Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=1[F:22].CN([CH:26]=[O:27])C>C1COCC1.O>[F:22][C:15]1[C:14]([F:13])=[CH:19][CH:18]=[C:17]([O:20][CH3:21])[C:16]=1[CH:26]=[O:27]
Reactant: COc1ccc(F)c(F)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)c(F)c1C=O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 75.8 %

Procedure:
To a solution of diisopropylamine (14.6 mL, 103.5 mmol) in dry THF (50 mL) cooled to −78° C. was added a solution of BuLi (1.6 M in hexane, 47 mL, 75.9 mmol) dropwise under argon, keeping the temperature below −60° C. It was stirred at this temperature for 15 minutes after which a solution of 1,2-difluoro-4-(methyloxy)benzene (10 g, 69 mmol) in dry THF (50 mL) was added slowly. The mixture was left stirring at −78° C. for 45 minutes followed by slow addition of DMF (6.37 mL, 82.8 mmol) maintaining the temperature below −60° C. The resulting mixture was stirred at −78° C. for circa 3.5 hours after which water (100 mL) was added and the cooling removed to allow it to warm up to room temperature. It was diluted with EtOAc and the organic separated. The aqueous was re-extracted with EtOAc (3×) and the combined organics washed with brine and dried over MgSO4. The crude material (10.26 g) was purified by flash chromatography to afford the title compound (D25) (9 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([O:13][CH3:14])[CH:5]=[CH:4][CH:3]=1.[Br:15]Br.C(O)(=O)C>O>[Br:15][C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([C:2]=1[Cl:1])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: BrBr
Reactant: CCOC(=O)c1c(Cl)cccc1OC
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(OC)ccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of ethyl 6-chloro-2-methoxybenzoate (1.8 g, 8.4 mmol), bromine (1.41 g, 8.8 mmol) and acetic acid (5 ml) is stirred at room temperature for 24 hours. The reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is separated and concentrated and the residue is purified by column chromatography (petrol ether:ethyl acetate, 95:5 v/v) yielding the pure product as a yellow oil, 1.7 g, (69%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1.[OH:24]O.[OH-].[Na+].Cl>C(O)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([NH2:23])=[O:24])[CH:5]=[CH:6][CH:7]=1
Reactant: OO
Reactant: N#Cc1cnc2c(C(F)(F)F)cccc2c1-c1cccc(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(N)c1
Temperature: 40 °C

Procedure:
A mixture of 4-(3-aminophenyl)-8-(trifluoromethyl)quinoline-3-carbonitrile (0.30 g, 0.96 mmol), 30% hydrogen peroxide (5 mL), NaOH (0.5 g, 12 mmol) and ethanol (15 mL) was heated to ˜40° C. for 3 hours. The pH of the solution was adjusted to ˜6 by diluted HCl. The reaction mixture was partitioned between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate. The combined organic phases were washed with water, brine, and dried with magnesium sulfate. The organic phases were concentrated and the residue was loaded onto silica gel and chromatographed with hexanes:ethyl acetate (50% to 100%) to afford 0.13 g of the title compound as an off-white solid. MS (ESI) m/z 332;
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34](C)=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]=O)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][C@@H:51]1[CH2:56][NH:55][CH2:54][C@H:53]([CH3:57])[NH:52]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:55]6[CH2:54][C@H:53]([CH3:57])[NH:52][C@H:51]([CH3:50])[CH2:56]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(C=O)c3)c2C)c1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4C[C@@H](C)N[C@@H](C)C4)c3)c2)c1
Yield: 40.1 %

