Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH:5]([NH:6][C:7](=[O:16])[CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]([S:17]NC2C=CC=CC=2)[N:3]1[CH:25]([C:30]([CH3:32])=[CH2:31])[C:26]([O:28][CH3:29])=[O:27].CO.B(F)(F)F.C[CH2:40][O:41]CC>C(Cl)Cl>[CH3:40][O:41][CH2:31][C:30]1([CH3:32])[CH:25]([C:26]([O:28][CH3:29])=[O:27])[N:3]2[C:2](=[O:1])[CH:5]([NH:6][C:7](=[O:16])[CH2:8][O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C@H:4]2[S:17]1
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)COc2ccccc2)C1SNc1ccccc1
Reactant: CCOCC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CO
Product: COCC1(C)S[C@@H]2C(NC(=O)COc3ccccc3)C(=O)N2C1C(=O)OC
Reaction time: 3 h

Procedure:
Methyl 2-oxo-3-(2-phenoxyacetamido)-4-anilinothio-α-isopropenyl-1-azetidineacetate (454 mg) was dissolved in methylene chloride (20 ml). To this solution were added methanol (5 ml) and then boron trifluoride etherate (0.124 g) under cooling at 0° C. The mixture was stirred for 3 hours at the same temperature and further stirred for 2 hours at 5° to 10° C. After the reaction, the reaction mixture was washed with 5% sodium bicarbonate aqueous solution and then with water, dried and the solvent was distilled off. The oily residue (25 g) was subjected to column chromatography on silica gel and eluted with chloroform. The eluate was separated into each 50 ml fraction and the seventh and eighth fractions were combined. The solvent was distilled off to give oily methyl 2-methoxymethyl-2-methy-6-(2-phenoxyacetamido)penam-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:22]1[CH:27]=[CH:26][CH2:25][CH2:24][CH2:23]1.C([O-])(O)=O.[Na+]>COC(C)(C)C>[CH3:7][C:4]([CH3:8])([CH2:5][O:6][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][O:22]1)[C:3]([O:2][CH3:1])=[O:9]
Reactant: COC(=O)C(C)(C)CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: COC(=O)C(C)(C)COC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of hydroxypivalic acid methyl ester (50.0 g, 378 mmol) and p-toluenesulfonic acid monohydrate (1.439 g, 7.57 mmol) in 250 mL of methyl-tert-butylether was added dihydropyran (48.1 mL, 568 mmol) slowly with cooling. The mixture was stirred at room temperature overnight, 50 mL of saturated NaHCO3 added and the mixture shaken and separated. The organic layer dried over MgSO4 and concentrated. Purification of the residue by flash chromatography using 330 g column, 0%-5% ethyl acetate in hexane gave methyl 2,2-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)propanoate as a clear oil: 1H NMR (400 MHz, CDCl3) δ 4.5 (s, 1H), 3.8-3.6 (m, 2H), 3.6 (m, 3H), 3.4 (s, 1H), 3.25 (m, 1H), 1.7 (m, 1H), 1.6-1.18 (m, 5H), 1.05 (m, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[N:11][O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[N:11][O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)CON=Cc1cccc([N+](=O)[O-])c1
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)(C)OC(=O)CON=Cc1cccc(N)c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
tert-Butyl 3-aminophenylmethyleneaminooxyacetate may be obtained as follows: 0.75 g of platinum oxide is added to a solution of 7.5 g of tert-butyl 3-nitrophenylmethyleneaminooxyacetate in 100 cm3 of ethanol. The suspension is stirred for 1 hour at a temperature in the vicinity of 20° C. under a hydrogen atmosphere (130 kPa). The catalyst is separated by filtration and the filtrate is concentrated to dryness under reduced pressure at 45° C. The residue is dissolved in 50 cm3 of ethyl acetate and the organic phase is washed with 50 cm3 of water, dried over magnesium sulphate and concentrated under reduced pressure. 6.2 g of tert-butyl 3-aminophenylmethyleneaminooxyacetate are thus obtained in the form of an oil, used as it is in subsequent syntheses.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[Cl:5][C:6]1[N:11]=[C:10](Cl)[N:9]=[C:8]([N:13]([CH:39]2[CH2:44][C:43]([CH3:46])([CH3:45])[NH:42][C:41]([CH3:48])([CH3:47])[CH2:40]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]([C:31]2[N:36]=[C:35]([Cl:37])[N:34]=[C:33](Cl)[N:32]=2)[CH:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[N:7]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Cl:5][C:6]1[N:11]=[C:10]([NH:4][CH2:1][CH:2]=[CH2:3])[N:9]=[C:8]([N:13]([CH:39]2[CH2:40][C:41]([CH3:47])([CH3:48])[NH:42][C:43]([CH3:45])([CH3:46])[CH2:44]2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]([C:31]2[N:36]=[C:35]([Cl:37])[N:34]=[C:33]([NH:4][CH2:1][CH:2]=[CH2:3])[N:32]=2)[CH:21]2[CH2:22][C:23]([CH3:29])([CH3:30])[NH:24][C:25]([CH3:28])([CH3:27])[CH2:26]2)[N:7]=1
Reactant: C=CCN
Reactant: CC1(C)CC(N(CCCCCCN(c2nc(Cl)nc(Cl)n2)C2CC(C)(C)NC(C)(C)C2)c2nc(Cl)nc(Cl)n2)CC(C)(C)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCNc1nc(Cl)nc(N(CCCCCCN(c2nc(Cl)nc(NCC=C)n2)C2CC(C)(C)NC(C)(C)C2)C2CC(C)(C)NC(C)(C)C2)n1
Reaction time: 19 h

