Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6](S(C2C=NC=CC=2)(=O)=O)[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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>[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[C:2]1[NH:6][CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:3]=1
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1cc(F)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CN(Cc1c[nH]c(-c2cc(F)ccc2F)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (2,5-difluorophenyl)boronic acid (220 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (220 mg), the title compound was obtained as a colorless oil (yield 135 mg, 60%).
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[N+](=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)[CH3:13]
Reactant: OCC1CC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCCCCCC
Product: CCOC(=O)COCC1CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 85.7 %

Procedure:
To a solution of cyclopropylmethanol (720 mg, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixture is stirred at rt for 5 min. The reaction mixture is diluted with heptane, filtered through celite, and the filtrate is evaporated and the residue is vacuum distilled at 150° C. to give 1.22 g of the product 462. 1H NMR (CDCl3) δ 4.2 (q, 2H), 4.09 (s, 2H), 3.37 (d, 2H), 1.27 (t, 3H), 1.09 (m, 1H), 0.2t6-0.51 (m, 2H), 0.25-0.2 (m, 2H); MS: m/z 191 (M+)
Reaction SMILES: [Br:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][C:7]=1[Cl:15].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:43][CH2:44][C:45]1[C:46]([OH:53])=[N:47][C:48]([CH3:52])=[CH:49][C:50]=1[CH3:51]>O.ClCCl.C(N(CC)CC)C>[Br:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:43][CH2:44][C:45]2[C:46]([OH:53])=[N:47][C:48]([CH3:52])=[CH:49][C:50]=2[CH3:51])=[O:12])=[CH:8][C:7]=1[Cl:15]
Reactant: N#Cc1c(Br)cccc1Oc1ccc(C(=O)O)cc1Cl
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2ccc(Oc3cccc(Br)c3C#N)c(Cl)c2)c(O)n1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A mixture of 4-(3-bromo-2-cyanophenoxy)-3-chlorobenzoic acid (1 g, 2.8 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.08 g, 5.7 mmol), N-hydroxybenzotriazole (769 mg, 5.7 mmol), triethylamine (0.1 mL) and dichloromethane (5 mL) was stirred at 25° C. for half an hour. And then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (430 mg, 2.8 mmol) was added. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (10 mL) was added and the mixture was extracted with dichloromethane (10 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 4-(3-bromo-2-cyanophenoxy)-3-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide as a white solid (1.1 g, 83%). LRMS (M+H+) m/z: calcd 485.01. found 485. 1H NMR (300 MHz, d6-DMSO): δ 11.44 (s, 1H), 8.52 (s, 1H), 8.12 (s, 1H), 7.90-7.87 (m, 1H), 7.61-7.52 (m, 2H), 7.37 (d, J=6.0 Hz, 1H), 6.86 (d, J=6.3 Hz, 1H), 5.82 (s, 1H), 4.25 (s, 2H), 2.45 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)[CH:19]=1)=[O:13].CCN(CC)CC.C(OC([N:46]1[CH2:51][CH2:50][CH:49]([C:52](O)=[O:53])[CH2:48][CH2:47]1)=O)(C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CS(C)=O.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:28]=[N:27][N:26]([CH:29]([CH3:31])[CH3:30])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([C:52]([CH:49]3[CH2:50][CH2:51][NH:46][CH2:47][CH2:48]3)=[O:53])[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCNCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C(=O)C4CCNCC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Reaction time: 8 h
Yield: 83 %

Procedure:
N-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.) was dissolved in DMSO, to which Et3N (3 equiv.) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2 equiv.) were added to it. The reaction mixture was stirred at room temperature for 15 min before PYBOP (1.5 equiv.) was added to it and stirring was continued overnight. After completion of the reaction, water was added to it. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure to afford crude material which was taken up in purified by column chromatography. The Boc protecting group was removed using standard conditions to give the desired compound (83% yield). LCMS: 532.35 (M+1)+; HPLC: 99.04% (@ 254 nm) (Rt; 5.006); 1H NMR (DMSO-d6, 400 MHz) δ 11.54 (bs, 1H), 8.83 (t, 1H), 8.47 (bs, 1H), 8.30 (s, 1H), 8.26 (bs, 1H), 7.86 (s, 1H), 6.92 (bs, 1H), 5.89 (s, 1H), 5.21-5.18 (m, 1H), 4.38 (d, 2H, J=4 Hz), 4.22 (bs, 2H), 3.75 (m, 2H), 3.32 (m, 3H), 2.96 (m, 2H), 2.80 (bs, 1H), 2.67 (bs, 1H), 2.20 (s, 3H), 2.12 (s, 3H), 1.84-1.73 (m, 4H), 1.51 (d, 6H, J=6.8 Hz).
Reaction SMILES: [CH2:1]1[CH:10]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][NH:2]1.[Cl:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:35][CH3:36])=[C:27]([O:30][CH2:31][CH2:32][CH2:33]Cl)[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH:15]=[CH:16][C:17]=1[F:18].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CN(C=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:35][CH3:36])=[C:27]([O:30][CH2:31][CH2:32][CH2:33][N:2]4[CH2:3][CH2:4][CH:5]5[CH:10]([CH2:9][CH2:8][CH2:7][CH2:6]5)[CH2:1]4)[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: C1CCC2CNCCC2C1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2CCCCC2C1
Temperature: 80 °C
Yield: 48.7 %

