Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[CH2:2]([O:9][C:10]([CH3:14])([CH:12]=C)[CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:16].[Na+]>[Os](=O)(=O)(=O)=O.O1CCOCC1>[CH2:2]([O:9][C:10]([CH3:11])([CH3:14])[CH:12]=[O:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=CC(C)(C)OCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
A mixture of 100 mL of water, 200 mL of dioxane, 20 g (0.11 mol) of 2-benzyloxy-2-methyl-3-butene and 1 g of osmium tetroxide was stirred at room temperature for 30 minutes then 51 g (0.22 mol) of finely ground sodium periodate was added in portions over 30 minutes. Stirring was continued for 2 hours then the mixture filtered and the filtrate extracted with several portions of ether. The combined extracts were dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. Distillation afforded 7.3 g (0.041 mol, 37%) of product, b.p. 85°-88° C. (2 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:16](I)[CH3:17]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:16][CH3:17])[CH:10]=[CH:11][C:12]=2[CH3:13])=[CH:6][CH:7]=1
Reactant: CCI
Reactant: Cc1cc[nH]c1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc(C)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
A solution of 2-(4-chlorophenyl)-3-methyl-1H-pyrrole (prepared according to the procedure given in Tetrahedron Letters 46 (2005) 4539-4542, 1.0 g, 5.22 mmol) in DMF (10 ml) was added dropwise to a stirred suspension of Sodium hydride (0.23 g, 5.74 mmol, 60% dispersion in mineral oil) in 20 ml DMF at 0° C. under a nitrogen atmosphere. The reaction mixture was then stirred at about 0° C. for 30 min. Ethyl iodide (0.89 g, 0.47 ml, 5.74 mmol) was then added to the reaction mixture maintaining the temperature at 0° C. The reaction mixture was then stirred at 25° C. for 3 hrs. The progress of the reaction was monitored by TLC. The reaction mixture was slowly quenched with cold water (30 ml) and the resulting mixture was then extracted with ethyl acetate (2×30 ml). The combined organic layer was then washed with brine (lx 30 ml) and dried over sodium sulfate. The dried organic layer was then concentrated under reduced pressure to obtain crude product as semi-solid mass (0.8 g), which was then purified by flash column chromatography using 5% ethyl acetate in hexanes as an eluent to obtain the title compound (0.6 g, 52.3%).
Reaction SMILES: COC[O:4][C:5]1[CH:45]=[CH:44][C:8]2[CH:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][S:33][CH2:34][CH2:35][CH2:36][C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39])[C:10]([C:14]3[CH:19]=[CH:18][C:17]([O:20]COC)=[CH:16][CH:15]=3)([CH3:13])[CH2:11][O:12][C:7]=2[CH:6]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CO>[OH:4][C:5]1[CH:45]=[CH:44][C:8]2[CH:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][S:33][CH2:34][CH2:35][CH2:36][C:37]([F:43])([F:42])[C:38]([F:39])([F:40])[F:41])[C:10]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)([CH3:13])[CH2:11][O:12][C:7]=2[CH:6]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCSCCCC(F)(F)C(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 66.1 %

Procedure:
(3RS,4RS)-7-Methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylthio)nonyl]-2,3-dihydro-4H-benzopyran (100 mg, 0.15 mmol) and pyridinium p-toluenesulfonate (380 mg, 1.5 mmol) were dissolved in methanol (5 ml) and refluxed for 4 hours. The reaction solution was cooled to room temperature and, after adding water, extracted with ethyl acetate. The extracted organic layer was dried over magnesium sulfate and concentrated. The residue was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to obtain 57 mg (yield: 66%) of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28]C(=O)OC(C)(C)C)[CH2:23]2)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=3[F:20])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.[ClH:43]>C(Cl)Cl>[ClH:43].[NH2:28][C@@H:24]1[CH2:25][CH2:26][CH2:27][N:22]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:21])[C:13]4[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=4[F:20])[C:4]=23)[CH2:23]1
Reactant: Cc1ccc(F)c(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)c1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)c(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](N)C4)c23)c1
Yield: 61 %

