Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[O:4][CH2:5][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1>ClCCl.O=[Pt]=O>[CH3:1][C@@H:2]1[NH:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][O:4][C:3]1=[O:14]
Reactant: CC1=N[C@@H](c2ccccc2)COC1=O
Agent: O=[Pt]=O
Solvent: ClCCl
Product: C[C@@H]1NC(c2ccccc2)COC1=O
Reaction time: 5 h
Yield: 73.2 %

Procedure:
To a solution of (5S)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one (1.70 g, 9.0 mmol, 1.0 equiv.) in anhydrous dichloromethane (60 mL) under an atmosphere of nitrogen was added PtO2 (170 mg, 0.1 equiv.). The mixture was consecutively degassed and purged three times with hydrogen and then stirred for 5 hours under an atmosphere of hydrogen. Filtration through a short pad of CELITE® diatomaceous earth and removal of solvent from the filtrate in vacuo yielded the crude product which was purified by recrystallisation in dichloromethane, diethyl ether and hexane to furnish the title compound as white needles (1.26 g, 74%); m.p. 81.0-82.0° C. (lit. m.p. 81.0-82.0° C.); v(max)(KBr) 3314 (N—H), 2981 (C—H), 1736 (C═O), cm−1; δH (250 MHz, CDCl3) 7.43-7.26 (5H, m, Ph); 4.42-4.23 (3H, m, CHCl2), 3.88 (1H, q, /6.76 Hz, CHCH3), 1.80 (1H, br, NH), 1.50 (3H, d, J 6.76 Hz, CH3); δc (62.5 MHz, CDCl3) 170.7, 138.1, 129.3, 129.1, 127.5, 75.4, 58.2, 55.4, 19.0; m/z (CL, NH3), 192 (MH+, 30%), 147 (68%), 132 (64%), 104 (100%), and 91 (10%); HRMS for C11H13NO2 requires 192.1025 found 192.1019. [α]D20 +88.8 (c 0.96 CHCl3) (lit. [α]D20 +92.3 (c 0.84 CHCl3)).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH2:24][CH3:25])[C:17](=[O:23])[N:18]([CH2:21][CH3:22])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[NH2:6].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:52][C:53]1[CH:61]=[CH:60][CH:59]=[C:58]([CH3:62])[C:54]=1[C:55](O)=[O:56].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:2][O:3][C:4](=[O:27])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:26])[N:16]([CH2:24][CH3:25])[C:17](=[O:23])[N:18]([CH2:21][CH3:22])[C:19]=2[CH3:20])=[CH:12][CH:13]=1)[NH:6][C:55]([C:54]1[C:58]([CH3:62])=[CH:59][CH:60]=[CH:61][C:53]=1[Cl:52])=[O:56]
Reactant: CCn1c(C)c(-c2ccc(C[C@H](N)C(=O)OC)cc2)c(=O)n(CC)c1=O
Reactant: Cc1cccc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(C)c(-c2ccc(C[C@H](NC(=O)c3c(C)cccc3Cl)C(=O)OC)cc2)c(=O)n(CC)c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.9 %

Procedure:
To a suspension of 4-(1,3-diethyl-6-methyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester hydrochloride salt (0.758 mmol, 300 mg), HBTU (0.84 mmol, 318 mg) and 2-chloro-6-methylbenzoic acid (0.84 mmol, 142 mg) in DMF (2 mL) was added diisopropylethylamine (1.9 mmol, 0.33 mL) at room temperature. After 5 min, everything went into solution and the clear yellow solution was stirred for 48 h at room temperature. The resulting dark-brown solution was diluted with ethyl acetate (30 mL). The ethyl acetate layer was washed successively with 1N hydrochloric acid (2×30 mL), saturated sodium bicarbonate solution (30 mL), and brine solution (30 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave the crude product which was purified by silica gel chromatography using a Biotage (40m) column to afford 380 mg (98% yield) of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3-diethyl-6-methyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C27H30ClN3O5 (M+Na) 535.1026, found 535.1024.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](Cl)[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]([NH:24][C:23]2[CH:22]=[CH:21][C:20]([N:17]3[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]3)=[CH:26][CH:25]=2)[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: NC(=O)c1cc(F)c(Cl)nc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(Nc3nc(Cl)c(C(N)=O)cc3F)cc2)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 32.8 %