Procedure:
A mixture of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-2-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.000152 mol) in 1,2-dichloroethane (4 mL) with (2R,6S)-2,6-dimethylpiperazine (27.4 mg, 0.00024 mol) and sodium triacetoxyborohydride (68 mg., 0.00032 mol) and AcOH (12 μL) was placed on an oscillating shaker overnight at room temperature. The reaction was quenched with sat. aq. NaHCO3, then extracted with 1,2-dichloroethane (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. Purification was carried out on a Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP Column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of 1,2-dichloroethane and transferred to a vial and pumped down to afford the title compound as a pale brown colored solid [45.3 mg (39%)]. LC-MS m/z 757.5 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C:9]2[O:13][C:12](=[O:14])[NH:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].IC.[CH3:19]N(C)C=O.[H-].[Na+]>O>[CH3:19][N:11]1[N:10]=[C:9]([CH2:8][C:7]2[CH:15]=[CH:16][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[O:13][C:12]1=[O:14]
Reactant: O=c1[nH]nc(Cc2ccc([N+](=O)[O-])cc2)o1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1nc(Cc2ccc([N+](=O)[O-])cc2)oc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a mixture of 5-(4-nitrobenzyl)-1,3,4-oxadiazol-2(3H)-one (1.0 g), iodomethane (0.97 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.20 g) at room temperature. The reaction mixture was stirred at room temperature for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-methyl-5-(4-nitrobenzyl)-1,3,4-oxadiazol-2(3H)-one as colorless crystals (0.75 g, yield 71%) from a fraction eluted with hexane-ethyl acetate (3:1-2:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 115-116° C.
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][CH2:20][C:21]#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][OH:36].[OH-:37].[K+]>C(#N)C.CCOC(C)=O>[O:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[O:19][CH2:20][C:21]#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36]
Reactant: [OH-]
Reactant: OCCCCCCCCCCCCCC#CCOC1CCCCO1
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(O)CCCCCCCCCCCCC#CCOC1CCCCO1
Reaction time: 0.17 h
Yield: 91 %

Procedure:
RuCl3 (10 mg) and potassium persulphate (2.8 g, 10.2 mmol) were added to a solution of 16-(tetrahydro-2H-pyran-2-yloxy)hexadec-14-yn-1-ol (1.2 g, 3.55 mmol) in acetonitrile (20 mL). After 10 min, KOH (30 mL of a 2 M soln) was added. After an additional 3 h, the reaction mixture was neutralized to pH 7, diluted with EtOAc (100 mL), and washed with water (3×75 mL). The combined aqueous extracts were back-extracted with EtOAc (3×75 mL). All of the organic extracts were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by SiO2 column chromotography using 20% EtOAc/hexanes as eluent to give 16-(tetrahydro-2H-pyran-2-yloxy)hexadec-14-ynoic acid (1.05 g, 91%) as a colorless oil that was used without further purification. TLC: 50% EtOAc/hexanes, Rf≈0.35. Lit. ref.: R. S. Varma; M. Hogan Tetrahedron Lett. 1992: 33, 719.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([CH2:14][OH:15])=[CH:12][N:11]=[C:10]3[N:16]([S:19]([C:22]4[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[CH:17]=[CH:18][C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH:1]1([NH:7][C:8]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[C:10]3[N:16]([S:19]([C:22]4[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=4)(=[O:21])=[O:20])[CH:17]=[CH:18][C:9]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCCC4)c(CO)cnc32)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(NC4CCCCC4)c(C=O)cnc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.6 %

Procedure:
A mixture of (4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol (1.12 g, 2.80 mmol) and manganese dioxide (5.48 g, 63.1 mmol) in chloroform (70 mL) was stirred at ambient temperature for about 18 h. The reaction mixture was diluted with chloroform (100 mL) and the reaction mixture was filtered through a pad of Celite® while washing with chloroform (50 mL). The filtrate was concd under reduced pressure to give 4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (0.975 g, 87%) as an off white solid: LC/MS (Table 1, Method c) Rt=1.70 min; MS m/z: 398 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([O:23]C)[CH:16]=2)=[N:10][C:9]=1[C:25]1[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>>[CH2:1]([C:8]1[S:12][C:11]([CH2:13][CH2:14][C:15]2[CH:16]=[C:17]([OH:23])[C:18]([OH:21])=[CH:19][CH:20]=2)=[N:10][C:9]=1[C:25]1[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2nc(CCc3ccc(OC)c(OC)c3)sc2Cc2ccccc2)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2nc(CCc3ccc(O)c(O)c3)sc2Cc2ccccc2)cc1
Yield: 52.2 %