Procedure:
17.2 g (0.3 mole) of anhydrous allylamine are added dropwise, in the course of one hour, at 30°-40° and while stirring, to a solution of 103.6 g (0.15 mole) of N,N'-bis-(2,4-dichloro-1,3,5-triazin-6-yl)-N,N'-bis-(2,2,6,6-tetramethylpiperid-4-yl)-hexamethylenediamine in 500 ml of toluene. A solution of 12.0 g (0.3 mole) of sodium hydroxide in 100 ml of water is then added at approx. 30°, and stirring is continued for a further 19 hours at 50°. The mixture is worked up by separating off the aqueous phase in a separating funnel, washing the organic phase with three times 200 ml of water, drying it over sodium sulfate and removing the solvent by vacuum distillation. The solid residue is recrystallised from ethyl methyl ketone, which gives pure N,N'-bis-(2-chloro-4-allylamino-1,3,5-triazin-6-yl)-N,N'-bis-(2,2,6,6-tetramethylpiperid-4-yl)-hexamethylenediamine of melting point 210°-211°.
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:13][C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:22]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])(=[O:29])/[CH:23]=[CH:24]/[CH2:25][CH2:26][CH2:27][CH3:28]>C1COCC1>[CH2:6]([N:13]([C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C@@H:24]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:23][C:22]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[C@H](NCc1ccccc1)c1ccccc1
Reactant: CCCC/C=C/C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[C@@H](CC(=O)OC(C)(C)C)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
n-Butyllithium (2.5M in hexanes, 27.66 ml) was added to a stirred solution of (S)—N-benzyl-1-phenylethanamine (15.59 g) in THF (150 mL) at −78° C. The reaction mixture was stirred for 30 mins then the product from step (i) (8.5 g) in THF (50 mL) was added and the reaction mixture stirred for 2 h at −78° C. The mixture was quenched with sat. NH4Cl solution and warmed to rt. The product was partitioned between EtOAc and water, the organic phase was washed with water, dried, and evaporated. The residue was purified by column chromatography eluting with 5% EtOAc in isohexane to give the subtitle compound 12.7 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:22]1(O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C>CCCCCC>[C:22]1([O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)Oc1ccccc1
Yield: 42 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using phenol (10 mg, 0.1 mmol) as the coupling partner. Chromatography (1:1 ethyl acetate:hexane) through SiO2 yielded 26 mg (42%) of the titled compound. ESI-MS m/z 368 (MH+), 366 (M−H−).
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]([NH:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:36]([O:40][C:41]([NH:43][CH2:44][C:45]([NH:47][CH2:48][C:49](O)=[O:50])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:36]([O:40][C:41]([NH:43][CH2:44][C:45]([NH:47][CH2:48][C:49]([NH:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][NH:7][C:8]2[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[N:11]=[C:10]([NH:20][C:21]3[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])=[CH:23][CH:22]=3)[N:9]=2)=[CH:4][CH:3]=1)=[O:50])=[O:46])=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(N)cc3)nc(OCC(F)(F)F)n2)cc1
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)Nc1ccc(CNc2nc(Nc3ccc(C(=O)OC(C)(C)C)cc3)nc(OCC(F)(F)F)n2)cc1
Yield: 100.2 %

