Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=2)[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:12][CH2:13][OH:14])[C:6]1=[O:15])[CH3:4].[CH3:30]I>CN(C=O)C>[CH2:3]([C:5]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:17]=2)[CH2:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:12][CH2:13][O:14][CH3:30])[C:6]1=[O:15])[CH3:4]
Reactant: CCC1(c2cccc(OCc3ccccc3)c2)CCCCN(CCO)C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1(c2cccc(OCc3ccccc3)c2)CCCCN(CCOC)C1=O
Reaction time: 16 h

Procedure:
Sodium hydride (0.017 g, 0.425 mmol) was added to a solution of 3-ethyl-1-(2-hydroxy-ethyl)-3-(3-benzyloxyphenyl)-azepan-2-one, as described in Example 54, Step C, (0.12 g, 0.327 mmol) in DMF (5 mL) at 0° C. with stirring. After 20 min CH3I (0.041 mL, 0.653 mmol) was added and stirring was continued at room temperature for 16 h. The reaction was quenched with H2O and the solvents removed in vacuo. The residue was partitioned between EtOAc and saturated NaHCO3 solution. The organic layer was separated, washed with brine and dried (MgSO4). Filtration and concentration gave the title compound.
Reaction SMILES: Cl.C([C@@H]1C(OC)=[N:9][C@@H:8]([CH2:13][C@@H:14]([CH:26]([CH3:28])[CH3:27])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:7]([O:29]C)=N1)(C)C.[C:31]([O-])(O)=[O:32].[Na+]>C(#N)C>[CH3:31][O:32][C:7](=[O:29])[C@@H:8]([NH2:9])[CH2:13][C@@H:14]([CH:26]([CH3:27])[CH3:28])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([CH3:24])([CH3:23])[CH3:25])=[CH:20][CH:21]=1
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1C[C@H](Cc1ccc(C(C)(C)C)cc1)C(C)C
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)[C@@H](N)C[C@H](Cc1ccc(C(C)(C)C)cc1)C(C)C
Temperature: 25 °C

Procedure:
With stirring at room temperature, 36 ml of 1N hydrochloric acid are added to a solution of 3.55 g of 2(R)-isopropyl-5(S)-[2(S)-isopropyl-3-(p-tert-butylphenyl)-propyl]-2,5-dihydro-3,6-dimethoxy-pyrazine in 36 ml of acetonitrile and the mixture is then stirred for a further 3 hours. The reaction solution is then poured onto a mixture of 45 ml of saturated NaHCO3 solution and ice and the suspension is extracted with dichloromethane. The extracts are concentrated by evaporation and purified by FC (700 g of silica gel, eluant: dichloromethane/methanol/NH3 =200:10:1) yielding the title compound: Rf (dichloromethane/methanol/conc. ammonia=200:10:1)=0.70.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[OH:8][C:9]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:10]([O:12][C@@H:13]1[CH:18]2[CH2:19][CH2:20][N+:15]([CH2:21][CH2:22][CH2:23][NH:24]C(NC3C=CC=CC=3)=O)([CH2:16][CH2:17]2)[CH2:14]1)=[O:11].[CH2:46]([C:50]1[CH:55]=[CH:54][C:53]([N:56]=[C:57]=[O:58])=[C:52]([CH3:59])[CH:51]=1)[CH2:47][CH2:48][CH3:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[CH2:46]([C:50]1[CH:55]=[CH:54][C:53]([NH:56][C:57](=[O:58])[NH:24][CH2:23][CH2:22][CH2:21][N+:15]23[CH2:16][CH2:17][CH:18]([CH2:19][CH2:20]2)[C@@H:13]([O:12][C:10](=[O:11])[C:9]([OH:8])([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:14]3)=[C:52]([CH3:59])[CH:51]=1)[CH2:47][CH2:48][CH3:49]
Reactant: O=C(NCCC[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2)Nc1ccccc1
Reactant: CCCCc1ccc(N=C=O)c(C)c1
Agent: O=C([O-])C(F)(F)F
Product: CCCCc1ccc(NC(=O)NCCC[N+]23CCC(CC2)[C@@H](OC(=O)C(O)(c2ccccc2)c2ccccc2)C3)c(C)c1

Procedure:
This compound is made via an analogous procedure to (R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(3-phenyl-ureido)-propyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate (Example 47) by replacing phenyl isocyanate with 4-butyl-1-isocyanato-2-methyl-benzene.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].Br[CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH:12]([CH3:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])([O-:3])=[O:2]
Reactant: CCOC(=O)C(C)Br
Reactant: O=[N+]([O-])c1ccccc1O
Product: CCOC(=O)C(C)Oc1ccccc1[N+](=O)[O-]

