Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].[N+:8]([C:11]1[CH:30]=[CH:29][C:14]([CH2:15][O:16][C:17]([N:19]2[CH2:27][CH2:26][N+:25]3[C-:21](C(=O)O[N:24]=3)[CH2:20]2)=[O:18])=[CH:13][CH:12]=1)([O-:10])=[O:9]>CC1C=CC=CC=1C>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][O:16][C:17]([N:19]2[CH2:27][CH2:26][N:25]3[N:24]=[C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH:3]=[C:21]3[CH2:20]2)=[O:18])=[CH:29][CH:30]=1)([O-:10])=[O:9]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CC[n+]2noc(=O)[c-]2C1
Reactant: C#CC(=O)OCC
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cc2n(n1)CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C2

Procedure:
Ethyl propiolate (cont. 99%) (8.28 g) was added to the o-xylene (348 mL) solution of 5-(4-nitrobenzyloxycarbonyl)-3-oxo-3a,4,6,7-tetrahydro-3H-2-oxa-1,5-diaza-7a-azoniainden-3a-ide (22.3 g) under a nitrogen atmosphere and refluxed for 16 h. The solution was concentrated under reduced pressure, followed by silica-gel column chromatography 3 times (n-hexane/AcOEt=2/1-1/3). The titled compound was obtained as pale yellow crystals (16.78 g, 64%). Besides, 6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-3,5-dicarboxylic acid 3-ethyl ester 5-(4-nitrobenzyl) ester was obtained as pale yellow crystals (6.18 g, 24%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=O)=[N:10][N:11]([CH3:13])[CH:12]=2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:50][C:51]1[C:66]([F:67])=[CH:65][C:54]2[NH:55][C:56]([CH2:58][CH:59]3[CH2:64][CH2:63][CH2:62][CH2:61][NH:60]3)=[N:57][C:53]=2[CH:52]=1>CN(C=O)C.C(OCC)C>[F:50][C:51]1[C:66]([F:67])=[CH:65][C:54]2[NH:55][C:56]([CH2:58][CH:59]3[CH2:64][CH2:63][CH2:62][CH2:61][N:60]3[C:14]([C:9]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[CH:12][N:11]([CH3:13])[N:10]=3)=[O:16])=[N:57][C:53]=2[CH:52]=1
Reactant: Cn1cc(-c2ccc(F)cc2)c(C(=O)O)n1
Reactant: Fc1cc2nc(CC3CCCCN3)[nH]c2cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc(F)cc2)c(C(=O)N2CCCCC2Cc2nc3cc(F)c(F)cc3[nH]2)n1
Reaction time: 16 h
Yield: 57 %

Procedure:
A solution of 4-(4-fluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (73 mg, 0.33 mmol), HATU (124 mg, 0.33 mmol) and N,N-diisopropylethylamine (0.35 ml) in DMF (6 ml) was stirred at room temperature under argon for 0.5 h. The mixture was then treated with (RS)-5,6-difluoro-2-piperidin-2-ylmethyl-1H-benzoimidazole.2HCl, D20 (105 mg, 0.33 mmol) and stirring, under argon was continued for 16 h. The reaction mixture was diluted with diethyl ether and washed with water (3×), dried (MgSO4) and the solvent removed in vacuo. Chromatography (silica gel, ethyl acetate) afforded the title compound (88 mg, 57%).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[O:5]1[CH2:10][CH2:9][CH2:8][CH:7]=[CH:6]1>C1(C)C=CC=CC=1>[O:5]1[CH:6]=[CH:7][CH2:8][CH:9]([C:1]([Cl:4])=[O:2])[CH2:10]1
Reactant: C1=COCCC1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)C1CC=COC1
Temperature: 60 °C
Reaction time: 5 h
Yield: 56709.5 %