Procedure:
A mixture of decahydroisoquinoline (200 mg, 1.44 mmol, 1 eq), N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (570 mg, 1.44 mmol, 1 eq) and K2CO3 (238 mg, 1.70 mmol, 1.2 eq) in DMF (15 mL) was heated at 80° C. overnight and cooled to room temperature. To this, 100 mL of CH2Cl2 was added, the mixture was washed with brine (20 mL×3) and water (20 mL×2). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo and the residue was chromatographed with a silica gel column (20:1 (v/v) CH2Cl2/MeOH) to afford the title compound as a yellow solid (350 mg, 49.00%), HPLC: 90.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 499.2 (M+1); 1H NMR (CDCl3, 400 MHz) δ: 1.27-1.59 (12H, m), 1.80-1.82 (2H, m), 2.07-2.33 (2H, m), 2.40-2.51 (2H, m), 3.22-3.26 (2H, m), 4.22-4.24 (2H, m), 7.14-7.16 (1H, m), 7.23 (1H, s), 7.47 (1H, s), 7.65-7.69 (1H, m), 8.00-8.02 (1H, m), 8.64 (1H, s) ppm.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[Cl-].C[Al+]C.CO[C:12]([C:14]1[S:18][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:16][C:15]=1[CH2:25][O:26][CH3:27])=[O:13]>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:12]([C:14]1[S:18][C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:16][C:15]=1[CH2:25][O:26][CH3:27])=[O:13]
Reactant: CNOC
Reactant: COCc1nc(-c2ccccc2)sc1C(=O)OC
Agent: C[Al+]C
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Product: COCc1nc(-c2ccccc2)sc1C(=O)N(C)OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
A solution of N,O-dimethylhydroxylamine hydrochloride (13.3 g, 136.3 mmole, 6.0 eq) in dry CH2Cl2(250 ml) at 0° C. was treated dropwise with neat dimethylaluminum chloride (12.7 ml, 136.3 mmole, 6.0 eq) and the resulting mixture stirred at 0° C. for 2 hours then allowed to warm to RT. To this mixture was added dropwise a solution of the above-prepared 4-methoxymethyl-2-phenyl-thiazole-5-carboxylic acid methyl ester (5.98 g, 22.71 mmole, 1.0 eq) in CH2Cl2 (20 ml). The yellow mixture was then stirred at room temperature under nitrogen for one hour and re-cooled to 0° C. The mixture was quenched slowly by adding 2.0N NaOH dropwise, warmed to room temperature, and extracted with two portions of CH2Cl2. The organic phase was washed successively with 1.0N NaOH and brine, dried over MgSO4, and concentrated in vacuo to give a yellow oil. Silica gel chromatography eluting with (4:1) hexanes-ethyl acetate to give 6.5 g (97%) of the title compound as a yellow waxy crystalline solid. 1H NMR (CDCl3): δ 3.35 (s, 3H), 3.5 (s, 3H), 3.7 (s, 3H), 4.95 (s, 2H), 7.4-7.5 (m, 3H), 8.0 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([C:8]2(O)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(N(CC)CC)C.Cl.CN(C)C.S(Cl)(C)(=O)=O>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([C:8]2[CH2:13][CH2:12][O:11][CH2:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1C1(O)CCOCC1
Agent: CN(C)C
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(Br)cnc1C1=CCOCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.8 %