Procedure:
Starting from 2-nitrophenol (10 g, 1 eq, 71.9 mmol) and ethyl 2-bromopropionate (10.2 ml, 1.1 eq, 79.09 mmol) the procedure of Step (i), preparation 17 was followed to obtain ethyl 2-(2-nitrophenoxy)propanoate in crude form (16 g) which was used for step (ii).
Reaction SMILES: [S:1]([CH2:5][CH2:6][C:7]#[CH:8])([CH3:4])(=[O:3])=[O:2].I[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[S:1]([CH2:5][CH2:6][C:7]#[C:8][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])(=[O:3])=[O:2]
Reactant: Ic1ccccc1
Reactant: C#CCCS(C)(=O)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCC#Cc1ccccc1
Reaction time: 20 h
Yield: 52.7 %

Procedure:
A mixture of 1-mesylbut-3-yne (758 mg, 5.10 mmol), iodobenzene (1.25 g, 6.00 mmol), copper(I) iodide (40 mg), PdCl2(PPh3)2 (70 mg) in 12 mL of Et3N is stirred under N2 for 20 hr. The mixture is filtered and washed with Et3N (3×15 mL). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product as a pale yellow oil (560 mg, 50%) 1H NMR (CDCl3) 2.91 (t, J=6.6 Hz, 2 H), 4.39 (t, J=6.6 Hz, 2 H), 7.30 (m, 3 H), 7.38 (m, 2 H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[F:23])#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Reactant: C#Cc1ccccc1F
Product: CC(C)(C)c1cc2ncc(C#Cc3ccccc3F)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=294.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 1-ethynyl-2-fluoro-benzene.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:7](=[O:23])[N:8]3[C:13]=2[C:12]([CH3:14])=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][CH:16]=2)[CH:10]=[CH:9]3)[CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:30][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH:10]=[CH:9][N:8]3[C:13]([C:12]=2[CH3:14])=[C:4]([CH:1]2[CH2:3][CH2:2]2)[CH:5]=[C:6]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:7]3=[O:23])=[CH:16][CH:17]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(CO)cc3)ccn2c1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(CBr)cc3)ccn2c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
327 mg of ethyl 1-cyclopropyl-8-(4-hydroxymethylphenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (Example 51) was dissolved in 11 ml of dichloromethane. 380 mg of carbon tetrabromide was added to the obtained solution, and they were cooled to 0° C. 355 mg of triphenylphosphine was added to the reaction mixture, and they were stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by the silica gel column chromatography (eluent: hexane/ethyl acetate=1/1) to obtain 291 mg of ethyl 8-(4-bromomethylphenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15](OC)=[O:16])=[CH:11][O:10][N:9]=2)=[CH:4][C:3]=1[F:19].[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][CH2:14][CH2:15][OH:16])=[CH:11][O:10][N:9]=2)=[CH:4][C:3]=1[F:19]
Reactant: COC(=O)CCc1conc1-c1ccc(Cl)c(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1conc1-c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of methyl 3-[3-(4-chloro-3-fluorophenyl)-4-isoxazolyl]propionate (3.69 g) in tetrahydrofuran (30 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 30 ml) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[3-(4-chloro-3-fluorophenyl)-4-isoxazolyl]propan-1-ol (3.06 g, yield 92%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 54–55° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[C:9]([CH:11]=1)[NH2:10])(=[O:4])=[O:3].[Cl:13][CH2:14][C:15](Cl)=[O:16]>>[Cl:13][CH2:14][C:15]([NH:10][C:9]1[CH:11]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=1[CH3:12])=[O:16]
Reactant: Cc1ccc(S(C)(=O)=O)cc1N
Reactant: O=C(Cl)CCl
Product: Cc1ccc(S(C)(=O)=O)cc1NC(=O)CCl