Procedure:
125 g (1.25 mmol) of phosgene gas were introduced over the course of 2.5 hours at 45°-50° C. into a solution of 84 g (1 mol) of 5,6-dihydro-4H-pyran in 50 g of toluene. The mixture was subsequently stirred at 60° C. for a further 5 hours. Work-up was carried out as described in Example 1. Vacuum distillation at 76° C./1 mbar gave 103.9 g (80%) of valuable product.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].C([Li])CCC.[CH3:17][C:18]([CH3:27])([CH2:23][CH2:24][CH2:25][CH3:26])[C:19](OC)=[O:20]>CCCCCC.O1CCCC1>[O:20]=[C:19]([C:18]([CH3:27])([CH3:17])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCCCC(C)(C)C(=O)OC
Reactant: COP(C)(=O)OC
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCC(C)(C)C(=O)CP(=O)(OC)OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 18.4 g. (0.116 moles) dimethyl methylphosphonate (Aldrich) in 200 ml. dry tetrahydrofuran is cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution is added 67.3 ml. of 1.90 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 40 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 10.2 g. (58.1 mmoles) methyl 2,2-dimethylhexanoate is added dropwise at a rate that kept the reaction temperature less than -70°(20 minutes). After 1.0 hour at -78° the reaction mixture is allowed to warm to ambient temperature, neutralized with 10 ml. acetic acid and rotary evaporated to a white gel. The gelatinous material is taken up in 75 ml. water, the aqueous phase extracted with 100 ml. portions of chloroform (3×), the combined organic extracts are backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled (b.p. 80°-85° at 0.05 mm) to give dimethyl 2-oxo-3,3-dimethylheptylphosphonate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:27]=1>C1(C)C=CC=CC=1.CCO.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:33]([O:32][C:28]1[CH:27]=[C:26]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:11][CH:12]=2)[CH:31]=[CH:30][N:29]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)Oc1cc(Br)ccn1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(-c2ccnc(OC(C)(C)C)c2)cc1
Temperature: 75 °C

Procedure:
To a solution of 4-((tert-butoxycarbonylamino)methyl)phenylboronic acid (1 g, 3.98 mmol), potassium carbonate (1.1 g, 7.96 mmol), 4-Bromo-2-(t-butoxy)pyridine (1.1 g, 4.78 mmol) in degassed toluene/EtOH/water (2:1:1) (6 mL) was added [1,1′-Bis (diphenylphosphino)ferrocene]dichloropalladium (II) (0.14 g, 0.199 mmol). The reaction mixture was then heated in the microwave at 75° C. for 30 min. After cooling the mixture, it was purified by silica gel chromatography (eluent: CH2Cl2/ethyl acetate 95:5) to yield tert-butyl 4-(2-tert-butoxypyridin-4-yl)benzylcarbamate (1). MS found for C21H28N2O3 as (M+H)+ 356.8. To the above Boc protected compound (462 mg, 1.3 mmol) in CH2Cl2 (3 mL), 4.0 M HCl dioxane (1.6 mL, 6.5 mmol) was added and stirred at rt for 1 h. The reaction mixture was then diluted with ether and the resulting solids were filtered and washed with ether and dried to give 4-(4-(aminomethyl)phenyl)pyridin-2(1H)-one (2) as hydrochloride salt. C12H12N2O 201.0 (M+1).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=2)[CH:13]=[C:14]([C:16]2[S:20][CH:19]=[N:18][CH:17]=2)[CH:15]=1.CN(C)[CH:34]=[O:35]>O1CCCC1>[CH3:9][C:10]1[CH:15]=[C:14]([C:16]2[S:20][C:19]([CH:34]=[O:35])=[N:18][CH:17]=2)[CH:13]=[C:12]([NH:21][C:22]2[N:27]=[C:26]([C:28]([F:29])([F:31])[F:30])[CH:25]=[CH:24][N:23]=2)[CH:11]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C=O)s2)c1
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 85.2 %