Procedure:
A procedure similar to that in Example 7 was used. 5-benzyl-2-[2-(3,4-dimethoxy-phenyl)-ethyl]-4-(4-methoxy-phenyl)-thiazole prepped in step 4 of Example 77 and boron tribromide were as starting materials, the crude product was recrystallized with acetone to obtain a product as a white solid in a yield of 52.2%, mp: 177-178 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 2.82 (2H, t, J=8.16 Hz, ArH), 3.11 (2H, t, J=8.16 Hz, ArH), 4.20 (2H, s, CH2), 6.48 (1H, d, J=8.12 Hz, ArH), 6.58˜6.64 (2H, m, ArH), 6.82 (2H, d, J=8.40 Hz, ArH), 7.14˜7.26 (3H, m, ArH), 7.32 (2H, t, J=7.28 Hz, ArH), 7.44 (2H, d, J=8.40 Hz, ArH), 8.69 (1H, s, OH), 8.75 (1H, s, OH), 9.61 (1H, s, OH); EI-MS m/e (%): 403.2 (M+, 67), 281.2 (100); HREI-MS Calcd. for C24H21NO3S: 403.1242. found: 403.1238.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[C:4]([CH3:10])[CH:3]=1.[N+:11]([CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1)([O-])=[O:12].C1(N=C=O)C=CC=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:14]([CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:9]=2)=[C:4]([CH3:10])[CH:3]=1
Reactant: C#Cc1ccc(Br)cc1C
Reactant: O=[N+]([O-])CCOC1CCCCO1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O=C=Nc1ccccc1
Product: Cc1cc(Br)ccc1-c1cc(COC2CCCCO2)no1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a flask containing a solution of 4-bromo-1-ethynyl-2-methylbenzene (875 mg, 4.49 mmol) (may be prepared according to the procedures in Journal of Chemical Research (2007), 12 728-732) in toluene (20 mL), was added 2-(2-nitroethoxy)tetrahydro-2H-pyran (1.34 g, 7.63 mmol), phenyl isocyanate (1.82 g, 15.3 mmol), and triethylamine (1.50 mL, 10.8 mmol). The reaction was heated at 100° C. and stirred under nitrogen overnight. The reaction was cooled, quenched with methanol and filtered. The filtrate was evaporated in vacuo onto silica gel. Chromatography on silica gel with a heptane-ethyl acetate gradient (0-35% ethyl acetate) eluted 5-(4-bromo-2-methylphenyl)-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]isoxazole as an orange oil (581 mg, 36.8%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.57-1.71 (m, 4 H) 1.73-1.82 (m, 1 H) 1.82-1.91 (m, 1 H) 2.51 (s, 3 H) 3.56-3.62 (m, 1 H) 3.89-3.96 (m, 1 H) 4.69 (d, J=12.88 Hz, 1 H) 4.76-4.79 (m, 1 H) 4.86 (d, J=12.88 Hz, 1 H) 6.51 (s, 1 H) 7.42-7.46 (m, 1 H) 7.48 (d, J=1.56 Hz, 1 H) 7.59 (d, J=8.20 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](O)=[O:9].S(Cl)([Cl:20])=O>Cl.C(N(CC)CC)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([Cl:20])=[O:9]
Reactant: O=C(O)c1cccnc1Oc1cccc(Cl)c1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Cl)c1cccnc1Oc1cccc(Cl)c1
Yield: 97.8 %

Procedure:
In the same manner as in Example 1(a), 22.1 grams 2(3-chlorophenoxy)nicotinic acid, 13.0 grams (0.1 mole) thionyl chloride, 0.5 grams triethylamine hydrochloride and 200 milliliters chloroform were combined to yield 23.2 grams (98.3% of theoretical) of 2(3-chlorophenoxy)nicotinoyl chloride, m.p. 72°-74° C. The structure was confirmed by mass spectrometry.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COCCOC>[NH2:14][C:13]1[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Nc1ccccc1Br
Reactant: Cc1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Cc1ccccc1-c1ccccc1N
Temperature: 25 °C
Yield: 84.9 %