Procedure:
tert-butyl 4-(4-(4-aminobenzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (100 mg, 0.204 mmol), 2-(2-(tert-butoxycarbonylamino)acetamido)acetic acid (56.8 mg, 0.245 mmol), HATU (116 mg, 0.306 mmol), and Hunig's Base (0.178 mL, 1.019 mmol) were stirred in DCM (3 mL) for 16 h. The solvent was removed and the crude material was purified by silica gel chromatography using EtOAc to give tert-butyl 4-(4-(4-(2-(2-(tert-butoxycarbonylamino)acetamido)acetamido)benzylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (144 mg).
Reaction SMILES: [Br:1]Br.[NH2:3][C@@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:5][NH:6][C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=1>CC(O)=O>[NH2:3][C@@H:4]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:5][NH:6][C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[C:10]([Br:1])=[CH:9][CH:8]=1
Reactant: N[C@H](CNc1cccc(-c2ccncc2)n1)Cc1ccccc1
Reactant: BrBr
Solvent: CC(=O)O
Product: N[C@H](CNc1ccc(Br)c(-c2ccncc2)n1)Cc1ccccc1
Reaction time: 1 h

Procedure:
A mixture of bromine (1.6 gm, 10 mmole) and HOAc (10 mL) was added in three portions to a stirred solution of 6-((S)-2-Amino-3-phenylpropylamino)-2-(4-pyridyl)pyridine (3.04 gm, 10 mmole) in HOAc (20 mL) at rt. After 1 hr, the mixture was concentrated and purified (SiO2, CH2Cl2/MeOH/NH4OH: 100/11/8) to give 6-((S)-2-Amino-3-phenylpropylamino)-3-bromo-2-(4-pyridyl)pyridine. MS (m/z): Calcd. C19H19N4Br (M+): 383, found : 383.1 and 385.1.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.C1CCCCC1.Cl.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1>C(O)(=O)C>[Br:16][C:17]1[CH:22]=[C:21]2[C:20](=[CH:19][CH:18]=1)[NH:23][C:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][C:4]2=1
Reactant: NNc1ccc(Br)cc1
Reactant: CC1CCC(=O)CC1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1CCCCC1
Product: CC1CCc2[nH]c3ccc(Br)cc3c2C1
Yield: 74.2 %

