Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:18](CC(C)C)[CH2:19][C:20]([OH:22])=[O:21])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].S(Cl)(Cl)=O.CN(C=O)C>ClCl>[NH:18]([C:1]([O:3][CH2:4][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:2])[C@H:19]([C:20]([OH:22])=[O:21])[CH2:4][CH:5]([CH3:17])[CH3:6]
Reactant: CC(C)CN(CC(=O)O)C(=O)OCC1c2ccccc2-c2ccccc21
Agent: ClCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reaction time: 5 h

Procedure:
FMOC-Leu*-Cl was prepared by dissolving FMOC-N-isobutylglycine (150 mg, 0.42 mmol) in CH2 Cl2 (2.8 mL), and adding thionyl chloride (309 μL, 4.2 mmol) and 3 μL DMF (0.04 mmol). The reaction mixture was stirred for 5 hours and concentrated in vacuo, repeatedly dissolving in CH2 Cl2 (3××) to provide FMOC-Leu*-Cl as a colorless oil (146 mg, 92%): IR (cm−1) -1804, 1720, 1715. FMOC-Phe*-Cl was similarly prepared.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([OH:28])[CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]3[S:25][C:24]([CH3:26])=[N:23][C:22]=3[CH:27]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)Cl>CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>[CH3:26][C:24]1[S:25][C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH:15]([OH:28])[CH2:14][N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:27][C:22]=2[N:23]=1
Reactant: Cc1nc2cc(OCC(O)CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2cc(OCC(O)CN3CCNCC3)ccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-piperazine-1-carboxylic acid tert-butyl ester, a compound of formula (5) (2.0 g, 4.9 mmol), and 25% trifluoroacetic acid/methylene chloride (20 ml) was allowed to stir at room temperature overnight. The solvent was evaporated (in vacuo) to yield an oil. The oil was diluted with acetone (20 ml) and solid potassium carbonate was added until the foaming stopped. The resulting mixture was allowed to stir overnight. The solution was filtered through Celite 512, and the filtrate was evaporated (in vacuo), to yield an oil. The oil was placed under high vacuum overnight, to yield 1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol, as a clear viscous oil (3.4 g. 6.3 mmol).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:44]([O:46]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:45])[CH2:10][S:11][CH2:12][CH2:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:17][C@@H:16]([NH:31][C:32]([C:34]2[NH:35][C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[C:15]1=[O:43])=O)(C)(C)C.C(OC(N[C@H](C(OC(C1C=CC=CC=1)C1C=CC=CC=1)=O)CSCCN1C2C=CC=CC=2C(C2C=CC=CC=2)=N[C@H](NC(C2NC3C(C=2)=CC=CC=3)=O)C1=O)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C@H:9]([C:44]([OH:46])=[O:45])[CH2:10][S:11][CH2:12][CH2:13][N:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:17][C@H:16]([NH:31][C:32]([C:34]2[NH:35][C:36]3[C:41]([CH:42]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[C:15]1=[O:43]
Reactant: CC(C)(C)OC(=O)N[C@@H](CSCCN1C(=O)[C@H](NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21)C(=O)OC(c1ccccc1)c1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H](CSCCN1C(=O)[C@@H](NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21)C(=O)OC(c1ccccc1)c1ccccc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](CSCCN1C(=O)[C@@H](NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of a mixture (0.66 g) of (3R)-1-[2-((2R)-2-tert-butoxycarbonylamino-2-benzhydryloxycarbonylethylthio)ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepine-2-one and (3S)-1-[2-((2R)-2-tert-butoxycarbonylamino-2benzhydryloxycarbonylethylthio)ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepine-2-one, anisole (0.6 ml), trifluoroacetic acid (1.5 ml) and dichloromethane (15 ml) was stirred for 3.0 hours at room temperature. After removal of the solvent, the residue was mixed with ethyl acetate (50 ml) and water (50 ml). The mixture was adjusted to pH 6-7 with 5% aqueous solution of sodium bicarbonate under stirring. The organic layer was separated and concentrated. The resultant precipitate was collected by filtration, washed with water and dried to give a mixture (0.20 g) of (3R)-1-[2-((2R)-2-amino-2-carboxyethylthio)ethyl]-1,3-dihydro -3-(2-indolylcarbonylamino -5-phenyl-2H-1,4-benzodiazepine- 2-one and (3S)-1-[2-((2R)-2-amino-2-carboxyethylthio) ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepine-2-one.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7]Cl)([O-:3])=[O:2].[CH3:15][C:16]1[C:24]([CH3:26])([CH3:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.[I-:27].[Na+]>S1(CCCC1)(=O)=O>[I-:27].[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7][N+:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:24]([CH3:26])([CH3:25])[C:16]=1[CH3:15])([O-:3])=[O:2]
Reactant: CC1=Nc2ccccc2C1(C)C
Reactant: O=[N+]([O-])c1cc(CCl)cc([N+](=O)[O-])c1
Agent: [I-]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Product: CC1=[N+](Cc2cc([N+](=O)[O-])cc([N+](=O)[O-])c2)c2ccccc2C1(C)C
Temperature: 25 °C
Yield: 57 %

Procedure:
3,5-Dinitrobenzyl chloride (100 mg, 0.46 mmol), 2,3,3-trimethylindole (74 μ, 73.2 mg, 0.46 mmol) and sodium iodide (69 mg, 0.46 mmol) were heated at 100° C. in sulpholane (5 ml) for 16 hours. After cooling to room temperature the product was isolated by reverse phase HPLC (89.7 mg, 0.26 mmol, 57% yield).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH:17]([NH:19][C:20]2[N:25]=[C:24]([N:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]=[CH:27]3)[CH:23]=[CH:22][N:21]=2)[CH3:18])[CH2:12]1)=O)C1C=CC=CC=1.Br>C(Cl)Cl.C(O)(=O)C>[NH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH:17]([NH:19][C:20]2[N:25]=[C:24]([N:26]3[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[N:28]=[CH:27]3)[CH:23]=[CH:22][N:21]=2)[CH3:18])[CH2:12]1
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCN(C(=O)OCc2ccccc2)C1
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCNC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85.5 %