Procedure:
Added together 2-methylphenyl boronic acid (24.7 g, 181 mmol), 2-bromo aniline (25.7 g, 151 mmol), palladium(II)acetate (0.85 g, 3.78 mmol), triphenylphosphine (4.0 g, 15.1 mmol), a 2 M solution of potassium carbonate (204 mL) and ethylene glycol dimethyl ether (223 mL) and heated the reaction mixture at reflux for 18 hours. After the reaction was cooled to room temperature, the aqueous phase was separated from the organic phase. The aqueous phase was extracted with ethyl acetate and the organic extractions were combined, dried over magnesium sulfate and filtered. The crude product was purified by silica gel column chromatography using 10% ethyl acetate in hexanes as the eluants. The pure fractions were collected, combined and concentrated to give 2-amino-2′-methyl-biphenyl (23.5 g, 84.8% yield) whose structure was confirmed by GCMS and NMR.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>O1CCOCC1>[NH:11]1[CH2:12][CH2:13][CH:8]([C:5]2[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=2)[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccncc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1cc(C2CCNCC2)ccn1
Yield: 99.9 %

Procedure:
1.54 ml of a 4N solution of hydrochloric acid in dioxane are added dropwise using a dropping funnel to a 25 ml round-bottomed flask comprising 0.552 g of tert-butyl 4-(pyridin-4-yl)piperidine-1-carboxylate. Stirring is maintained for 1 hour. The product is subsequently concentrated under vacuum and then treated with a 1N aqueous sodium hydroxide solution. The aqueous phase is extracted 3 times with dichloromethane. The organic phase is dried over sodium sulfate and concentrated under reduced pressure. 0.341 g of 4-(piperidin-4-yl)pyridine is obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:50]1[CH:54]=[C:53]([C:55]2[CH:56]=[C:57]([NH2:61])[CH:58]=[CH:59][CH:60]=2)[CH:52]=[N:51]1>CN(C=O)C>[NH:50]1[CH:54]=[C:53]([C:55]2[CH:56]=[C:57]([NH:61][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:58]=[CH:59][CH:60]=2)[CH:52]=[N:51]1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2cn[nH]c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cn[nH]c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 25.5 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-pyrazol-4-yl)-phenylamine (0.011 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.006 g of product in 24% yield: LCMS (ESI) m/z 362 (MH+).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][C:4]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1.CCOC(/N=N/C(OCC)=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([O:1][CH:2]2[CH2:5][C:4]3([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]3)[CH2:3]2)=[CH:40][CH:39]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O)C2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(Oc1ccc(Cl)cc1)C2
Temperature: 0 °C
Reaction time: 14 h
Yield: 99.8 %

Procedure:
Under an inert atmosphere, 0.60 g (2.49 mmoles) of tert-butyl 2-hydroxy-7-aza-spiro[3.5]-nonane-7-carboxylate (WO 2003084948) is dissolved in 25 ml of toluene. 1.024 g (3.90 mmoles) of triphenylphosphine and 0.384 g (2.98 mmoles) of 4-chlorophenol are added. The medium is cooled to 0° C., then a solution of 0.528 g (3.03 mmoles) of diethylazodicarboxylate in 3 ml of toluene is added. The medium is stirred for 14 hrs at ambient temperature then concentrated under vacuum. The residue obtained is taken up in a saturated aqueous solution of sodium carbonate and extracted twice with dichloromethane. The combined organic phases are washed once with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, filtered and concentrated under vacuum. 0.874 g of a residue is obtained, which is used as such in the following stage.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][OH:8])[C:5](=[O:9])[CH:4]([CH3:10])[N:3]1[CH2:11][C:12]#[CH:13].[Cl:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[NH:25][C@H:26]([C:30](O)=[O:31])[CH:27]([CH3:29])[CH3:28].CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C=O>[Cl:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[NH:25][CH:26]([CH:27]([CH3:29])[CH3:28])[C:30]([O:8][CH2:7][N:6]1[C:5](=[O:9])[CH:4]([CH3:10])[N:3]([CH2:11][C:12]#[CH:13])[C:2]1=[O:1])=[O:31]
Reactant: C#CCN1C(=O)N(CO)C(=O)C1C
Reactant: CC(C)[C@H](Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C#CCN1C(=O)N(COC(=O)C(Nc2ccc(C(F)(F)F)cc2Cl)C(C)C)C(=O)C1C
Reaction time: 2 h