Procedure:
To a mixture of 2,6-dichloro-5-fluoronicotinamide (1 g, 4.78 mmol) and 4-(4-methylpiperazin-1-yl)aniline (1.007 g, 5.26 mmol) in THF (30 mL) was added lithium bis(trimethylsilyl)amide (16.75 mL, 16.75 mmol) portionwise at −78° C. The mixture was stirred at −78° C. for 20 min and then removed from the dry ice bath. Next, the mixture was stirred at rt for 30 min. Two isomeric products were formed. The reaction mixture was quenched with water, extracted with ethyl acetate twice, washed the combined organic with water, and concentrated. The dark brown residue was triturated with methylene chloride, to give 570 mg of 2-chloro-5-fluoro-6-(4-(4-methylpiperazin-1-yl)phenylamino)nicotinamide as light brown solid. The mother liquor was concentrated and triturated again with methylene chloride to give 540 mg of 6-chloro-5-fluoro-2-(4-(4-methylpiperazin-1-yl)phenylamino)nicotinamide as brown solid. The mother liquor was purified twice by mPLC (ISCO, 7% ammonia/methanol/methylene chloride, 40 g+12 g stacked columns) to give an additional 490 mg of 6-chloro-5-fluoro-2-(4-(4-methylpiperazin-1-yl)phenylamino)nicotinamide as brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH:10]=O)=[C:4]([O:12][CH2:13][C:14]#[CH:15])[CH:3]=1.[O-]S([O-])(=O)=O.[Mg+2].[CH3:22][N:23]([CH3:25])[NH2:24]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH:10]=[N:24]/[N:23]([CH3:25])[CH3:22])=[C:4]([O:12][CH2:13][C:14]#[CH:15])[CH:3]=1
Reactant: C#CCOc1cc(Br)ccc1/C=C/C=O
Reactant: CN(C)N
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: C#CCOc1cc(Br)ccc1/C=C/C=N/N(C)C
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A solution of (E)-3-(4-bromo-2-(prop-2-ynyloxy)phenyl)acrylaldehyde (2.85 g, 10.8 mmol) in dichloromethane (200 mL) containing anhydrous MgSO4 (16 g) was cooled in an ice bath with stirring. To the ice-cold solution was added 1,1-dimethylhydrazine (2.45 mL, 32.4 mmol) dropwise and the reaction mixture was allowed to warm up to ambient temperature and was stirred for 18 h. The volatiles were concentrated under reduced pressure and the residue was coevaporated sequentially with dichloromethane (50 mL), dichloroethane (50 mL) and heptane (50 mL). (E)-2-((E)-3-(4-bromo-2-(prop-2-ynyloxy)phenyl)allylidene)-1,1-dimethylhydrazine (2.7 g, 8.79 mmol, 90% yield, 90% purity) was obtained as a yellow powder. 1H NMR (500 MHz, CDCl3) δ 7.39 (d, J=7.9 Hz, 1H), 7.20-7.10 (m, 3H), 7.00-6.86 (m, 2H), 4.75 (d, J=2.3 Hz, 2H), 2.95 (s, 6H), 2.58 (t, J=2.3 Hz, 1H); LCMS (Method B) (ESI) m/e 307.0, 309.0 Br pattern [(M+H)+, calcd for C14H15BrN2O 307.0].
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)=[CH:12][CH:11]=1)[CH2:2]2.CC(O)=O.[Br:27]N1C(=O)CCC1=O>CC#N>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]1[N:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([Br:27])[CH:17]=3)=[CH:12][CH:11]=1)[CH2:2]2
Reactant: Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)nn2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CC(=O)O
Product: Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)nn2)cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The product of Example 29F (150 mg, 0.5 mmol) was treated with HOAc (36 μL, 36 mg, 0.6 mmol) in MeCN (5 mL) at ambient temperature for 5 min. N-bromosuccinimide (Aldrich, 100 mg, 0.55 mol) in MeCN (5 mL) was then added to the above solution at 0° C. and stirred at 0° C. for 1 h. It was then concentrated under reduced pressure. The title compound was purified by preparative HPLC (Xterra™, column, Xterra RP-18 5 μm, 30×100 mm. Eluting Solvent, MeCN/H2O (NH4HCO3, 0.1 M, pH=10) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) (100 mg, yield, 53%). 1H NMR (300 MHz, CD3OD) δ 1.45-1.65 (m, 1H), 1.65-1.94 (m, 2H), 1.93-2.16 (m, 1H), 2.19-2.39 (m, 1H), 2.67-3.11 (m, 5H), 3.37-3.54 (m, 1H), 5.18-5.35 (m, 1H), 6.91 (d, J=8.5 Hz, 1H), 7.19 (d, J=9.2 Hz, 1H), 7.70 (dd, J=8.5, 2.0 Hz, 1H), 7.95 (d, J=9.5 Hz, 1H), 8.03 (d, J=2.0 Hz, 1H) ppm. MS (DCl/NH3): 375 (M+H)+, 377 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([OH:32])[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].Cl>C(O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][C:19]2([OH:32])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(O)CCNCC1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