Procedure:
A solution of (R)-tert-butyl 1-(5-bromo-3-(2-fluoro-5-methylbenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (120 mg, 0.22 mmol) in DCM (3 mL) was treated with TFA followed by 1M HCl as described in Example 62, Step C, to provide (R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-fluoro-5-methylbenzamide hydrochloride (0.070 g, 61% yield). 1H NMR (400 MHz, D2O) δ 8.17 (s, 1H), 7.50-7.48 (m, 1H), 7.45 (s, 1H), 7.33-7.30 (m, 1H), 7.09-7.04 (m, 1H), 3.50-3.48 (m, 1H), 3.31-3.29 (m, 2H), 3.18-3.13 (m, 1H), 3.06-3.03 (m, 1H), 1.86-1.82 (m, 1H), 1.68-1.64 (m, 1H), 1.43-1.41 (m, 2H); LCMS (APCI+) m/z 446, 448 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)([CH3:3])[CH3:2].Br[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[I-].[Na+].C(OCC)(=O)C>CN(C)C=O>[C:18]([CH2:17][CH2:16][CH2:15][CH2:14][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=[C:4]1[CH:1]([CH3:3])[CH3:2])([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CCCCBr
Reactant: CC(C)c1nc2ccccc2[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCn1c(C(C)C)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Part A. Sodium hydride (1.62 g of a 50% slurry, 33.8 mmol) was washed with hexane and dried under vacuum. Dimethylformamide (50 mL) was added, followed by a solution of 2-isopropyl-1H-benzimidazole (5.41 g, 33.8 mmol) in dimethylformamide (15 mL). After stirring at ambient temperature for two hours, the mixture was treated with ethyl 5-bromovalerate (5.50 mL, 34.8 mmol) and sodium iodide (1.19 g, 7.94 mmol). The mixture was heated to 80° C. for 18 hours, then cooled and poured into ethyl acetate (200 mL). This was washed with water (4×200 mL), then brine (200 mL), and dried over anhydrous magnesium sulfate, filtered and evaporated. The product, 1-(4-carboethoxybutyl)-2-(1-methylethyl)-1H-benzimidazole, was obtained as an oil after purification by silica gel chromatography (1:2 ethyl acetate-hexane) (9.54 g, 33.1 mmol, 98%). 1H NMR (CDCl3): 7.75 (1H, dd, J= 5.6, 3.1 Hz); 7.34-7.19 (3H, m); 4.12 (2H, q, J=7.1 Hz); 1.92-1.80 (2H, m); 1.78-1.65 (2H, m); 1.45 (6H, d, J=6.6 Hz); 1.24 (3H, t, J=7.0 Hz).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[NH2:17].C([BH3-])#N.[Na+].C(O)(=O)C>CC1C=CC=CC=1C.C(OCC)(=O)C>[CH3:13][C:14]1[CH:15]=[C:16]([NH:17][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=2)[CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22]
Reactant: Cc1cc(N)ccc1[N+](=O)[O-]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: Cc1cc(NCc2ccc(C(F)(F)F)cc2)ccc1[N+](=O)[O-]
Temperature: 140 °C
Yield: 82.2 %