Procedure:
To a solution of 4-methylcyclohexanone (5.47 mL, 44.6 mmol), cyclohexane (70 mL) and glacial acetic acid (50 mL) was added 4-bromophenylhydrazine hydrochloride (10.0 g, 44.6 mmol) and the reaction mixture was refluxed for 23 h under a nitrogen atmosphere. The cooled reaction mixture was filtered and the filtrate was evaporated. Diethyl ether was added and the mixture was washed with a saturated sodium bicarbonate solution and then water; the ether solution was dried and evaporated. The crude product was recrystallised from ethanol over an ice bath, filtered, washed with cold PS and dried in vacuo to afford 6-bromo-3-methyl-1,2,3,4-tetrahydrocarbazole (8.73 g, 33.1 mmol, 74%) as an off-white solid, mp 108-110° C.
Reaction SMILES: C([N:8]([C@H:28]([CH2:44][OH:45])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([C:39]2[NH:40][CH:41]=[CH:42][CH:43]=2)=[O:38])=[CH:32][CH:31]=1)[CH2:9][C@H:10]([OH:27])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19]CC2C=CC=CC=2)=[CH:15][CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[OH:45][CH2:44][C@@H:28]([NH:8][CH2:9][C@H:10]([OH:27])[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1)[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([NH:36][C:37]([C:39]2[NH:40][CH:41]=[CH:42][CH:43]=2)=[O:38])=[CH:34][CH:35]=1
Reactant: O=C(Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccc(OCc3ccccc3)cc2)cc1)c1ccc[nH]1
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1ccc(C[C@@H](CO)NC[C@H](O)COc2ccc(O)cc2)cc1)c1ccc[nH]1
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of N-[4-[(2S)-2-[N-benzyl-N-[(2S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl]amino]-3-hydroxypropyl]-phenyl]-1H-pyrrole-2-carboxamide (40 mg) in methanol (2.0 ml) was added 10% palladium on activated carbon (50% wet, 10 mg) and the mixture was hydrogenated at 1 atm for 3 hours. The catalyst was filtered off and washed with methanol. The filtrate was concentrated in vacuo and the residue was powdered from ether and dried to give N-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]propyl]-phenyl]-1H-pyrrole-2-carboxamide (26 mg) as a gray powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH2:17])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(O[C:22](=N)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Reactant: CCOC(=N)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2nnc(-c3ccccc3)o2)CC1
Yield: 20.9 %

Procedure:
To a stirred solution of 4-hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (1.15 g, 4.73 mmol, 1.0 eq) in EtOH (15 mL) was added benzimidic acid ethyl ester hydrochloride (921 mg, 4.96 mmol, 1.05 eq.) and the reaction mixture was refluxed for 48 h. The inorganic precipitate was filtered off, washed with ethyl acetate, and the solvent of the mother liquor was evaporated in vacuo. The residue was purified by column chromatography (ethyl acetate/heptanes) to give the title compound as a white solid (327 mg, 0.99 mmol). MS (m/z, MH+): 330.2
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[OH:17][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[N:9]
Reactant: O=Cc1ccccc1
Reactant: N#CCc1ccccc1
Product: N#CC(c1ccccc1)C(O)c1ccccc1
Yield: 53 %

Procedure:
Reaction of phenylacetonitrile and benzaldehyde on a 15 mmol scale according to the procedure in Example 1, and recrystallization from toluene/hexane gave 1.81 g of the desired anti-aldol product (53%). NMR (1H, 13C), IR, and Mass spectra were consistent with the structure assigned previously by Wade et al. (J. Org. Chem. 52, 2973-2977 (1987)).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:7]([F:10])([F:9])[F:8])=[N:4][NH:5][CH:6]=1.Cl[CH2:12][C:13]([N:15]1[CH2:20][CH2:19][CH2:18][C:17]2[N:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[N:22]=[CH:23][C:16]1=2)=[O:14].C([O-])([O-])=O.[K+].[K+]>C1COCC1.CN(C=O)C>[Cl:1][C:2]1[C:3]([C:7]([F:10])([F:9])[F:8])=[N:4][N:5]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][CH2:18][C:17]3[N:21]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[N:22]=[CH:23][C:16]2=3)=[O:14])[CH:6]=1
Reactant: O=C(CCl)N1CCCc2c1cnn2-c1ccc(F)cc1
Reactant: FC(F)(F)c1n[nH]cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Cn1cc(Cl)c(C(F)(F)F)n1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 60 °C
Yield: 87.3 %