To a solution of tert-butyl 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate (prepared as described in Part E of Example 4, 14.94 g, 33.91 mmol) in ethanol (170 mL) was added a solution of HCl in ethanol (2.7 M, 31 mL, 84.7 mmol). The solution was heated at reflux for 1 h, during which time a precipitate formed. The mixture was allowed to cool to rt and the volatiles were removed under reduced pressure. To the residue was added water (400 mL) followed by 50% aqueous NaOH until the pH=10. The solution was extracted with dichloromethane (3×100 mL). The aqueous layer was treated with 50% aqueous NaOH until the pH=12, then was extracted with dichloroemethane (2×100 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting solid was triturated with hot ethyl acetate and the remaining solid was isolated by filtration to afford 4-{[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidin-4-ol (7.0 g, 61%) as an off-white powder.
Reaction SMILES: [S:1]1[CH2:6][S:5][CH2:4][S:3][CH2:2]1.C([Li])CCC.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=[O:14]>O1CCCC1>[O:21]([C:18]1[CH:17]=[CH:16][C:15]([C:13]([CH:2]2[S:3][CH2:4][S:5][CH2:6][S:1]2)([OH:14])[CH3:12])=[CH:20][CH:19]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C1SCSCS1
Reactant: CC(=O)c1ccc(Oc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)(c1ccc(Oc2ccccc2)cc1)C1SCSCS1
Temperature: -60 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
In 30 ml of anhydrous tetrahydrofuran was suspended 2.6 g of 1,3,5-trithiane, and 12 ml of 1.6M n-butyl lithium was added dropwise under an argon atmosphere at a temperature of about -20° C. After completion of the dropwise addition, the resulting mixture was stirred for 2 hours. Next, the reaction mixture was cooled to about -60° C., and then a solution of 4.0 g of 4-phenoxyacetophenone dissolved in 10 ml of tetrahydrofuran was dropped thereinto. After completion of the dropping, the reaction temperature was slowly raised to 0° C. The mixture thus obtained was stirred at 0° C. for another 1 hour. Thereafter, the same treatment as in Example 1 was carried out to obtain a crude product, which was then purified by a silica gel column chromatography (chloroform) to give 3.4 g of the desired compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][N:11]1[C:15]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)=[N:14][CH:13]=[N:12]1.[NH2:25][C@@H:26]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46]([F:49])([F:48])[F:47])[CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[O:37]=[C:36]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:38])[N:28]1[CH2:27][C@@H:26]([NH:25][C:20](=[O:22])[C:19]1[CH:18]=[CH:17][C:16]([C:15]2[N:11]([CH3:10])[N:12]=[CH:13][N:14]=2)=[CH:24][CH:23]=1)[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46]([F:48])([F:47])[F:49]
Reactant: Cn1ncnc1-c1ccc(C(=O)O)cc1
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncnc1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
Hunig's base (0.084 ml, 0.48 mmol) was added to a suspension of 4-(1-methyl-1H-1,2,4-triazol-5-yl)benzoic acid (39.3 mg, 0.19 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (62 mg, 0.16 mmol), and PyBroP (75 mg, 0.16 mmol) in DCM (1 ml). The reaction mixture became clear and was stirred at RT overnight. The reaction mixture was loaded directly on a 25S Biotage column, which was eluted with 50-100% EA/DCM to give 67.3 mg of product. LC-MS (ES) m/z=534 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:36](I)C>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1
Reactant: CCI
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F

