Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O)([CH3:9])([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH2:1]=[C:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: [Li]CCCC
Reactant: CC(C)(C)C1CCCCC1=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C=C1CCCCC1C(C)(C)C
Yield: 44.6 %

Procedure:
Methyltriphenylphosphonium bromide (346 g, 0.97 mole) was suspended in ether (1500 ml) and treated with n-butyllithium (2.5M in ether; 388 ml, 0.97 mole), followed by 2-t-butylcyclohexanone (50 g, 0.324 mole), following the procedure described in Example 12, Part A. The reaction mixture was heated under reflux for 2 days and then worked up in the usual manner. The crude product was fractionated to provide methylene-2-t-butylcyclohexane (22 g), which was pure by GC.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=3)=[O:13])=[C:9]([NH:22][C:23]([C@H:25]3[CH2:30][CH2:29][C@H:28]([N:31]4[CH2:35][CH2:34][CH2:33][C:32]4=[O:36])[CH2:27][CH2:26]3)=[O:24])[C:8]=2[CH:37]=1)(O)=[O:2].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.N1C=CC=CC=1>[N:38]1([C:1]([C:4]2[CH:5]=[CH:6][C:7]3[O:11][C:10]([C:12]([NH:14][C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=4)=[O:13])=[C:9]([NH:22][C:23]([C@H:25]4[CH2:26][CH2:27][C@H:28]([N:31]5[CH2:35][CH2:34][CH2:33][C:32]5=[O:36])[CH2:29][CH2:30]4)=[O:24])[C:8]=3[CH:37]=2)=[O:2])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4=O)CC3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cn1)c1oc2ccc(C(=O)N3CCOCC3)cc2c1NC(=O)[C@H]1CC[C@H](N2CCCC2=O)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Trans-5-carboxy-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (830 mg) obtained in Example 77 is suspended in N,N-dimethylformamide-pyridine (1:1, 30 ml), and thereto are added successively morpholine (196 mg), 1-hydroxybenzotriazole (406 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (576 mg) under ice-cooling, and the mixture is stirred at room temperature for 17 hours. To the reaction solution are poured ice-water and a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with ethyl acetate, washed with water and a saturated brine, and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the resulting residue is purified by NH-silica gel column chromatography (eluent: chloroform). The resulting residue is suspended in ethyl acetate-n-hexane, and the precipitates are collected by filtration, and dried to give the title compound (805 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][C:8]([NH:12][C:13]1[N:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=1)=[CH:7]2.[NH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:49]([O-])(=[O:51])C.[Na+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:19]([C:16]1[N:17]=[CH:18][C:13]([NH:12][C:8]2[N:9]=[CH:10][C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[C:49]([NH:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:51])=[N:14][CH:15]=1)#[N:20]
Reactant: NCCN1CCOCC1
Reactant: N#Cc1cnc(Nc2cc3cccc(Br)c3cn2)cn1
Reactant: CC(=O)[O-]
Agent: [Pd+2]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: N#Cc1cnc(Nc2cc3cccc(C(=O)NCCN4CCOCC4)c3cn2)cn1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 32.5 %

Procedure:
A mixture of 5-(8-bromoisoquinolin-3-ylamino)pyrazine-2-carbonitrile (33 mg, 0.10 mmol), N-(2-aminoethyl)morpholine (26 mg, 0.20 mmol), triphenylphosphine (8 mg, 0.030 mmol), and sodium acetate (3.3 mg, 0.040 mmol) in DMF (1 mL) was degassed by bubbling N2 through the solution for 5 mins. Palladium (II) acetate (6.8 mg, 0.030 mmol) was added and the mixture degassed for a further 5 minutes. Carbon monoxide was then bubbled through the solution for 5 minutes, before the reaction vessel was sealed. The solution was stirred at 80° C. under a balloon of carbon monoxide for 90 minutes and then partitioned between ethyl acetate and aqueous sodium hydrogen carbonate (2.5%). The phases were separated and the aqueous phase washed with ethyl acetate. The combined organic phases were washed with aqueous sodium hydrogen carbonate (2.5%) before being dried (Na2SO4) and then passed sequentially through two PS-Thiol cartridges and concentrated to dryness. Preparative HPLC gave the title compound (5.1 mg, 0.013 mmol, 12%). 1H NMR (d6-DMSO, 400 MHz) δ 11.05 (s, 1H), 9.58 (s, 1H), 8.83 (d, 1H, J=1.2 Hz), 8.73 (d, 1H, J=1.2 Hz), 8.63 (br t, 1H, J=5.8 Hz), 8.56 (s, 1H), 8.00 (d, 1H, J=8.4 Hz), 7.75 (dd, 1H, J=7.1, 8.3 Hz), 7.57 (d, 1H, J=6.8 Hz), 3.62-3.68 (m, 4H), 3.46-3.52 (m, 2H), 2.52-2.58 (m, 2H), 2.46-2.52 (m, 4H, partially obscured by DMSO). LC-MS (2) Rt=1.95 min; m/z (ESI+) 404 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([CH:8]=1)[NH2:7].[C:16](Cl)(=[O:18])[CH3:17]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH:7][C:16](=[O:18])[CH3:17])[CH:8]=1
Reactant: Nc1cc(F)ccc1Oc1ccccc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(F)ccc1Oc1ccccc1
Yield: 91.3 %