Procedure:
A suspension of 4-trifluoromethylbenzaldehyde (819 μL, 6.00 mmol), 3-methyl-4-nitroaniline (609 mg, 4.00 mmol), and Amberlite IRC-84 (200 mg, H+ form) in o-xylene (4 mL) was heated under nitrogen at 140° C. for 6 hours. It was then cooled to room temperature, diluted with ethyl acetate (5 mL), dried over sodium sulfate, filtered, and volatiles were evaporated. The residue was dissolved in acetonitrile (20 mL) and sodium cyanoborohydride (503 mg, 8.00 mmol) was added in one portion, followed by acetic acid (1 mL) in several portions over 15 minutes. After a further 30 minutes solvents were evaporated and the residue was partitioned between ethyl acetate (50 mL), brine (25 mL), and 10% aqueous potassium carbonate (25 mL). The organic layer was dried over sodium sulfate, solvents were evaporated, and the residue was purified on a FlashMaster system (silica, eluted with heptane/ethyl acetate mixtures) to yield the title compound as a yellow powder (1.02 g, 82%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH2:13][NH2:14])=[CH:8][CH2:9][O:10]2)=[CH:5][CH:4]=1>[Ni].CO.CC(O)=O>[ClH:2].[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([CH2:13][NH2:14])[CH2:8][CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: NCC1=CCOc2cc(Cl)ccc21
Agent: [Ni]
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: NCC1CCOc2cc(Cl)ccc21
Yield: 92 %

Procedure:
Hydrogenation of 1-(7-chloro-2H-chromen-4-yl)methanamine hydrochloride (500 mg, 2.6 mmol) was carried out in the presence of Raney Nickel (300 mg) in 2:1 MeOH/HOAc under 50 psi of H2 for 16 h at 30° C. The reaction was filtered through Celite and concentrated in vacuo. Precipitation from EtOAc and filtration gave 280 mg (56%) of the title compound as a white solid. [M+H] calc'd for C10H12ClNO, 198. found 198.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][C:15]2([CH2:19][C:20]([OH:22])=[O:21])O)=[CH:11][CH:10]=1>ClCCl>[F:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14]/[C:15]/2=[CH:19]\[C:20]([OH:22])=[O:21])=[CH:11][CH:10]=1
Reactant: O=C(O)CC1(O)CCc2ccc(F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C1\CCc2ccc(F)cc21
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
Trifluoroacetic acid (100 mL) was added to a stirred, chilled (ice-methanol bath) solution of 2-(6-Fluoro-1-hydroxy-1-indanyl)acetic acid (37.5 g, 0.18 mol) in dichloromethane (900 mL). After 15 min, the mixture was concentrated in vacuo to give (E)-2-(6-fluoro-1-indanylidene)acetic acid as a yellowish-tan solid (33.0 g, 95%), m.p., 203°-205° C.; NMR (DMSO-d6): d 12.05 (br s, 1H, COOH), 7.16-7.65 (m, 3H, Ar), 6.37 (t,1H, =CH), 2.94-2.98, 3.15-3.20 (2m's, 4H, 2XCH2); steady-state nOe:irradiation at 6.37 d, observed 24% nOe at 7.65 d.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH2:10]([C:12]([CH3:18])([CH2:16][CH3:17])[CH2:13][CH:14]=O)[CH3:11]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:11]/[CH2:10][C:12]([CH2:16][CH3:17])([CH3:18])[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCC(C)(CC)CC=O
Solvent: ClCCl
Product: CCC(C)(CC)C/C=N/CC(=O)OC(C)(C)C
Yield: 100.9 %

