 1H); 6.78 (d, J=8.61 Hz, 1H); 5.59 (s, 2H); 4.20 (t, J=5.38 Hz, 2H); 3.94 (s, 3H); 3.84 (s, 2H); 3.73 (s, 2H); 3.00 (t, J=5.48 Hz, 2H); 2.56 (s, 3H). m/z (ESI, +ve ion) 445.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6][C:7]1[N:12]=[C:11](O)[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)[CH3:2].P(Cl)(Cl)([Cl:23])=O>>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6][C:7]1[N:12]=[C:11]([Cl:23])[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)[CH3:2]
Reactant: CCOC(=O)CSc1nc(O)cc(-c2ccccc2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)CSc1nc(Cl)cc(-c2ccccc2)n1

Procedure:
A solution of 18.0 g of (4-hydroxy-6-phenyl-2-pyrimidinylthio)acetic acid ethyl ester in 200 ml. of phosphorus oxychloride was heated under reflux for 17 hr. The excess phosphorus oxychloride was removed in a rotary evaporator. The residual oil crystallized on standing. Recrystallization from petroleum ether afforded 8.7 g of the title compound, mp. 82°-84°C.
Reaction SMILES: [CH:1]12[O:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)[CH2:2]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].C(Cl)Cl>CC#N>[CH3:32][C:31]([CH3:34])([CH3:33])[C:30](=[O:35])[CH2:29][N:7]1[CH2:8][CH:1]2[O:9][CH:5]([CH2:4][N:3]([CH2:10][CH2:11][CH2:12][NH:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH2:2]2)[CH2:6]1
Reactant: N#Cc1ccc(NCCCN2CC3CNCC(C2)O3)cc1
Reactant: CC(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)C(=O)CN1CC2CN(CCCNc3ccc(C#N)cc3)CC(C1)O2
Yield: 75.4 %

Procedure:
A mixture of 4-{[3-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)propyl]amino}-benzonitrile (Preparation C; 5.73 g, 0.02 mol), K2CO3 (11.05 g, 0.08 mol) in MeCN (300 mL) was treated with 1-chloropinacolone (4.44 g, 0.032 mol). The mixture was stirred at 50° C. overnight before DCM was added and the mixture filtered. The filter cake was then washed with a mixture of DCM and MeCN before the solvent was evaporated from the filtrate. The resulting residue was purified by chromatography on silica, eluting with a gradient of ethyl acetate methanol:ammoniacal methanol (95:5:0 to 95:0:5), to give the title compound (5.8 g, 73.9%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)[N:3]=1.[C:22]1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C[Sn](C)(C)C.C(N(CC)CC)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH3:22][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)[N:3]=1
Reactant: Cc1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)n1
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Pd]
Agent: C[Sn](C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2nc(C)c3c([N+](=O)[O-])cccc32)n1
Temperature: 80 °C
Yield: 394.5 %

Procedure:
A dried flask equipped with a reflux condenser and a nitrogen line was charged with 3-iodo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (100 mg, 0.254 mmol), tri-o-tolylphosphine (15.4 mg, 0.051 mmol), and tris(dibenzylideneacetone)dipalladium (0) (23 mg, 0.025 mmol). The flask was purged with nitrogen and anhydrous DMF (30 mL) and tetramethylstannane (0.04 mL, 0.28 mmol) were added, followed by triethylamine (0.04 mL, 0.30 mmol). The flask was degassed under nitrogen and heated at 80° C. for 6 hours. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted multiple times with DCM and EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was subjected to preparative thin-layer chromatography on silica with 2% MeOH/DCM as eluent to afford 56.8 mg of desired product as a yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH3:21])=[C:15](B(O)O)[CH:16]=1.[F-].[Cs+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([C:13]2[CH:12]=[C:11]([Cl:10])[CH:16]=[CH:15][C:14]=2[O:20][CH3:21])[N:3]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: Clc1cc(Cl)nc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: COc1ccc(Cl)cc1-c1cc(Cl)cc(Cl)n1
Yield: 32.1 %

Procedure:
To a mixture of 2,4,6-trichloropyridine (50 mg, 0.27 mmol), 5-chloro-2-methoxy-phenylboronic acid (54 mg, 0.28 mmol), cesium fluoride (100 mg, 0.66 mmol) in ethylene glycol dimethyl ether (10 ml), degassed with argon, was added tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.026 mmol). The mixture was heated under reflux for 2 hours and filtered through a pad of celite under suction. The filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography eluting with ethyl acetate-hexane (1:9) to provide 2,4-dichloro-6-(5-chloro-2-methoxy-phenyl)-pyridine (25 mg, 32% yield). 1H NMR (acetone-d6) δ 3.95 (s, 3H, CH3), 7.24 (d, 1H, J=8.9 Hz, Ar), 7.49 (dd, 1H, J=8.9 Hz, J=2.8 Hz, Ar), 7.56 (d, 1H, J=2.8 Hz, Ar), 7.94 (d, 1H, J=2.8 Hz, Ar), 8.10 (d, 1H, J=1.6 Hz, Ar).
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][C:23]([C:26]2[N:30]([CH2:31][CH3:32])[N:29]=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(=O)[O-])(C)C.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34].[NH2:5][CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][C:23]([C:26]2[N:30]([CH2:31][CH3:32])[N:29]=[CH:28][CH:27]=2)=[CH:24][CH:25]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCn1nccc1-c1ccc(C(=O)NC(Cc2ccccc2)CN(C(=O)[O-])C(C)(C)C)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1nccc1-c1ccc(C(=O)NC(CN)Cc2ccccc2)s1
Reaction time: 1 h
Yield: 50 %

Procedure:
1,1-Dimethylethyl[2-({[5-(1-ethyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (74 mg, 0.16 mmol) was dissolved in DCM (2 mL) and treated with TFA (1 mL). After 1 h, the solution was concentrated and neutralized through silica using 4% MeOH in DCM (1% NH4OH). The title compound was further purified using reverse-phase HPLC (C18 column: H2O/CH3CN, 40-10%) affording the bis-TFA salt of the title compound (47 mg, 50%) as a white solid: LCMS (ES) m/z 355 (M+H)+, 1H NMR (d4-MeOD, 400 MHz) δ ppm 7.71 (d, J=3.8 Hz, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.34-7.22 (m, 6H), 6.51 (d. J=1.8 Hz, 1H), 4.55 (m, 1H), 4.34 (q, J=7.1 Hz, 2H), 3.22 (dd, J=3.5, 13.1 Hz, 1H), 3.13 (dd, J=10.1, 13.1 Hz, 1H), 3.00 (m, 2H), and 1.42 (t, J=7.1 Hz, 3H).