Procedure:
4-(5-Bromo-3-methylpyridin-2-yl)-tetrahydro-2H-pyran-4-ol (2.95 g), triethylamine (3 ml) and trimethylamine monohydrochloride (103 mg) were suspended in toluene (50 ml), mesyl chloride (1.26 ml) was added thereto under ice-cooling, then warmed to room temperature, and stirred for 72 hours. After completion of the reaction, water was added thereto, extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The obtained residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give the titled compound (2.39 g) as a white solid. MS (ESI) m/z: 254, 256 (M+H)+.
Reaction SMILES: [Cl:1]C1C=C[C:5]([C@H:8](C(C)C)[C:9]([S:11][CH2:12][C@:13]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])([OH:20])[CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=O)=[CH:4]C=1.[OH-].[K+].C(Br)CCC>CO>[CH2:9]([S:11][CH2:12][C@:13]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28])([OH:20])[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)[CH2:8][CH2:5][CH3:4].[ClH:1]
Reactant: CC(C)[C@H](C(=O)SC[C@](O)(Cn1ccnc1)c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCBr
Product: CCCCSC[C@](O)(Cn1ccnc1)c1ccc(Cl)cc1Cl
Product: Cl
Reaction time: 2 h
Yield: 601.4 %

Procedure:
To a suspension of (R)-3-[(S)-2-(4-chlorophenyl)isovalerylthio]-2-(2,4-dichlorophenyl)-1-(imidazol-1-yl)-2-propanol (VIb) (49.5 g) obtained in Example 1 in methanol (500 ml) were added a 10% methanolic potassium hydroxide solution (240 g) and n-butylbromide (21.6 g) at -5° to 0° C. in nitrogen atmosphere. The slurry was stirred at the same temperature for 2 hours and then at 30° C. for 3 hours. Methanol was removed by distillation under atmospheric pressure, and the residue was treated with water (200 ml) and extracted with 1,2-dichloroethane (200 ml). The extract was washed successively with water and 12% hydrochloric acid (200 ml) and concentrated in vacuo. To the residue were added toluene (100 ml) and methyl ethyl ketone (35 ml), and the slurry was stirred at 15° C. for 3 hours. Filtration and drying in vacuo gave a crude product (25.7 g), which was recrystallized from methyl ethyl ketone to give (R)-3-(n-butylthio)-2-(2,4-dichlorophenyl)-1-(imidazol-1-yl)-2-propanol (I: n=3) hydrochloride (21.8 g) as colorless needles. Yield, 55%. M.P., 168.5°-170° C. [α]D20 -89.8° (c=1, methanol).
Reaction SMILES: [Na].[NH:2]1[CH:6]=[N:5][CH:4]=[N:3]1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.O.C(OCC)(=O)C>CN(C=O)C>[N:2]1([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(-n2cncn2)cc1
Yield: 72.5 %

Procedure:
1,2,4-Triazole sodium derivative (90%) (17.74 g, 0.18 mol) and 1-fluoro-4-nitrobenzene (25 g, 0.18 mol), in DMF, (150 ml) was stirred at room temperature for 4 days. Water (300 ml) and ethyl acetate (500 ml) were added and the mixture extracted. The organic layer was separated, washed with water (3×300 ml), dried (MgSO4) and evaporated to give the desired product (24.8 g); δ (360 MHz, CDCl3) 7.92 (2H, d, J=9.1 Hz, Ar--H); 8.17 (1H, s, Ar--H); 8.40.(2H, d, J=9.1 Hz, Ar--H); 8.48 (1H, s, Ar--H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=2[O:21][CH3:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:23]I>>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=2[O:21][CH3:22])[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CI
Reactant: COc1cccc(Nc2nc(Cl)nc3ccccc23)c1OC
Product: COc1cccc(N(C)c2nc(Cl)nc3ccccc23)c1OC