Procedure:
5-fluoro-2-phenoxyaniline 3 (5.14 g, 25 mmol) was dissolved in pyridine (15 mL) in a dry flask. At 0° C., acetyl chloride (2.3 mL, 33 mmol) was slowly added to the reaction, which was then refluxed for one hour, and subsequently, concentrated by vacuum. The residue was purified via column chromatography (silica gel) using CHCl3 as the eluent to give N-(5-fluoro-2-phenoxyphenyl)acetamide 4 as white solid (5.6 g, 90%): 1H-NMR (300 MHz, CDCl3) δ 8.29 (dd, J=10.5, 3.0 Hz, 1H), 7.74 (br s, 1H), 7.36 (t, J=7.5 Hz, 2H), 7.15 (t, J=7.5 Hz, 1H), 6.98 (d, J=7.5 Hz, 2H), 6.81 (2d, J=5.4, 5.1 Hz, 1H), 6.70 (2 dd, J1=J2=J3=J4=3 Hz, 1H), 2.17 (s, 3H). MS (GC) m/z 245(M., 100%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[N:17]1>>[CH:9]1([NH:15][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]=[N:17]3)[N:7]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Clc1ccnc(Cl)n1
Reactant: c1ccc2[nH]ncc2c1
Reactant: NC1CCCCC1
Product: c1ccc2c(c1)cnn2-c1nccc(NC2CCCCC2)n1

Procedure:
Was prepared according to Method A from 2,4-dichloropyrimidine, cyclohexylamine and indazole. LC-ESI-HRMS of [M+H]+ shows 294.173 Da. Calc. 294.17187 Da, dev. 3.8 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](S)=[N:7][C:6]=2[CH:11]=1.[CH3:12][N:13]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N:16]3[CH2:17][CH2:18][CH2:19][N:13]([CH3:12])[CH2:14][CH2:15]3)=[N:7][C:6]=2[CH:11]=1
Reactant: Sc1nc2cc(Cl)ccc2o1
Reactant: CN1CCCNCC1
Solvent: Cc1ccccc1
Product: CN1CCCN(c2nc3cc(Cl)ccc3o2)CC1

Procedure:
5-Chloro-2-mercaptobenzoxazole (1 g) was dissolved in toluene (50 ml), N-methylhomopiperazine (3.3 ml) was added dropwise to the solution and then the mixture was stirred with heating for 2 hours. After evaporation of the solvent, the thus obtained mixture was purified by a silica gel column chromatography (methylene chloride:methanol=20:1) to obtain the title compound 5-chloro-2-(4-methyl-1-homopiperazinyl)-benzoxazole (882 mg).
Reaction SMILES: [CH2:1]([C:5]1[O:10][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:7]=2[N:6]=1)[C:2]([CH3:4])=O.[CH3:17][NH:18][NH2:19]>C(O)(=O)C>[CH3:17][N:18]1[C:5]([NH:6][C:7]2[C:8](=[CH:12][CH:13]=[C:14]([CH3:16])[CH:15]=2)[C:9]([OH:10])=[O:11])=[CH:1][C:2]([CH3:4])=[N:19]1
Reactant: CC(=O)Cc1nc2cc(C)ccc2c(=O)o1
Reactant: CNN
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)O)c(Nc2cc(C)nn2C)c1
Yield: 49.3 %