Procedure:
The subtitle compound was prepared from 5-methanesulphonyl-2-methylaniline (0.82 g) and chloroacetyl chloride (0.72 ml) by the method of Example 33 step (iii) as a beige solid. Yield: 0.61 g
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:12][N:13]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[CH:32]=[C:31]([OH:33])[C:24]3[CH2:25][CH:26]([CH:28]([F:30])[F:29])[O:27][C:23]=3[CH:22]=2)=[O:20])=[N:14]1>>[CH3:12][N:13]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[CH:32]=[C:31]([O:33][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[C:24]3[CH2:25][CH:26]([CH:28]([F:30])[F:29])[O:27][C:23]=3[CH:22]=2)=[O:20])=[N:14]1
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C(F)F)C3)n1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3c(c2)OC(C(F)F)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 33, from 4-fluorophenyl methyl sulfone (28.2 mg, 0.162 mmol) and 2-difluoromethyl-4-hydroxy-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (223a) (50 mg, 0.160 mmol) to give a white solid (18 mg, 24% yield). 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1 H) 7.85-8.02 (m, 2 H) 7.22-7.38 (m, 2 H) 7.02-7.21 (m, 3 H) 6.77 (d, J=2.02 Hz, 1 H) 5.94 (t, 1 H) 5.02 (br. s., 1 H) 3.78 (s, 3 H) 3.55-3.65 (m, 1 H) 3.23-3.33 (m, 1 H) 3.09 (s, 3 H); LCMS for C21H19F2N3O5S m/z 464.00 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(O)[C:18]1[CH:23]=[CH:22]C=[CH:20][CH:19]=1>C(O)C>[O:1]=[C:2]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1)=[O:5]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)CC(=O)CCc1ccccc1
Solvent: CCO
Product: O=C(CCc1ccccc1)CC(=O)OCc1ccccc1

Procedure:
Ethyl 3-oxo-5-phenylpentanoate (64.2 g, 0.29 mole) was heated between 190° and 210° C. under nitrogen with benzyl alcohol (28.9 ml, 0.28 mole) for 6 hours, the ethanol formed being distilled out of the reaction mixture. The resulting pale yellow oil was essentially pure product, slightly contaminated by starting materials, n.m.r. δ(CCl4) 7.23 (5H, s), 7.06 (5H, s), 5.03 (2H, s), 3.23 (2H, s) and 2.73 (4H, s).
Reaction SMILES: C([C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:16]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:8]([O:10]CCCl)=O)CCC.[Li+].[BH4-].Cl>C1COCC1.CCCCCC>[CH2:6]([C:6]1[CH:5]=[C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:15]=[CH:14][C:7]=1[CH2:8][OH:10])[CH2:5][CH2:16][CH3:15]
Reactant: CCCCc1cc(C(=O)OCCCl)ccc1-c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCc1cc(-c2ccccc2)ccc1CO

Procedure:
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added 2-chloroethyl 3-butyl-4-phenylbenzoate (570 mg, 1.80 mmol), THF (9 mL) and LiBH4 (9 mL of a 2M solution in THF, 18 mmol). This mixture was heated at reflux for 18 h. The cooled reaction mixture was treated with 1N HCl and extracted with EtOAc. The combined EtOAc extracts were washed with H2O and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. This material was chiromatographed on silica gel using 20% EtOAc in hexane as eluant to afford the title compound as a crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].S([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+].OS(O)(=O)=O>O.CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[S:10]([OH:12])=[O:11]
Reactant: O=S(=O)(Cl)c1cc(F)c(F)cc1F
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=S(O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
2,4,5-Trifluoro-benzenesulfonyl chloride ([220227-21-4], 2.5 g) was added portionwise onto a solution of sodium sulfite (10.3 g) in 50 mL of water. The reaction mixture was kept under basic conditions by the addition of the proper amount of 20% NaOH and was stirred at room temperature for 1 hour. Methanol was added to the reaction mixture, and the reaction mixture was stirred at room temperature for another hour. After such time, the reaction mixture was cooled down with an ice bath and was then acidified by the addition of 20% H2SO4 solution until reaching pH 2. The aqueous solution was then extracted several times with diethyl ether and ethyl acetate. The aqueous solution was further extracted with ethyl acetate using a Kutscher-Steudel apparatus (continuous extraction). The combined organic phases were dried (sodium sulfate) an concentrated in vacuo to yield the title compound as a white solid (2.1 g).
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[S:21][CH:20]=[N:19][CH:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.[C:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>CS(C)=O>[S:21]1[C:17]([C:14]2[N:13]=[CH:12][C:11]3[CH:10]=[N:9][N:8]([C:6]4[N:7]=[C:2]([N:32]5[CH2:31][CH2:30][N:29]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:34][CH2:33]5)[CH:3]=[CH:4][CH:5]=4)[C:16]=3[CH:15]=2)=[CH:18][N:19]=[CH:20]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1cccc(-n2ncc3cnc(-c4cncs4)cc32)n1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(-n3ncc4cnc(-c5cncs5)cc43)n2)CC1
Temperature: 95 °C