Procedure:
Step E In a manner similar to the method described in Example 1a, glycine tert-butyl ester (1.0 g, 7.8 mmol) was reacted with 3-ethyl-3-methyl-pentanal (1 g, 7.8 mmol) in CH2Cl2 at room temperature for 5 h to give [3-ethyl-3-methyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (1.9 g, 100%).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:27])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH:10]([NH2:25])[C:9]1=[O:26])([CH3:4])([CH3:3])[CH3:2].[C:28]1([CH3:37])[CH:33]=[CH:32][CH:31]=[C:30]([N:34]=[C:35]=[O:36])[CH:29]=1>C(Cl)Cl>[C:1]([NH:5][C:6](=[O:27])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][CH:10]([NH:25][C:35]([NH:34][C:30]2[CH:29]=[C:28]([CH3:37])[CH:33]=[CH:32][CH:31]=2)=[O:36])[C:9]1=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(C)(C)NC(=O)CN1C(=O)C(N)CC(c2ccccc2)c2ccccc21
Solvent: ClCCl
Product: Cc1cccc(NC(=O)NC2CC(c3ccccc3)c3ccccc3N(CC(=O)NC(C)(C)C)C2=O)c1
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a 25 ml round-bottomed flask equipped with N2 inlet were added N-tert-butyl-2-[3-amino-2-oxo-5-phenyl-2,3,4,5-tetrahydro-1H-(1)benzazepin-1-yl]ethanoic acid amide (0.50 g, 1.368 mmoles) and 10 ml methylene chloride under nitrogen, and the reaction cooled in an ice bath. A solution of m-tolyl isocyanate (0.194 ml, 1.5 mmol) in 5 ml methylene chloride was then added dropwise. A solid formed immediately. Stirring was continued for 15 minutes and then the ice bath removed, allowing the reaction to come to room temperature for several hours. The solid was filtered and washed with methylene chloride/hexane (1:1), yielding 600 mg (87.9%) of product, mp 263°-266° C.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[CH2:11]([NH2:14])[CH:12]=[CH2:13].[Cl:15][CH2:16][CH2:17][N:18]=[C:19]=[O:20]>>[Cl:15][CH2:16][CH2:17][NH:18][C:19]([N:14]([CH2:11][CH:12]=[CH2:13])[CH:9]1[O:10][CH2:2][C@H:3]([OH:4])[C@H:5]([OH:6])[C@H:7]1[OH:8])=[O:20]
Reactant: O=C=NCCCl
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)CO
Reactant: C=CCN
Product: C=CCN(C(=O)NCCCl)C1OC[C@H](O)[C@H](O)[C@H]1O
Yield: 62.3 %

Procedure:
4.5 g of L-arabinose, 2.5 g of 2-propenylamine and 3.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 31-(1). 5.5 g of 1-(2-chloroethyl)-3-(2-propenyl)-3-(L-arabinopyranosyl)urea are thereby obtained as colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]([C:23]2[C:24](=[O:36])[N:25]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:26]([CH3:29])[C:27]=2[CH3:28])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[CH3:37][C@H:38]1[CH2:40][O:39]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:20][C:21]([C:23]2[C:24](=[O:36])[N:25]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:26]([CH3:29])[C:27]=2[CH3:28])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH2:37][C@@H:38]([OH:39])[CH3:40])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: C[C@H]1CO1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OC[C@H](C)O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C

Procedure:
The title compound was prepared according to the procedure described in Example 2 by using N-(3-fluoro-4-((7-hydroxyquinolin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1.00 g, 2.07 mmol), (S)-2-methyloxirane (1.44 mL, 20.70 mmol) and Cs2CO3 (1.35 g, 4.14 mmol) in 10 mL DMF. The title compound was obtained as a white solid (663 mg, 55%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:30])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:51][C:52]1[O:53][C:54](=[O:58])[O:55][C:56]=1[CH3:57].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([O:30][CH2:51][C:52]2[O:53][C:54](=[O:58])[O:55][C:56]=2[CH3:57])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: Cc1oc(=O)oc1CO
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(OCc4oc(=O)oc4C)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.1 %