Procedure:
Lithium diisopropylamide (1.8M in tetrahydrofuran, 25 ml, 4.46 mmol) was added dropwise to a cooled −78° C. solution of INTERMEDIATE 4 (500 mg, 1.49 mmol) in tetrahydrofuran (7.5 ml). The mixture was stirred at −78° C. for 35 minutes. N,N-dimethylformamide (230 μl, 2.97 mmol) was added, and the resulting mixture was stirred at −78° C. for 1 hour. The mixture then was quenched at −78° C. by the addition of 1 mL of methanol. The mixture was then warmed to room temperature and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The layers were separated and the aqueous layer was extracted once more with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography (ethyl acetate/hexanes) afforded 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazole-2-carbaldehyde (464 mg, 1.27 mmol, 86% yield) as a yellow solid. ESI: [M+H]+ m/z 365.0.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH:20]1([C@@H:26]([NH2:29])[CH2:27][OH:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>>[CH:20]1([C@@H:26]([NH:29][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH2:27][OH:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: N[C@@H](CO)C1CCCCC1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@@H](CO)C2CCCCC2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (R)-1-cyclohexyl-2-hydroxy-ethylamine and DIEA to give 2-((R)-1-cyclohexyl-2-hydroxy-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 382 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:5]2.[N:27]1([CH2:33][CH2:34][NH2:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[Cl-].[Na+]>CN(C)C=O>[N:27]1([CH2:33][CH2:34][NH:35][C:18]([CH:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:9]3[CH:10]=[C:2]([CH3:1])[CH:3]=[C:4]4[C:8]=3[NH:7][C:6]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:5]4)[CH2:13][CH2:14]2)=[O:20])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: Cc1cc(NC2CCC(C(=O)O)CC2)c2[nH]c(-c3ccccc3)cc2c1
Reactant: NCCN1CCOCC1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1cc(NC2CCC(C(=O)NCCN3CCOCC3)CC2)c2[nH]c(-c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
The compound obtained in Example 55 (30 mg, 0.09 mmol) was dissolved in N,N-dimethyl formamide 5 ml. 2-Morpholine-4-yl-ethylamine (22 mg, 0.17 mmol), EDC (25 mg, 0.19 mmol) and HOBT (18 mg, 0.19 mmol) were added. The mixture was stirred for 8 hours at room temperature. Saturated 1N aqueous sodium chloride solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered. The filtrate was distilled under reduced pressure and purified by column chromatography to give the title compound 40 mg (Yield 100%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:10]([CH2:11][C@H:12]([O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)[C@@H:13]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:33])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[C@H:18]([CH3:24])[CH2:19][CH2:20][C:21](O)=[O:22])[CH2:9]1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+].Cl>O1CCCC1.O.C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:10]([CH2:11][C@H:12]([O:34][CH:35]3[CH2:40][CH2:39][CH2:38][CH2:37][O:36]3)[C@@H:13]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:33])[C@H:14]3[CH2:15][CH2:16][C@@H:17]2[C@H:18]([CH3:24])[CH2:19][CH2:20][CH2:21][OH:22])[CH2:9]1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@@H](OC4CCCCO4)C[C@@H]4C[C@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](CCCO)[C@H]1CC[C@H]2[C@@H]3[C@@H](OC4CCCCO4)C[C@@H]4C[C@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
To a solution of compound (2) (9.80 g; 17.48 mmoles) in anhydrous tetrahydrofuran (250 ml), at -70° C. under magnetic stirring and nitrogen atmosphere, N-methylmorpholine (1.76 g; 17.48 mmoles) and isobutyl chloroformate (2.87 g; 21.0 mmoles) were added. The reaction mixture was left to react for 30 min., the separated solid was then removed by filtration and the filtrate was added to a sodium borohydride solution (1.65 g; 43.6 mmoles) in water (10 ml) kept at -10° C. under magnetic stirring at room temperature, in about 30 min., and the resulting mixture was left to react overnight at r.t. Thereafter the reaction mixture was diluted with ethyl acetate (20 ml) and water (80 ml), acidified with 5% hydrochloric acid and extracted with ethyl acetate (3×50 ml). The combined organic phases were washed with saturated water (1×50 ml), dried over sodium sulfate and concentrated under vacuum. A residue (9.40 g) was obtained which was subjected to flash chromatography on SiO2 (φ=5.5 cm, h=20 cm): eluting with 99/1 chloroform/methanol, 6.8 g of compound (3) were obtained, (71%); 1H-NMR (CDCl3)δ 0,7 (s, 3H, 18-CH3); 0,9-1,0 (m, 6H, 19-CH3, 21-CH3); 2,15-2,3 (s, 1H, --OH); 3,3-4,1 (m, 8H, 3-CH-, 24-CH2 -, 2x-O-CH2 -); 4,4-4,75 (m, 2H, 2x-O-CH-O-).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: NCCCSc1ccncc1
Reactant: CCCCCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC(=O)NCCCSc1ccncc1
Yield: 93.1 %