Procedure:
The title compound was prepared in an analogous manner to that described for 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) with the following notable exception: ethyl iodide was used instead of methyl iodide in the procedure outlined in step B. MS (M+H, ES+) 506.
Reaction SMILES: [CH3:1][Mg:2][Br:3].[O:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[O:10][CH2:11][C:12](=[O:21])[CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1.[CH2:22](OCC)C>>[CH3:1][Mg:2][Br:3].[CH3:22][C:12]([OH:21])([CH2:13][O:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[CH2:11][O:10][CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][O:4]1
Reactant: O=C(COC1CCCCO1)COC1CCCCO1
Reactant: CCOCC
Agent: C[Mg]Br
Product: CC(O)(COC1CCCCO1)COC1CCCCO1
Reaction time: 16 h

Procedure:
A solution of 0.14 moles of methylmagnesium bromide in diethyl ether was prepared by dissolving 15.5 g of 3M methylmagnesium bromide solution (in diethyl ether) in 100 ml of specially dried diethyl ether. While stirring at 25°-30° , a solution of 25.8 g of 1,3-bis(2-tetrahydropyranyloxy)-2-propanone, prepared as above, in 100 ml of diethyl ether was added dropwise. A white solid separated and refluxing occurred. The mixture was warmed to maintain reflux for 1 hour, then allowed to stand for 16 hours. Saturated ammonium chloride solution (100 ml) was added very slowly and when addition was completed, the layers were separated. The aqueous layer was extracted (2 × 100 ml) with diethyl ether. The ether solutions were combined, washed (2 × 100 ml) with water and dried over magnesium sulfate. The dried solution was concentrated and distilled to give 16.2 g of 2-methyl-1,3-bis(2-tetrahydropyranyloxy)-2-propanol, b.p. 121°-136°/2--3 × 10- 4 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C.[Cl:28][C:29]1[N:34]=[C:33](Cl)[C:32]([Cl:36])=[CH:31][N:30]=1>CN(C=O)C.CN1C(=O)CCC1>[Cl:28][C:29]1[N:34]=[C:33]([NH:1][C:2]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=2[C:4]([NH:6][CH3:7])=[O:5])[C:32]([Cl:36])=[CH:31][N:30]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CNC(=O)c1cc(C)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(C)ccc1Nc1nc(Cl)ncc1Cl
Yield: 138.3 %