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(2,3-dimethoxy-phenyl)-amine and methyl iodide by a procedure similar to example 36 (71% yield). 1H NMR (CDCl3): 7.74 (d, J=8.4 Hz, 1H), 7.53-7.59 (m, 1H), 7.12 (t, J=8.4 Hz, 1H), 6.94-7.01 (m, 3H), 6.87 (dd, J=8.1 and 1.5 Hz, 1H), 3.89 (s, 3H), 3.56 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.C([O-])([O-])=O.[K+].[K+].[CH2:30]([CH:32]1[O:34][CH2:33]1)Cl>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:30][CH:32]3[CH2:33][O:34]3)=[CH:21][CH:22]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(O)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(OCC2CO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
To a solution of 2-(2,6-difluorophenyl)-5-(4-hydroxyphenyl)oxazole-4-carboxamide (0.100 g, 0.316 mmol) in DMF (5 ml) was added K2CO3 (0.066 g, 0.474 mmol). The resulting mixture was stirred at room temperature for 30 minutes, after which time epichlorohydrin (0.044 g, 0.474 mmol) was added. The reaction was heated to 100° C., stirred at this temperature for 2 h and then diluted with EtOAc before being washed with water and brine. Drying over Na2SO4 and removal of solvent under vacuum gave 2-(2,6-difluorophenyl)-5-(4-(oxiran-2-ylmethoxy)phenyl)oxazole-4-carboxamide (0.102 g, 0.274 mmol, 87%) as a golden oil. LCMS (1) 2.00 min; m/z (ES+) 374.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[C:10](=[O:15])[NH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.Br[C:24]1[NH:28][CH:27]=[N:26][N:25]=1.C(OCC)C>CO>[N:25]1[N:26]=[C:27]([N:19]2[CH2:20][CH2:21][CH2:22][C@@H:17]([NH:16][C:3]3[C:2]([F:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]4[C:10](=[O:15])[NH:11][CH:12]=[CH:13][CH:14]=4)[N:4]=3)[CH2:18]2)[NH:28][CH:24]=1
Reactant: O=c1[nH]cccc1Nc1ncc(F)c(N[C@@H]2CCCNC2)n1
Reactant: Brc1nnc[nH]1
Solvent: CO
Solvent: CCOCC
Product: O=c1[nH]cccc1Nc1ncc(F)c(N[C@@H]2CCCN(c3nnc[nH]3)C2)n1
Temperature: 150 °C
Yield: 40.4 %

Procedure:
A mixture of (R)-3-(5-fluoro-4-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridin-2(1H)-one (Preparation 22c, 50 mg, 0.16 mmol) and 3-bromo-4H-1,2,4-triazole (prepared as described in J. Med. Chem. 2004, 47(19), 4645, 12.2 mg, 0.08 mmol) was stirred and heated overnight at 150° C. The reaction mixture was cooled to ambient temperature and diluted with methanol. Diethyl ether was then added and the precipitate that formed was filtered. The filtrate was concentrated under reduced pressure and the resulting semisolid was suspended in diethyl ether and filtered to yield the title compound (12 mg, 40%) as a yellow solid.
Reaction SMILES: C1(S([NH2:10])(=O)=O)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].[CH:17]1([N:23]=[C:24]=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CC(C)=O.O1CCOCC1.O>[CH:17]1([NH:23][C:24](=[O:25])[NH2:10])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C=NC1CCCCC1
Reactant: NS(=O)(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)NC1CCCCC1
Reaction time: 6 h

Procedure:
7.6 g of 4-(β-<1-butyl-1,2-dihydro-2-oxo-nicotinamido>-ethyl)-benzenesulfonamide (melting point 162 - 163° C, prepared from 4-(β-aminoethyl)-benzenesulfonamide and 1-butyl-1,2-dihydro-2-oxo-nicotinic acid chloride in chloroform/soda solution) in 100 ml acetone and 50 ml dioxane were refluxed for 3 hours while stirring together with 5.5 g of pulverized potash. 2.5 g cyclohexyl isocyanate were then added and stirring was continued for 6 hours with reflux. After cooling, the reaction mixture was diluted with water, filtered and the filtrate acidified with 2N hydrochloric acid. The formed precipitate was filtered off with suction, dissolved in dilute ammonia and reprecipitated with dilute hydrochloric acid and finally recrystallized from methanol. The N-[4-(β-<1-butyl-1,2-dihydro-2-oxo-nicotinamido>-ethyl benzenesulfonyl]-N'-cyclohexyl urea obtained melted at 178 - 179° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[N:11]1[C:15](=[O:16])[CH2:14][S:13]/[C:12]/1=[N:17]\[C:18]([NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[CH:32][N:31]([C:34]3[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=3)[N:30]=2)=[CH:25][CH:24]=1)=[O:19])([CH3:3])[CH3:2].C1C(=O)C=CC2C=1C=C1C=2C=CC=C1.[B-](F)(F)(F)[F:60].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:60][CH:14]1[S:13]/[C:12](=[N:17]\[C:18]([NH:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[N:33]=[CH:32][N:31]([C:34]4[CH:35]=[CH:36][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:38][CH:39]=4)[N:30]=3)=[CH:27][CH:28]=2)=[O:19])/[N:11]([C:5]2[CH:6]=[C:7]([CH3:10])[CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])[C:15]1=[O:16]
Reactant: F[B-](F)(F)F
Reactant: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)NCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=C1C=CC2=c3ccccc3=CC2=C1
Solvent: CC#N
Product: Cc1ccc(C(C)C)c(N2C(=O)C(F)S/C2=N\C(=O)NCCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To (Z)-1-(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)-3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)urea (F5) (0.050 g, 0.080 mmol) and 2-fluorenone (0.0080 g, 0.044 mmol) in anhydrous acetonitrile (0.80 mL) was added Selectfluor® (0.062 g, 0.18 mmol). The reaction was stirred at room temperature overnight. Purification by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent provided the title compound as a yellow oil (0.033 g, 63%).
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:13][CH2:14]O>>[CH2:13]([O:11][C:10](=[O:12])[C@@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:1])[CH3:14]
Reactant: CCO
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Product: CCOC(=O)[C@H](N)Cc1ccccc1
Yield: 81 %