Procedure:
A solution of 5-[1-(6-fluoro-2-pyridyl)pyrazolo[4,3-c]pyridin-6-yl]thiazole (50 mg, 0.17 mmol) and 1-N-boc-piperazine (175 mg, 0.921 mmol) in dimethyl sulfoxide; 2.0 mL was heated at 95° C. for 8 h. The reaction was quenched with water and extracted with EtOAc. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum to give tert-butyl 4-[6-(6-thiazol-5-ylpyrazolo[4,3-c]pyridin-1-yl)-2-pyridyl]piperazine-1-carboxylate:
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:3]=1[NH:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1>C1COCC1.[Pd]>[F:1][C:2]1[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:3]=1[NH:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: O=[N+]([O-])c1ccc(NCCN2CCOCC2)c(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(NCCN2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a solution of 2-fluoro-N-(2-morpholinoethyl)-4-nitroaniline (0.60 g, 2.23 mmol) in THF (8.0 mL) was added catalyst Pd/C (0.03 g). The reaction mixture was stirred at rt under H2 overnight, then filtered. The filtrate was concentrated in vacuo to give the title compound as yellow oil (0.50 g, 94%).
Reaction SMILES: [CH2:1]([O:17][C:18]1[CH:27]=[CH:26][C:21]2[N:22]=[C:23]([CH3:25])[O:24][C:20]=2[CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C([OH:30])C.Cl>O>[C:23]([NH:22][C:21]1[CH:26]=[CH:27][C:18]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:19][C:20]=1[OH:24])(=[O:30])[CH3:25]
Reactant: CCO
Reactant: CCCCCCCCCCCCCCCCOc1ccc2nc(C)oc2c1
Agent: Cl
Solvent: O
Product: CCCCCCCCCCCCCCCCOc1ccc(NC(C)=O)c(O)c1
Reaction time: 4 h

Procedure:
A mixture of 111 g of 6-hexadecyloxy-2-methylbenzoxazole, 1,300 ml of ethanol, 110 ml of 33% hydrochloric acid and 550 ml of water was stirred at 55°-60° C. for 4 hours. The reaction solution was cooled to precipitate crystals, and the crystals were collected by filtration. 113 g of 2-acetylamino-5-hexadecyloxyphenol was obtained.
Reaction SMILES: CC(C)=O.Cl[C:6]1[N:11]=[C:10]([Cl:12])[N:9]=[C:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:7]=1.[CH:19]12[O:26][CH:23]([CH2:24][CH2:25]1)[CH2:22][NH:21][CH2:20]2>C(N(CC)CC)C>[Cl:12][C:10]1[N:9]=[C:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:7]=[C:6]([N:21]2[CH2:20][CH:19]3[O:26][CH:23]([CH2:24][CH2:25]3)[CH2:22]2)[N:11]=1
Reactant: C1CC2CNCC1O2
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: Clc1nc(N2CCOCC2)nc(N2CC3CCC(C2)O3)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred acetone/crushed ice suspension of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (1.5 g, 6.5 mmol), 8-oxa-3-azabicyclo[3.2.1]octane (980 mg, 6.5 mmol) and triethylamine (3 ml) was added and stirred at room temperature for 6 hours. At the end, the separated solid was filtered and washed with water. The crude product was found to be pure enough for further transformations. Yield: 2.0 g (99%); mp. 118; (M+H) 313.1
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[O:35]1[CH2:40][CH2:39][CH:38]([CH2:41][N:42]2[CH2:47][CH2:46][CH:45]([CH2:48][NH2:49])[CH2:44][CH2:43]2)[CH2:37][CH2:36]1.[OH-].[Na+]>O1CCCC1>[C:16]([O:15][C:13](=[O:14])[NH:1][C@@H:2]([C:10](=[O:12])[NH:49][CH2:48][CH:45]1[CH2:44][CH2:43][N:42]([CH2:41][CH:38]2[CH2:37][CH2:36][O:35][CH2:40][CH2:39]2)[CH2:47][CH2:46]1)[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: NCC1CCN(CC2CCOCC2)CC1
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)NCC1CCN(CC2CCOCC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution consisting of 10 g of Boc-D-Phe-OH, 40 ml of tetrahydrofuran and 4.6 ml of N-methylmorpholine is slowly dripped into a solution of 5.4 ml of isobutyl chloroformate in 60 ml of tetrahydrofuran cooled to 0° C., at a rate such that the inner temperature does not exceed 5° C. The resulting mixture is maintained under stirring at 0° C. for 0.5 hours. A solution consisting of 8.0 g of (11) in 20 ml of tetrahydrofuran is then dripped into the reaction mixture at a rate such that the temperature does not exceed 5° C. The solution is maintained under stirring at 0° C. for 1 hour, and at ambient temperature for 5 hours. 100 ml of 1M NaOH is added to the mixture, and the tetrahydrofuran is evaporated at low pressure. The residue is taken up with dichloromethane and water; the organic phase is washed with water (2×), and after a solvent change with ethyl acetate at low pressure, compound (12) is crystallised from ethyl acetate to obtain 15 g of white solid. Yield 87%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:20][CH:19]3[O:21][CH:16]([CH2:17][CH2:18]3)[CH2:15]2)[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1>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.COCCOC>[N:8]1([C:6]2[N:5]=[C:4]([N:14]3[CH2:20][CH:19]4[O:21][CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[N:3]=[C:2]([C:32]3[CH:33]=[CH:34][C:29]([NH2:28])=[CH:30][CH:31]=3)[N:7]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)nc(N2CC3CCC(C2)O3)n1
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: COCCOC
Product: Nc1ccc(-c2nc(N3CCOCC3)nc(N3CC4CCC(C3)O4)n2)cc1
Yield: 59 %