Procedure:
To a solution of triacetate 75 (1.55 g, 3.50 mmol) in THF (50 mL) at 0° C. was added polymer supported-triphenylphosphine (4.95 g, 10.50 mmol, Argonaut). To this mixture was added 4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one (0.91 g, 7.00 mmol), prepared according to the procedure of Alepegiani, Syn. Comm., 22(9), 1277-82 (1992) Diethyl azodicarboxylate (0.73 ml, 4.60 mmol) was then added dropwise. The resulting mixture was stirred at room temperature for 48 h, filtered and washed with MeOH and CHCl3. The filtrate was concentrated and purified by flash column chromatography (silica, acetone/CHCl3=10-20%) to afford dioxolone derivative 85 (1.38 g, 71%) as white solid: 1H (400 MHz, d6-DMSO);δ 7.06 (s, 2H), 6.00 (d, J=4.0 Hz, 1H), 5.92 (dd, J=6.6, 4.4 Hz, 1H), 5.56 (t, J=6.4 Hz, 1H), 5.30 (s, 2H), 4.38 (dd, J=11.6, 3.6 Hz, 1H), 4.25 (t, J=3.6 Hz, 1H), 4.10 (q, J=6.0 Hz, 1H), 2.23 (s, 3H), 2.08 (s, 3H), 2.07 (s, 3H), 2.00 (s, 3H); MS (+)-ES [M+H]+ m/z 555.3. Elemental Analysis calc'd for C21H22N4O12S.Me2CO: C, 47.06; H, 4.61; N, 9.15; S, 5.23. Found: C, 47.25; H, 4.37; N, 9.53; S, 5.52.
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:19][C:20]([F:31])([F:30])[O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br>>[F:19][C:20]([F:30])([F:31])[O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:2][CH2:3]1
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Reactant: FC(F)(F)Oc1cccc(CBr)c1
Product: Nc1nc(N)c2c(N3CCN(Cc4cccc(OC(F)(F)F)c4)CC3)cccc2n1
Yield: 70 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 3-(trifluoromethoxy)benzyl bromide (94.4 mg; 0.37 mmol) to obtain 58.9 mg. (70% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.0 (br s, 1H), 8.97 (br s, 1H), 7.72 (m, 2H), 7.50 (m, 2H), 7.28 (m, 1H), 7.29 (m, 4H), 3.64 (s, 2H), 3.04 (d, J=10.4 Hz, 2H), 2.93 (m, 4H), 2.32 (m, 2H). ESIMS+419.8 m/z
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18](=[O:20])[CH3:19].[C:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>O.C1(C)C=CC=CC=1.C(O)C.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>[C:18]([C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[CH:15]=[CH:16][CH:17]=[C:8]2[C:27]1[CH:28]=[CH:29][C:24]([C:21](=[O:23])[CH3:22])=[CH:25][CH:26]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1cccc2c(Br)cccc12
Reactant: CC(=O)c1ccc(B(O)O)cc1
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+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(-c2cccc3c(C(C)=O)cccc23)cc1
Reaction time: 0.25 h
Yield: 94.7 %

Procedure:
A solution of sodium carbonate (2.55 g, 24.09 mmol) in water (20 mL) was added to a solution of 1-(5-bromonaphthalen-1-yl)ethanone (1.2 g, 4.8 mmol) and 4-acetylphenylboronic acid (1.03 g, 6.26 mmol) in toluene (20 mL) and ethanol (20 mL) and then heterogeneous solution was vigorously stirred with bubbling nitrogen for 15 min. Then Pd(PPh3)4 (0.111 g, 0.096 mmol) was added and the reaction vessel was sealed and heated at reflux for 6 h. The reaction was cooled and concentrated to dryness. The crude residue was taken into EtOAc (˜150 mL) and water (˜100 mL). The layers were separated and the organic layer was washed with brine, dried (MgSO4), filtered and concentrated to an orange solid. The orange solid was purified on a BIOTAGE® Horizon (40 g SiO2, DCM) to yield 1-(4-(5-acetylnaphthalen-1-yl)phenyl)ethanone (1.31 g) as an off-white solid. LC-MS retention time 3.736 min; m/z 289.19 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, chloroform-d) δ ppm 8.75 (d, J=8.8 Hz, 1H), 8.11 (d, J=8.5 Hz, 2H), 7.99 (d, J=8.5 Hz, 1H), 7.94 (dd, J=7.2, 1.1 Hz, 1H), 7.67 (dd, J=8.5, 7.0 Hz, 1H), 7.58 (d, J=8.3 Hz, 2H), 7.45-7.51 (m, 2H), 2.79 (s, 3H), 2.70 (s, 3H).
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]([C:15]1[N:16]=[N:17][C:18]([Cl:21])=[CH:19][CH:20]=1)C(OC)=O.C(O)(=O)C>CO>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:15]1[N:16]=[N:17][C:18]([Cl:21])=[CH:19][CH:20]=1
Reactant: COC(=O)C(c1ccc(Cl)nn1)c1ccccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: Fc1ccccc1Cc1ccc(Cl)nn1
Reaction time: 1.5 h
Yield: 77.5 %