Procedure:
To a stirred solution of (2,4-dioxo-5-methyl-1-propargyl-3-imidazolidinyl)methanol (1.8 mmol), N-(2-chloro-4-trifluoromethylphenyl)valine (2.0 mmol) and dimethylaminopyridine (0.65 mmol) in 20 ml of methylene chloride and 2 ml of dimethylformamide is added N,N'-dicyclohexylcarbodiimide (2.0 mmol). The reaction mixture is stirred, under nitrogen, for two hours and then filtered and extracted with water. The aqueous phase is extracted with ether. The combined organic phases are washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over calcium sulfate and solvent evaporated. The crude product is chromatographed on a rotary chromatograph, eluting with 25% ether/hexane, to yield (2,4-dioxo-5-methyl-1-propargyl-3-imidazolidinyl)methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([CH2:15]Cl)[CH:12]=[CH:11][N:10]=2)[CH:4]=1.C([O:19][P:20]([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])C>C(Cl)Cl.CCCCCC>[CH3:23][CH2:22][O:21][P:20]([O:24][CH2:25][CH3:26])([CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([CH2:15][P:20]([O:21][CH2:22][CH3:23])([O:24][CH2:25][CH3:26])=[O:19])[CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: ClCc1ccnc(-c2cc(CCl)ccn2)c1
Reactant: CCOP(OCC)OCC
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOP(=O)(Cc1ccnc(-c2cc(CP(=O)(OCC)OCC)ccn2)c1)OCC

Procedure:
Compound 5 (2.6 g, 10.3 mmol) was refluxed overnight under N2 in triethylphosphite (50 ml). Excess P(OEt)3 was evaporated and the resulting brown oil was column chromatographed (Al2O3, CH2Cl2/MeOH: 98/2). The yellow oil thus obtained was dissolved in a mixture of CH2Cl2/hexane (1/50 ml) and let stand in the freezer to afford after filtration 4 g (85%) of compound 6 as a slightly yellow crystalline solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH2:12][CH3:13])[N:3]=1.CO.[CH3:16][NH2:17]>O>[CH2:12]([O:11][C:4]1[N:3]=[C:2]([NH:17][CH3:16])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)[CH3:13]
Reactant: CN
Reactant: CCOc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: O
Solvent: CO
Product: CCOc1ccc([N+](=O)[O-])c(NC)n1
Reaction time: 1.5 h

Procedure:
In a stirred mixture consisting of 202.6 g (1 mole) of 2-chlor-6-ethoxy-3-nitropyridine and 500 ml of methanol, 202 g (2.6 mole) of a 40% monomethylamine solution is added drop by drop while stirring in the course of 90 minutes and at 25°-30° C. sump temperature. Subsequently, the mixture is again stirred for yet another 5 hours, is reacted with 650 ml of water, and then the product is filtered off by suction, is washed again with ample water and dried. Melting point 106°-7° C., Yield: 183.2 g (92.9% of theory).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31](O)=[O:32])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:14]=23)[CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:37][CH2:36]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[C:19]([C:31]([NH:34][C@@H:35]4[CH2:40][CH2:39][C@H:38]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:37][CH2:36]4)=[O:32])=[C:20]([CH3:30])[N:21]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])[C:14]=23)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c1
Product: Cc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-methylphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c6) and commercially available tert-butyl cis-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.