Procedure:
2-Amino-5,N-dimethyl-benzamide (2.0 g, 12.2 mmol), potassium carbonate (2 eq) or diisopropylethylamine (2 eq) and 2,4,5-trichloropyrimidine (2.24 g, 12.2 mmol) were combined in DMF or NMP (25 mL) and heated at 50-100° C. until HPLC indicated consumption of the starting materials. The reaction can either be concentrated in vacuo or directly partitioned between water and dichloromethane. The product is extracted, dried and concentrated to afford the crude material, which is then chromatographed on silica gel (ethyl acetate:hexanes) to afford 2-(2,5-dichloro-pyrimidin-4-ylamino)-5,N-dimethyl-benzamide (5.25 g, 56%) as a light yellow solid. m.p.=192-210° C.; LCMS (m/e) 311 (M+1); 1H-NMR (DMSO-d6, 400 MHz) δ 12.02 (s, 1H), 8.82 (m, 1H), 8.45 (s, 1H), 8.38 (d, 1H, J=8.5 Hz), 7.63 (s, 1H), 7.42 (d, 1H, J=8.5 Hz), 2.80 (d, 3H, J=4.4 Hz), 2.34 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[C:9](#[N:13])[CH:10]([CH3:12])[CH3:11].C([N-]C(C)C)(C)C.[Li+].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:9]([C:10]([CH3:12])([CH3:11])[CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[OH:8])#[N:13]
Reactant: CC(C)C#N
Reactant: O=Cc1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C#N)C(O)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.6 %

Procedure:
3-Pyridinecarboxaldehyde (300 μL, 3.18 mmol) and isobutyronitrile (428 μL, 4.77 mmol) were dissolved in tetrahydrofuran (6.0 mL). To this, lithium diisopropylamide (a 2.0 mmol solution, 2.38 mL, 4.77 mmol) was slowly added dropwise under a nitrogen atmosphere at −78° C. and the mixture was stirred at room temperature for 1 hour. Then, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol 19/1) to give 3-(2-cyano-2-methyl-1-hydroxypropyl)pyridine (Compound CU) (166 mg, yield: 30%).
Reaction SMILES: F[C:2]1[C:3](CC#N)=[N:4][CH:5]=[CH:6][CH:7]=1.F[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[N:13]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1(C)C=CC=CC=1>[F:18][C:14]1[N:13]=[C:12]([C:2]2([C:3]#[N:4])[CH2:7][CH2:6][CH2:5]2)[CH:17]=[CH:16][CH:15]=1
Reactant: Fc1cccc(F)n1
Reactant: N#CCc1ncccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#CC1(c2cccc(F)n2)CCC1
Yield: 64 %

Procedure:
Following the same procedure as above for 2-(3-fluoropyridin-2-yl)acetonitrile with 2,6-difluoropyridine (5.0 g, 43 mmol, 1.0 equiv), cyclobutylcarbonitrile (3.5 g, 43 mmol, 1.0 equiv) and NaHMDS (2.0 M in THF, 24 mL, 47 mmol, 1.1 equiv) in toluene (100 mL) gave the desired product (4.9 g, 64%) as a colorless oil following purification over silica gel using 25% EtOAc/hexanes as eluent.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C@H:5]([CH2:9][C:10]1[C:15]([I:16])=[CH:14][C:13]([O:17]C)=[C:12]([O:19]C)[CH:11]=1)[NH:6][CH:7]=[O:8])[CH3:2].B(Br)(Br)Br>>[CH2:1]([O:3][C:4](=[O:21])[C@H:5]([CH2:9][C:10]1[C:15]([I:16])=[CH:14][C:13]([OH:17])=[C:12]([OH:19])[CH:11]=1)[NH:6][CH:7]=[O:8])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1cc(OC)c(OC)cc1I)NC=O
Agent: BrB(Br)Br
Product: CCOC(=O)[C@H](Cc1cc(O)c(O)cc1I)NC=O

Procedure:
exposing the product of step (2) to BBr3 to form N-formyl-3,4-dihydroxy-6-iodo-L-phenylalanine ethyl ester,
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]([OH:24])[N:8]([C:15]([CH3:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:9]2=[O:14].CN(CCN(C)C)C.C([Li])(CC)C.CCCCCC.[I:44]I>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:11]([I:44])=[C:10]2[C:6]=1[CH:7]([OH:24])[N:8]([C:15]([CH3:16])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:23])[C:9]2=[O:14]
Reactant: II
Reactant: COCOc1cccc2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1ccc(I)c2c1C(O)N(C(C)(C)c1ccccc1)C2=O
Yield: 64.9 %