Procedure:
To a solution of 1.21 g (5.00 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.79 ml (20.0 mmol) of triethylamine in 50 ml of methylene chloride was added 1.02 ml (6.00 mmol) of caproyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with hexane and dried to obtain 1.24 g of the desired compound (84.2%, colorless powder), mp: 48.0°-49.0° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:10](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO>[CH3:10][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCN2
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the indoline product of Example 42 (110 mg, 0.420 mmol) and acetic acid (0.1 mL) in methanol (4 mL), 37% aqueous formaldehyde (0.04 mL, 0.5 mmol) was added dropwise at room temperature. The reaction mixture was stirred at room temperature under nitrogen for 1 h, and then sodium cyanoborohydride (66 mg, 1.05 mmol) was added in portions at room temperature. The mixture was stirred at room temperature under nitrogen for 3 h and then quenched with 2 N NaOH and extracted (3×) with methylene chloride. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, EtOAc/methanol, 10:1) to afford the N-methyl indoline product, Example 41, as a white solid (92 mg, 80%): mp 88-90° C.; 1H NMR (500 MHz, CDCl3) δ7.17-7.28 (m, 5H), 6.59 (d, J=8.0 Hz, 1H), 6.26 (d, J=8.0 Hz, 1H), 4.17 (dd, J=8.5, 5.4 Hz, 1H), 3.62 (d, J=15.0 Hz, 1H), 3.43 (d, J=15.0 Hz, 1H), 3.31 (m, 2H), 2.96 (dd, J=11.3, 5.4 Hz, 1H), 2.82 (m, 2H), 2.70 (s, 3H), 2.54 (dd, J=11.3, 8.5 Hz, 1H), 2.42 (s, 3H); CI MS m/z=279 [C19H22N2+H]+; IR (KBr) 3020, 2940, 2773, 1610, 1487 cm−1; Anal. Calcd for C19H22N2-0.1 H2O: C, 81.45; H, 7.99; N, 10.00. Found: C, 81.21; H, 8.00; N, 9.74.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.[CH3:10][C:11]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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.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.[Pd]>[NH2:9][CH2:8][C:4]1[CH:3]=[C:2]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([CH2:23][N:20]3[CH2:21][CH2:22][N:17]([C:15]([O:14][C:11]([CH3:13])([CH3:12])[CH3:10])=[O:16])[CH2:18][CH2:19]3)[CH:25]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(B(O)O)c2)CC1
Reactant: NCc1cccc(Br)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Temperature: 150 °C
Yield: 83.7 %

Procedure:
To a solution of [(3-bromophenyl)methyl]amine hydrochloric salt (0.556 g, 2.5 mmol) in 1,4-dioxane (15 mL) and H2O (5 mL) was added {3-[(4-{[(1,1-dimethylethyl)-oxy]carbonyl}-1-piperazinyl)methyl]phenyl}boronic acid (1.041 g, 3.25 mmol), Pd(PPH3)4 (0.144 g, 0.125 mmol), and K2CO3 (1.382 g, 10 mmol). This mixture was heated in a microwave oven at about 150° C. for about 15 mins. The organic layer was separated, dried using a Glas-Col evaporator (Sigma-Aldrich), and was then purified by CombiFlash chromatograph to afford the title compound 0.798 g (84%). LC-MS m/z 382 (M+H)+.
Reaction SMILES: [Mg].II.[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:19][C@@H:20]([CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH:21]=[O:22].Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:4]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH:21]([OH:22])[CH:20]([CH3:19])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)CCC[C@H](C)C=O
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: II
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CC(C)CCCC(C)C(O)c1ccc(OCc2ccccc2)cc1
Yield: 47 %