Procedure:
A mixture of 4-chloro-3-(trifluoromethyl)pyrazole (0.026 g, 0.15 mmol), 2-chloro-1-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridine-4-yl]ethanone (0.045 g, 0.15 mmol) and K2CO3 (0.043 g, 0.31 mmol) in THF (0.6 mL) and DMF (0.3 mL) was heated at 60° C. for 1 hr. It was then cooled to rt. The mixture was partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by flash chromatography on SiO2 with a gradient elution of 0-60% EtOAc/hexanes to afford the desired product (0.056 g, 87%). 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.70 (s, 1H), 7.45 (m, 2H), 7.16 (dd, J=8.4, 8.4 Hz, 2H), 5.17 (s, 2H), 3.81 (m, 2H), 2.87 (t, J=6.2 Hz, 2H), 2.12 (m, 2H); MS: (ES) m/z calculated for C18H14ClF4N5O [M+H]+ 428.1, found 428.1.
Reaction SMILES: O.C(O[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([CH:15]=[O:16])=[O:14])CCC.[CH3:17][C:18]([NH2:30])([CH3:29])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]2[O:26][CH2:27][O:28][C:22]=2[CH:21]=1>CS(C)=O>[CH3:29][C:18]([N:30]=[C:15]([O:16][CH2:12][CH2:7][CH2:8][CH3:9])[C:13]([C:8]1[CH:7]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:14])([CH3:17])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]2[O:26][CH2:27][O:28][C:22]=2[CH:21]=1
Reactant: CCCCOc1ccccc1C(=O)C=O
Reactant: CC(C)(N)Cc1ccc2c(c1)OCO2
Solvent: O
Solvent: CS(C)=O
Product: CCCCOC(=NC(C)(C)Cc1ccc2c(c1)OCO2)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 700 mg of 2-n-butoxyphenylglyoxal hydrate, 500 mg of α,α-dimethyl-3,4-methylenedioxyphenethylamine and 1.5 ml of dimethylsulfoxide is stirred at room temperature for 45 minutes, whereby a solution of α-(α,α-dimethyl-3,4-methylenedioxyphenethylimino)-2-n-butoxyacetophenone in dimethylsulfoxide is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][OH:6].[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.C(O)(=O)C>O>[OH:6][CH2:5][CH2:4][C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[N:1]1[C:14](=[O:15])[C:13]2[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]1=[O:16]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ccccc1CCO
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1c1ccccc1CCO
Temperature: 100 °C
Yield: 39.6 %

Procedure:
A flask containing 2-aminophenethyl alcohol (565 mg, 4.12 mmol), phthalic anhydride (641 mg, 4.32 mmol) and acetic acid (4 mL) was heated at 100° C. for 1 h. The reaction mixture was poured into water (30 mL) and the solid was filtered off and the solids were washed with water. The crude was purified by flash column chromatography to afford the desired product as white solid (435 mg, 1.63 mmol, 40%). 1H NMR: 1.79 (br s, 1H), 2.78 (t, 2H, J=6.4 Hz), 3.81 (t, 2H, J=6.4 Hz), 7.20 (d, 1H, J=8 Hz), 7.36-7.41 (m, 1H), 7.46 (d, 2H, J=4 Hz), 7.79-7.83 (m, 2H), 7.94-7.97 (m, 21-1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([CH:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:3]=1.[BH4-].[Na+]>C(O)C>[NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[C:6]([CH:10]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)c1cc(-c2ccccc2OCc2ccccc2)nc(N)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)c1cc(-c2ccccc2OCc2ccccc2)nc(N)c1CO
Reaction time: 3 h
Yield: 47.6 %

Procedure:
To a solution of tert-butyl 1-{2-amino-6-[2-(benzyloxy)phenyl]-3-formyl-4-pyridinyl}-2-phenylethylcarbamate (0.040 g, 0.092 mmol) in ethanol (1.0 mL) was added NaBH4 (0.010 g, 0.26 mmol), and the stirring was continued for 3 hrs. The mixture was extracted with ethyl acetate and saturated aqueous ammonium chloride solution. The separated organic phase was washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was crystallized from ethanol to give tert-butyl 1-[2-amino-6-[2-(benzyloxy)phenyl]-3-(hydroxymethyl)-4-pyridinyl]-2-phenylethylcarbamate as a pale yellow solid (0.023 g, yield; 57%).
Reaction SMILES: C(O)(=O)C.[CH3:5][C:6](=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-])=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8]>[Fe].O>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:12]=[C:6]([CH3:5])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(C)=Cc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(C)=Cc1ccccc1N
Reaction time: 1 h