Procedure:
An aqueous solution of lithium hydroxide (2 g /10 ml of water) was added to a solution of methyl 2-(2-fluorophenyl)-2-(6-chloropyridazin-3-yl)acetate (4.25 g, 14.84 mmol) [prepared as described above] in methanol (30 ml). After 1.5 h, acetic acid (10 ml) was added and the stirring was continued overnight. The product was extracted into ether, and the extract was washed with water, aqueous NaHCO3, and brine, and dried over MgSO4. The solvent was removed in vacuo and the crude was chromatographed on a silica gel column (10% ethyl acetate in hexanes) to give 6-(2-fluorobenzyl)-3-chloropyridazine (2.56 g) as an oil.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:20].O1CCCC1>CO.C(O)(C)C>[Cl-:20].[CH:14]1([N:11]2[CH2:10][CH2:9][CH:8]([NH3+:7])[CH2:13][CH2:12]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Cl
Reactant: CC(C)(C)OC(=O)NC1CCN(C2CCCC2)CC1
Solvent: CC(C)O
Solvent: CO
Solvent: C1CCOC1
Product: [Cl-]
Product: [NH3+]C1CCN(C2CCCC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(1-Cyclopentyl-piperidin-4-yl)-carbamic acid tert-butyl ester (3) (6.70 g, 25 mmol, 1 equiv) was dissolved in methanol (30 mL), followed by the addition of 6 N HCl in isopropanol (10 mL). The solution was stirred at room temperature for 24 hours. Due to the incompleteness of the reaction, 6 N HCl in isopropanol (10 mL) and methanol (50 mL) were added to the solution. The solution was stirred at room temperature for another 24 hours. LC-MS indicated incompletion of the reaction. Tetrahydrofurane (20 mL), 6 N HCl in isopropanol (10 mL) and methanol (200 mL) were added to the solution. The solution was stirred at room temperature for 5 hours, followed by the addition of 6 N HCl in isopropanol (10 mL). The solution was stirred at room temperature for 72 hours. The solution was evaporated under reduced pressure to obtain 4 (4.20 g, 25 mmol, quantitative). LRMS (ES+): m/z 169.
Reaction SMILES: CO.C([O:10][CH2:11][CH2:12][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[N:30]=[CH:29][N:28]=[C:27]([O:31][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH:26]=1)[CH2:20][CH2:19]2)(=[O:15])=[O:14])C1C=CC=CC=1.[H][H]>[OH-].[Pd+2].[OH-].C(OCC)(=O)C>[OH:10][CH2:11][CH2:12][S:13]([C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[N:21]([C:25]1[N:30]=[CH:29][N:28]=[C:27]([O:31][CH:32]3[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]3)[CH:26]=1)[CH2:20][CH2:19]2)(=[O:14])=[O:15]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(=O)(=O)CCOCc5ccccc5)ccc43)ncn2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(N3CCc4cc(S(=O)(=O)CCO)ccc43)ncn2)CC1
Yield: 80 %

Procedure:
Palladium hydroxide (100 mg) was added to a methanol (10 mL)/ethyl acetate (10 mL) mixed solution of the tert-butyl 4-{[6-(5-{[2-(benzyloxy)ethyl]sulfonyl}indolin-1-yl)pyrimidin-4-yl]oxy}piperidine-1-carboxylate (486 mg, 0.817 mmol) produced in Reference Example 44, and the mixture was stirred for 19.5 hours in a hydrogen atmosphere. The reaction solution was filtered through Celite (trade name), and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2-4:1, V/V) to obtain the title compound as white foam (330 mg, yield: 80%).