Procedure:
The benzoxazinone of Example 1 (15.31 g., 0.071 mole) was added to a solution of methylhydrazine (3.90 g., 0.085 mole) in acetic acid (150 ml.) and the resultant solution was stirred at 80° C. for 2.5 hours. The solvent was removed and the product was recrystallized (acetonitrile) to yield N-(1,3-dimethyl-5-pyrazolyl)-4-methylanthranilic acid (8.59 g., 49 percent), mp 188°-192° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:15][CH2:14][NH:13][C:12]2=[N:16][N+:17]([O-:19])=[O:18])=[CH:6][N:5]=1.[H][H].[CH:22](Br)([CH3:24])[CH3:23]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:15][CH2:14][N:13]([CH:22]([CH3:24])[CH3:23])[C:12]2=[N:16][N+:17]([O-:19])=[O:18])=[CH:6][N:5]=1
Reactant: CC(C)Br
Reactant: [H][H]
Reactant: O=[N+]([O-])N=C1NCCN1Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCN(Cc2ccc(Cl)nc2)C1=N[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.4 g of sodium hydride 60% in oil was added portion wise to a solution of 2.6 g of 1-(2-chloro-5-pyridylmethyl)-2-nitroiminoimidazolidine in 20 ml of dry dimethylformamide. The mixture was stirred at room temperature until the evolution of hydrogen ceased. A solution of 1.5 g of isopropyl bromide in 5 ml of dry dimethylformamide was added dropwise to the mixture at room temperature and stirred for 3 hours at room temperature after the addition. The reaction mixture was then poured into ice water, and the precipitated crystals filtered. This was recrystallized from ethanol to give 1-(2-chloro-5-pyridylmethyl)-3-isopropyl-2-nitroiminoimidazolidine. The yield was 1.5 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[CH:17][C:16]3[CH2:15][CH2:14][CH2:13][C:12](=[O:19])[C:11]=3[N:10]=2)=[CH:5][CH:4]=1.[Br:20]Br>Br>[Br:20][CH:13]1[C:12](=[O:19])[C:11]2[N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:18]=[CH:17][C:16]=2[CH2:15][CH2:14]1
Reactant: COc1ccc(-c2ncc3c(n2)C(=O)CCC3)cc1
Reactant: BrBr
Agent: Br
Product: COc1ccc(-c2ncc3c(n2)C(=O)C(Br)CC3)cc1

Procedure:
2-(4-Methoxy-phenyl)-6,7-dihydro-5H-quinazolin-8-one (300 mg; 1.2 mmol) in 48% HBr (30 ml) is treated drop-wise with Br2 (189 mg; 1.2 mmol) dissolved in 48% HBr (0.8 ml). The reaction mixture is heated to 350 C for 10 minutes, poured on NaHCO3/water (20 g/100 ml) and extracted with TBME three times. The organic phases are combined, dried over Na2SO4 and evaporated to dryness, yielding the desired product as brown-yellow crystals. 1H-NMR (400 MHz; DMSO-d6): 9.08 (s, 1H); 8.33 (d, 2H); 7.10 (d, 2H); 5.22 (m, 1H); 3.84 (s, 3H); 3.07 (m, 2H); 2.73 (m, 1H); 2.45 (m, 1H). MS (m/z) ES+: 335, 333 (MH+); 255 (80).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:18][O:19]C(Cl)Cl>[N+](CC)([O-])=O.ClC(Cl)C>[CH2:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=1[CH:18]=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1ccccc1
Reactant: COC(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC[N+](=O)[O-]
Solvent: CC(Cl)Cl
Product: CCCCCCCc1ccccc1C=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 87.7 g of n-heptylbenzene in a mixture of 160 ml of nitroethane and 480 ml of dichloroethane was added little by little 79.5 g of anhydrous aluminum chloride with ice cooling, followed by adding dropwise a solution of 54.5 ml. of dichloromethyl methyl ether in 60 ml of dichloroethane. After completion of the addition, the reaction was carried out at 0° C. for a further one hour. The reaction mixture was poured into ice water and extracted with chloroform. The organic layer was washed with water and dried, and the solvent was evaporated. The residue was chromatographed on silica gel column with a solvent of n-hexane - isopropyl ether (10:1) to give 17.3 g of 2-heptylbenzaldehyde as a colorless oil from the first eluted fractions and 64.8 g of 4-heptylbenzaldehyde as a colorless oil from the later eluted fractions.
Reaction SMILES: [CH3:1][NH2:2].[Br:3][CH:4]([CH2:16][Br:17])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](O)=[O:14])=[N:11][CH:12]=1.S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH3:1][NH:2][C:13](=[O:14])[C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][CH:4]([Br:3])[CH2:16][Br:17])=[CH:12][N:11]=1
Reactant: CN
Reactant: O=C(O)c1ccc(CCC(Br)CBr)cn1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1ccc(CCC(Br)CBr)cn1
Temperature: 8 °C