Procedure:
D-Phenylalanine (250 mg, 1.52 mmol) was dissolved in 5 ml EtOH previously bubbled in HCl (gas). The solution was brought to 100° C. and allowed to reflux overnight. The solvent was evaporated off affording 280 mg crude product. Recrystallization from EtOH/EtOAc/pentane gave 239 mg (81% yield) of D-phenylalanine ethyl ester as white crystals.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:11][C:12]1[CH:17]=[CH:16][C:15](CC(Cl)=O)=[CH:14][CH:13]=1.Cl.C([O:26][CH2:27][CH3:28])(=O)C>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:27]([CH2:28][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:26])=[CH:16][CH:17]=1
Reactant: c1ccccc1
Reactant: CCOC(C)=O
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(Cc1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 84 %

Procedure:
Benzene (200 mL) and aluminum chloride (74 g, 0.558 mol) are mixed into a flask and the mixture of 4-bromophenylacetyl chloride and benzene in Step (a) is added dropwise allowing the reaction to evolve HCl. The reaction mixture is stirred at room temperature for 1 to 1.5 hours and poured into ice water. Ethyl acetate (1 L) is added to dissolve the precipitated solids. The layers are separated and the organic layer is washed successively with 1 M aqueous HCl, saturated aqueous NaHCO3, brine and then dried over Na2SO2. The solvent is then evaporated to give a solid material which is recrystallized from ethylacetate/hexanes to give the title compound in 84% yield as a yellow solid.
Reaction SMILES: C(O[C:5]1[O:6][CH2:7][C:8](=[O:16])[C:9]=1[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])(C)C.C(OC(C)C)(=O)CC(OC(C)C)=O.ClCC(Cl)=O.[NH2:35][CH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.[NH:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][N:50]=2)[C:45]([CH:52]=O)=[CH:44]1.N1CCCCC1>CC(O)C>[NH:43]1[C:51]2=[N:50][CH:49]=[CH:48][CH:47]=[C:46]2[C:45]([CH:52]=[C:7]2[O:6][C:5]([NH:35][CH2:36][CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[C:9]([C:10]([O:12][CH:13]([CH3:14])[CH3:15])=[O:11])[C:8]2=[O:16])=[CH:44]1
Reactant: CC(C)OC(=O)C1=C(OC(C)C)OCC1=O
Reactant: NCC1CCCCC1
Reactant: O=Cc1c[nH]c2ncccc12
Agent: CC(C)OC(=O)CC(=O)OC(C)C
Agent: O=C(Cl)CCl
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: CC(C)OC(=O)C1=C(NCC2CCCCC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 20 %

Procedure:
A solution of isopropyl 2-isopropoxy-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.44 mmol) which similarly prepared according to the procedure described in the Example 74, Third step using diisopropyl malonate and chloroacetyl chloride, and aminomethylcyclohexane (0.063 mL, 0.48 mmol) in 2-propanol (2.0 mL) was stirred at ambient temperature for 14 h. To this reaction mixture, 7-azaindole-3-carboxaldehyde (0.065 g, 0.44 mmol) and piperidine (0.0044 mL, 0.044 mmol) were added then the mixture was refluxed for further 8 days. Cooled to ambient temperature, the reaction mixture was purified by preparative HPLC to afford the titled compound as solid (0.036 g, y. 19%).