Procedure:
Into 160 ml of acetic acid, 10 g (42.5 mmol) of (E) ethyl 2-methyl-3-(2-nitrophenyl)-2-propenate were dissolved. While the solution was stirred, 10.9 g (195.2 mmol) of iron powder (Koso Chem. Co.) and 12 ml of distilled water were added thereto at room temperature; and temperature was raised, so that reflux was carried out for 1 hour at 100° C. After the end point of the reaction was verified by TLC, the reaction liquid was cooled, and acetic acid was evaporated under a reduced pressure. Ethyl acetate was added to the residue, and insoluble matters were filtered out. With water being added thereto, the filtrate was fractionated. The resulting organic layer was successively washed with water and a saturated aqueous sodium hydrogencarbon ate solution, and then was dried for one night with sodium sulfate being added thereto. After sodium sulfate anhydride was filtered out, the filtrate was concentrated under a reduced pressure; and the resulting oily product was refined by a silica gel column chromatography (silica gel; developing solvent: ethyl acetate/hexane=1/3), whereby 6.4 g of the aimed compound were obtained as an oily product (yield: 71.5%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[N:10]=[C:4]2[CH:3]=1.[C:17]([O:21][C:22]([N:24]1[C@H:28]([CH2:29][F:30])[C@@H:27]([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[O:26][C:25]1([CH3:47])[CH3:46])=[O:23])([CH3:20])([CH3:19])[CH3:18].O.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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>[C:17]([O:21][C:22]([N:24]1[C@H:28]([CH2:29][F:30])[C@@H:27]([C:31]2[CH:32]=[CH:33][C:34]([C:2]3[CH:7]=[CH:6][N:5]4[CH:8]=[C:9]([CH2:11][NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[N:10]=[C:4]4[CH:3]=3)=[CH:35][CH:36]=2)[O:26][C:25]1([CH3:47])[CH3:46])=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)OC1(C)C
Reactant: CS(=O)(=O)NCc1cn2ccc(Br)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3ccn4cc(CNS(C)(=O)=O)nc4c3)cc2)OC1(C)C
Yield: 60.4 %

Procedure:
To the solution of N-(7-Bromo-imidazo[1,2-a]pyridin-2-ylmethyl)-methane sulfonamide (71 mg. 0.233 mmol) and (4S,5R)-4-Fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidine-3-carboxylic acid tert-butyl ester (111 mg, 0.256 mmol) in dimethoxyethane:water (2.2 mL:0.5 mL) in a microwave tube is added Na2CO3 (62 mg, 0.583 mmol) at room temperature. The resulting reaction mixture is degassed with nitrogen for 30 minutes then added Pd(PPh3)2Cl2 (9 mg, 0.0116 mmol) and heated in microwave at 120° C. for 2 hours. The solvent is evaporated and purified by flash column chromatography eluting in 2% methanol in CH2Cl2 to afford the title compound (75 mg). 1H-NMR (400 MHz, DMSO-d6) δ: 1.44 (s, 9H), 1.51 (s, 3H), 1.64 (s, 3H), 2.92 (s, 3H), 3.83-3.89 (m, 1H), 4.28 (d, J=6.12 Hz, 2H), 4.45-4.55 (m, 1H), 4.65-4.75 (m, 1H), 5.13 (d, J=7.2 Hz, 1H), 7.27-7.29 (dd, J1=1.6 Hz, J2=7.20 Hz, 1H), 7.56-7.58 (m, 3H), 7.82-7.88 (m, 4H), 8.61 (d, J=7.2 Hz, 1H). LC-MS (m/z): [M+H]=533.1.