Procedure:
According to the same method as Example 1 with cooling 30% aqueous methylamine solution (100 ml) was added to the chloroform solution (200 ml) of acid chloride prepared from 10 g of 5-(3,4-dibromobutyl)picolinic acid and 10 ml of thionyl chloride, and stirred at 8°C for an hour. Chloroform layer which was separated, was washed with 0.3% aqueous hydrochloride solution, 5% aqueous sodium bicarbonate solution, and then water. Chloroform was evaporated in reduced pressure to yield 8.7 g of crude product as oil. To purify the product, above crude product was chromatographed on silicagel using ethylacetate as developing solvent. The pure product was viscous oil and showed only one spot (Rf 0.60) on TLC (silicagel; ethylacetate, IR (liquid film) 1670 cm-1, UV λmaxMeOH 268 nm.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10](=[O:28])[N:11]([CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:14]=1)#[N:2].C(N(CC)CC)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)(Cl)Cl>[C:36]([N:25]1[CH2:24][CH2:23][CH:22]([CH2:21][N:11]2[CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:14]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])[C:10]2=[O:28])[CH2:27][CH2:26]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(CC2CCNCC2)c1=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(CC2CCN(C(=O)c3ccccc3)CC2)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.1 %

Procedure:
30 mg of 3-(2-cyanophenyl)-1-(piperidin-4-yl)methyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one was dissolved in 2 ml of chloroform. Under ice-cooling, 0.04 ml of triethylamine and 19 mg of benzoyl chloride were added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was diluted with chloroform, and washed with a saturated aqueous solution of sodium hydrogen carbonate and brine. The organic layer was dried over magnesium sulfate, and then evaporated and the residue was purified by silica gel chromatography (ethyl acetate/hexane), to give 25 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:16])=[C:4]([CH3:15])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[C:7](=[O:12])[C:6]=2[C:13]=1[CH3:14].[C:17]([CH2:21][C:22](Cl)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.O>ClCCl>[CH3:18][C:17]([CH3:20])([CH3:19])[CH2:21][C:22]([NH:1][C:2]1[C:3]([CH3:16])=[C:4]([CH3:15])[C:5]2[O:9][C:8]([CH3:10])([CH3:11])[C:7](=[O:12])[C:6]=2[C:13]=1[CH3:14])=[O:23]
Reactant: Cc1c(C)c2c(c(C)c1N)C(=O)C(C)(C)O2
Reactant: CC(C)(C)CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(=O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a solution of 5-amino-2,2,4,6,7-pentamethyl-1-benzofuran-3 (2H)-one obtained in Reference Example 57 (3.00 g, 13.7 mmol) and tert-butylacetyl chloride (2.03 g, 15.1 mmol) in dichloromethane (30 mL) was added triethylamine (2.3 mL, 16.4 mmol) at room temperature, and the mixture was stirred at room temperature for 30 minutes. Water was added to the residue to separate the organic layer, and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with 1 N hydrochloric acid and a saturated sodium hydrogen carbonate solution, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain the targeted product 2.34 g (yield 54%). Melting point: 155-156° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10](/[C:13](/[C:21](=[O:24])[CH:22]=[CH2:23])=[CH:14]\[CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[OH:25][CH:26]([C:31]1[CH:32]=[CH:33][C:34]([CH:37]=[O:38])=[N:35][CH:36]=1)[C:27]([OH:30])([CH3:29])[CH3:28].C(N(CC)CC)C.O1CCCC1>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10](/[C:13](=[CH:14]\[CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)/[C:21](=[O:24])[CH2:22][CH2:23][C:37]([C:34]3[CH:33]=[CH:32][C:31]([CH:26]([OH:25])[C:27]([OH:30])([CH3:28])[CH3:29])=[CH:36][N:35]=3)=[O:38])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: C=CC(=O)/C(=C/C1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CC(C)(O)C(O)c1ccc(C=O)nc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(O)C(O)c1ccc(C(=O)CCC(=O)/C(=C/C2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)nc1
Yield: 10.8 %