Procedure:
In a 200 ml-volume flask was charged 1.704 g of metallic magnesium. After displacing the atmosphere with nitrogen, a small amount of iodine was added thereto, followed by heating to activate the magnesium. Ten milliliters of tetrahydrofuran (THF) were added thereto, and a mixture comprising 18.5 g of 4-bromophenyl benzyl ether as prepared in Example 1 and 40 ml of THF was added dropwise to the system from a dropping funnel at room temperature over a period of 30 minutes. The reaction was continued at a refluxing temperature of THF for an additional 2.5 hours to prepare a Grignard reagent. To the resulting Grignard reagent was added a mixture of 10.0 g of (S)-2,6-dimethylheptanal and 30 ml of THF at 15° C., followed by allowing the mixture to react for 2 hours while keeping at that temperature. The reaction mixture was treated with diluted hydrochloric acid, neutralized with a sodium bicarbonate aqueous solution, and washed with water to obtain 21.8 g of a crude product. Purification by silica gel column chromatography (eluent: benzene) yielded 11.8 g (theoretical yield: 47%) of the entitled compound as a viscous yellow liquid.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([OH:25])=[C:20]([CH3:26])[CH:19]=1>>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[CH:19]=[C:20]([CH3:26])[C:21]([OH:25])=[CH:22][C:23]=3[CH3:24])=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(O)c(C)cc1N
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Product: Cc1cc(NC(=O)c2cc(NC3CCCCC3)ncn2)c(C)cc1O

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-amino-2,5-dimethylphenol (Aldrich), the title compound was obtained as a white solid yield after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([N:12]2[CH:16]=[C:15]([C:17]3[C:18]4[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=4[N:20]=[CH:21][N:22]=3)[CH:14]=[N:13]2)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.O1CCOCC1.CCN(C(C)C)C(C)C.[C:49]1([SH:55])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>[C:49]1([S:55][C:2]2[CH:3]=[C:4]([CH:8]([N:12]3[CH:16]=[C:15]([C:17]4[C:18]5[CH:25]=[CH:24][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:19]=5[N:20]=[CH:21][N:22]=4)[CH:14]=[N:13]3)[CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(Br)c4)c3)ncnc21
Reactant: Sc1ccccc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)c4cncc(Sc5ccccc5)c4)c3)ncnc21
Yield: 80.1 %

Procedure:
To the 3-(5-bromopyridin-3-yl)-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (0.130 g, 0.000248 mol) from Example 429 Step 2, in dry 1,4-dioxane (1.60 mL, 0.0205 mol) was added DIPEA (0.085 mL, 0.00049 mol). The solution was degassed with nitrogen, followed by addition of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.007 g, 0.00001 mol), is(dibenzylideneacetone)palladium(0) (0.0036 g, 0.0000062 mol), and benzenethiol (0.025 mL, 0.00025 mol). Again the solution was purged with nitrogen. The reaction mixture in a sealed tube was heated to reflux for 3 h. The reaction mixture was diluted with ethyl acetate, washed with water (2×), brine (1×), dried over magnesium sulfate, filtered, and the solvent was evaporated in vacuo. The crude product was triturated with hexane-ethyl acetate 9:1 to yield 3-[5-(phenylthio)pyridin-3-yl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (110 mg, 80%). LC/MS (M+H)+: m/z=554.2.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:46])[CH:6]([N:18]1[CH2:23][CH2:22][N:21]([C:24](=[O:42])[CH:25]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH:20]([CH2:43][O:44][CH3:45])[CH2:19]1)[CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=1.Cl>C1COCC1.O>[C:38]([O:37][C:35]([NH:34][CH:25]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:24]([N:21]1[CH2:22][CH2:23][N:18]([CH:6]([CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)[C:5]([OH:46])=[O:4])[CH2:19][CH:20]1[CH2:43][O:44][CH3:45])=[O:42])=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: COCC1CN(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCC1CN(C(Cc2ccc3ccccc3c2)C(=O)O)CCN1C(=O)C(Cc1ccc(F)cc1)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 100 %

Procedure:
LiOH (0.71 g, 29.7 mmol) is added to the cold solution of 2-{4-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-methoxymethyl-piperazine-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester, 63, (3.6 g, 5.9 mmol) in THF/H2O (2/1, 60 mL). The reaction mixture is stirred for overnight. The reaction mixture is cooled in ice bath and pH is adjusted to 3 with 1M HCl. The aqueous layer is extracted with EtOAc (3×100 mL) and dried over Na2SO4. The solution is concentrated in vacuo to afford 3.7 g 100% yield) of the desired product.