Procedure:
A mixture of 3-(4-chloro-6-morpholin-4-yl-1,3,5-triazin-2-yl)-8-oxa-3-azabicyclo[3.2.1]octane (2.0 g, 6.4 mmol), tetrakis(triphenylphosphine)palladium (0) in catalytic amount (100 mg), sodium carbonate solution 2 M (5 mL), 4-aminophenylboronic acid pinacol ester (1.5 g, 6.43 mmoles), DME (200 mL) was refluxed for 24 hours. The solvent was evaporated and the residue was dissolved in methylene chloride and filtered though Celite™. The organic layer was washed with water (200 mL) and dried over magnesium sulfate. It was filtered and the solvent was evaporated. The residue was chromatographed on silica gel column using Ethyl acetate/hexanes (1:1) as an eluent, to give 1.4 g, (59% yield) of the titled product. mp. 154; (M+H) 369.4.
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][NH:4][CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]2[CH2:15][O:14][CH2:13][CH2:12][C:10]=2[N:11]=1.[F:18][C:19]1[CH:36]=[CH:35][C:22]([C:23]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:31][C:32](O)=[O:33])[CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=1.CC#N.O>C(O)=O>[F:17][CH:2]([F:1])[CH2:3][N:4]([CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]2[CH2:15][O:14][CH2:13][CH2:12][C:10]=2[N:11]=1)[C:32](=[O:33])[CH2:31][N:28]1[CH2:29][CH2:30][CH:25]([C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:36][CH:35]=2)[CH2:26][CH2:27]1
Reactant: O=c1[nH]c(CNCC(F)F)nc2c1COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Solvent: O
Solvent: O=CO
Solvent: CC#N
Product: O=C(c1ccc(F)cc1)C1CCN(CC(=O)N(Cc2nc3c(c(=O)[nH]2)COCC3)CC(F)F)CC1

Procedure:
Following general procedure of Example 5, the title compound was prepared (0.046 g) from 2-((2,2-difluoroethylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one (0.18 g, 0.73 mmol, 1 eq.) and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid (0.20 g, 0.73 mmol, 1 eq.). 1H NMR (400 MHz, MeOD) δ ppm 8.00-8.18 (m, 2H), 7.17-7.36 (m, 2H), 5.83-6.44 (m, 1H), 4.56-4.68 (m, 2H), 4.42-4.52 (m, 2H), 4.30-4.42 (m, 2H), 3.80-4.08 (m, 4H), 3.66-3.79 (m, 3H), 3.42-3.61 (m, 1H), 3.09-3.26 (m, 1H), 2.56-2.71 (m, 2H), 1.93-2.28 (m, 4H). HRMS calculated for C24H28F3N4O4 493.2063. found (ESI, [M+H]+) 493.2062. MS (ESI) m/z 493.2 (M+H)+. Retention time: 4.65 min (5-95% CH3CN/H2O over 7.75 min with 0.1% formic acid, Inertsil ODS3 100×3 mm C18 column with flow rate of 1.0 mL/min).