Procedure:
A mixture of (1E)-2-[4-(cyclopropylsulfonyl)phenyl]-1-(tetrahydro-2H-pyran-4-yl)penta-1,4-dien-3-one (4.16 g), 5-(1,2-dihydroxy-2-methylpropyl)pyridine-2-carbaldehyde (2.58 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (0.32 g), triethylamine (0.84 mL), tetrahydrofuran (10 mL) and ethanol (10 mL) was stirred with heating under reflux for 2 hr. The reaction mixture was concentrated, and the residue was subjected to basic silica gel column chromatography, and the title compound (0.70 g, yield 79%) was obtained as yellow crystals from a fraction eluted with ethyl acetate. melting point 102-104° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:21]([NH:28][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[C:9]([Cl:10])[C:2]=1[Cl:1])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccc(-c2cccc3ccccc23)c(Cl)c1Cl
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Clc1c(CNCc2ccccc2)ccc(-c2cccc3ccccc23)c1Cl
Reaction time: 2 h

Procedure:
A solution of Example 5B (65 mg, 0.22 mmol) and benzylamine (0.024 mL, 0.22 mmol) in 1,2-dichloroethane (3 mL) at room temperature was treated with acetic acid (0.05 mL, 0.84 mmol), stirred for 2 hours, treated with sodium triacetoxyborohydride (64 mg, 0.31 mmol), stirred for 16 hours, and treated with saturated NaHCO3. The organic layer was dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 2:1 hexanes/ethyl acetate to ethyl acetate to provide the desired product. MS (ESI(+)) m/z 393 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ7.92 (d, 2H), 7.56-7.46 (m, 3H), 7.45-7.26 (m, 9H), 4.05 (s, 2H), 3.93 (s, 2H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH3:44])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([N:35]3[C:39]4=[N:40][CH:41]=[CH:42][CH:43]=[C:38]4[CH:37]=[CH:36]3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:45](OC1C(C(O)=O)=NC(CC2(N3C4=NC=CC=C4C=C3)CCCC2)=NC=1O)[C:46]1C=CC=C[CH:47]=1.[Si](OCCNC1CCC1)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH:44]1[CH2:47][CH2:46][CH2:45]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([N:35]3[C:39]4=[N:40][CH:41]=[CH:42][CH:43]=[C:38]4[CH:37]=[CH:36]3)[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: O=C(O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)(C)[Si](C)(C)OCCNC1CCC1
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1)C1CCC1

Procedure:
5-Benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclobutyl-amide (425) was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (405) from 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (8f) (140 mg, 0.32 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclobutyl-amine (108 mg, 0.47 mmol) to get a white sticky solid (200 mg, 97%, impure).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].C(N(CC)CC)C.[CH2:31]([N:37]=[C:38]=[O:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C1COCC1>[O:22]=[C:16]1[CH:15]([N:8]2[C:7](=[O:23])[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([CH2:3][NH:2][C:38]([NH:37][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:39])[CH:5]=3)[N:10]=[C:9]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: CCCCCCN=C=O
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCNC(=O)NCc1ccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.50 g, 1.5 mmol) and triethylamine (0.29 mL, 2.1 mmol) in THF (12 mL) at 5˜10° C., was added hexyl isocyanate (0.25 g, 1.9 mmol), and the mixture was stirred at room temperature overnight. The mixture was quenched with methanol (−1 mL), and the solvent was evaporated. The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-hexyl-urea as an off-white solid (410 mg, 65% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.05 min (99.0%); mp, 220-222° C.; 1HNMR (DMSO-d6) δ 0.85 (t, J=6 Hz, 3H, CH3CH2CH2), 1.24-1.38 (m, 8H, CH2CH2CH2CH2), 2.15-2.20 (m, 1H, CHH), 2.56-3.03 (m, 6H, CHCH2, CHO, 4.30 (d, J=6 Hz, 2H, ArCH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 5.97 (t, J=5 Hz, 1H, CH2NH), 6.40 (t, J=6 Hz, 1H, ArCH2NH), 7.55-7.89 (m, 3H, Ar), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.88, 20.93, 22.05, 23.38, 26.03, 29.94, 30.63, 31.02, 39.35, 42.44, 56.51, 119.96, 123.46, 126.40, 133.81, 139.87, 145.64, 154.36, 157.99, 160.46, 169.47, 172.60. LCMS MH=428; Anal Calcd For C22H29N5O4: C, 61.81; H, 6.84: N, 16.38. Found: C, 61.50; H, 6.82; N, 16.23.