Procedure:
In a similar manner to Step 3 of Example 16, 4-methoxymethoxy-3-hydroxy-2-(1-methyl-1-phenylethyl)isoindolinone (8.50 mg, 26.0 mmol) was dissolved in THF (340 mL), and the solution was treated with TMEDA (12.5 mL, 83.1 mmol), sec-butyllithium-hexane solution (0.99 mol/L, 8.4.0 mL, 83.1 mmol) and iodine (7.91 g, 31.2 mmol), followed by purification by flash column chromatography (hexane/ethyl acetate=90/10, 70/30) to obtain 4-methoxymethoxy-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (7.65 g, yield 65%).
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C:9]1([CH2:13][NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=3)[N:18]=[C:17]([N:26]3[CH2:32][CH2:31][C:30]([F:34])([F:33])[C:29]4[CH:35]=[CH:36][CH:37]=[CH:38][C:28]=4[CH2:27]3)[N:16]=2)[CH2:12][O:11][CH2:10]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:8][C:9]1([CH2:13][NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=3)[N:18]=[C:17]([N:26]3[CH2:32][CH2:31][C:30]([F:34])([F:33])[C:29]4[CH:35]=[CH:36][CH:37]=[CH:38][C:28]=4[CH2:27]3)[N:16]=2)[CH2:10][O:11][CH2:12]1
Reactant: Cc1ccc2nc(N3CCC(F)(F)c4ccccc4C3)nc(NCC3(N(Cc4ccccc4)Cc4ccccc4)COC3)c2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc2nc(N3CCC(F)(F)c4ccccc4C3)nc(NCC3(N)COC3)c2c1
Yield: 24 %

Procedure:
A solution of N-{[3-(dibenzylamino)oxetan-3-yl]methyl}-2-(5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-6-methylquinazolin-4-amine (190 mg, 0.314 mmol) and trifluororacetic acid (1 drop) in methanol was stirred in the presence of palladium hydroxide on carbon (50 mg) at room temperature under hydrogen atmosphere overnight. The resulting mixture was filtered, concentrated in vacuo. The residue was purified by preparative HPLC to afford 32 mg of the product as a white solid (yield was 24%). MS obsd. (ESI+) [(M+H)+] 426, 1H NMR (400 MHz, CD3OD) δ ppm 7.696 (s, 1 H), 7.654-7.636 (d, J=7.2 Hz, 1 H), 7.607-7.588 (d, J=7.6 Hz, 1 H), 7.404-7.367 (m, 2 H), 7.341-7.283 (m, 2 H), 5.011 (s, 2 H), 4.683-4.626 (m, 2 H), 4.556-4.540 (d, J=6.4 Hz, 2 H), 4.335-4.307 (t, J=5.6 Hz, 2 H), 4.084 (s, 2 H), 5.528-2.432 (m, 2 H), 2.398 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:13]=2[F:22])[C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH3:23][Si](C=[N+]=[N-])(C)C>CO.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:23][O:9][C:8]([C:5]1[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Si:18]([CH3:19])([CH3:21])[CH3:20])=[CH:14][C:13]=2[F:22])=[N:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10]
Reactant: C[Si](C)(C)c1ccc(Nc2nc(Cl)cnc2C(=O)O)c(F)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1ncc(Cl)nc1Nc1ccc([Si](C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a solution of 5-chloro-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-pyrazine-2-carboxylic acid (2.95 g, 8.68 mmol) in methanol (50 mL) and toluene (100 mL) at 0° C. under N2 was added a solution of 2M trimethylsilyldiazomethane in hexanes (9.55 mL, 19.0 mmol, 2.2 eq.), and the reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, water and brine, then dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 0 to 50% ethyl acetate in hexane) to give the desired compound as a yellow solid (2.18 g, 71.1%). 1H NMR (CDCl3, 400 MHz) δ ppm 10.54 (s, 1H), 8.36 (t, J=7.86 Hz, 1H), 8.06 (s, 1H), 7.34-7.26 (m, 2H), 4.05 (s, 3H), 0.28 (s, 9H); LCMS (method D1) RT=1.38 min, [M+H]+=354.