Procedure:
The 2-[1-(1-benzyloxycarbonylpiperidin-3-yl)-ethylamino]-4-[benzimidazol-1-yl]pyrimidine (900 mg, 1.97 mmol) was dissolved in CH2Cl2 (25 mL), and the mixture was cooled down to 0° C. To this was added 30% HBr in acetic acid (5 mL) slowly and continued stirring at 0° C. for 15 min The bath was removed, and the reaction mixture was stirred at room temperature for 45 min and then was diluted with H2O (25 mL). The reaction mixture was extracted with CH2Cl2 (2×20 mL; discarded), then the aqueous layer was made neutral with 5N NaOH and extracted with EtOAc (3×25 mL; discarded). The aqueous layer was made strongly basic (>pH 12) with SN NaOH, and was extracted with EtOAc (4×30 mL). The combined extracts were washed with brine and dried over Na2SO4. After removal of solvent under reduced pressure, 543 mg of the title compound was obtained which was used without purification. Partial 1H NMR (500 MHz, CDCl3): δ 8.61 (s, 1H); 8.36 (br s, 1H); 8.16 (d, J=8 Hz, 1H); 7.85 (d, J=8.5 Hz, 1H); 7.38 (m, 2H); 6.75 (d, J=5.4 Hz, 1H); 5.14 (s, 2H); 4.1 (m, 1H); 3.18 (d, J=12 Hz, 1H); 3.02 (d, J=12 Hz, 1H); 1.23 (d, J=6.6 Hz, 3H).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[OH:26][C:27]1([C:30](O)=[O:31])[CH2:29][CH2:28]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:30]([C:27]5([OH:26])[CH2:29][CH2:28]5)=[O:31])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: O=C(O)C1(O)CC1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1)C1(O)CC1

Procedure:
The title compound, white solid (18.3 mg, 64.8%), MS (ISP) m/z=415.2 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25 mg, 0.0681 mmol) and 1-hydroxycyclopropanecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]#[C:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][CH:11]=1)[NH2:8].[H][H]>O1CCCC1.[Ru]>[CH3:1][C:2]([CH3:13])([CH3:12])[CH2:3][CH2:4][CH:5]1[CH2:11][CH2:10][CH2:9][CH:7]([NH2:8])[CH2:6]1
Reactant: [H][H]
Reactant: CC(C)(C)C#Cc1cccc(N)c1
Agent: [Ru]
Solvent: C1CCOC1
Product: CC(C)(C)CCC1CCCC(N)C1
Temperature: 25 °C

Procedure:
0.5 g of Ru/C 5% is added to a solution consisting of 1.04 g (0.6 mol) of 3-(3,3-dimethylbut-1-yn-1-yl)aniline in 20 ml of tetrahydrofuran, and the mixture is hydrogenated with 100 bar of hydrogen at 120° C. for 40 hours. After cooling to room temperature, the catalyst is filtered off through kieselguhr and the product is concentrated under reduced pressure. This gives 0.9 g (81% of theory) of 3-(3,3-dimethylbutyl)cyclohexanamine as main component according to MSD-HPLC.
Reaction SMILES: O.Cl.[NH2:3][C@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1>[OH-].[Na+].C(O)C>[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][S:6][CH2:5][C@@H:4]([C:7]([OH:9])=[O:8])[NH2:3])=[CH:14][CH:13]=1
Reactant: Cc1ccc(CBr)cc1
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(CSC[C@H](N)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
L-Cysteine hydrochloride monohydrate (2.0 g) is dissolved in a 2 N aqueous sodium hydroxide solution (11.4 ml). To the solution is added a solution of α-bromo-p-xylene (2.3 g) in ethanol (10 ml). The mixture is stirred at room temperature for 40 minutes, and precipitating crystals are filtered off. The obtained crystals are purified by recrystallization to give the titled compound.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20](O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O1CCCC1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=O)cc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 150.6 %

Procedure:
A solution of 4.9 g (0.040 mol) 4-hydroxy-benzaldehyde, 10.0 g (0.050 mol) 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (analogously to K. L. Bhat, D. M. Flanagan, M. M. Jouille, Synth. Commun. 1985, 15, 587-598) and 13.1 g (0.050 mol) triphenylphosphine in 200 ml tetrahydrofuran is mixed at 5° C. with 7.9 ml (0.050 mol) azodicarboxylic acid diethyl ester and stirred for 24 hours at room temperature. After concentration the residue is purified by chromatography on a silica gel column (mobile solvent: isohexane/ethyl acetate 8:2, 7:3). After concentrating the appropriate column fractions one obtains 18.4 g (85%) of the title compound as a yellowish solid substance. Melting point. 63-64° C.; EI-MS: 305 (M+).
Reaction SMILES: C1(=O)[N:5]([O:6][CH2:7][C:8]([O:10][CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])C(=O)C2=CC=CC=C12.O.NN>C(Cl)Cl.CO>[NH2:5][O:6][CH2:7][C:8]([O:10][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: O=C(CON1C(=O)c2ccccc2C1=O)OC(c1ccccc1)c1ccccc1
Agent: NN
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: NOCC(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
To a solution of benzhydryl 2-phthalimidooxyacetate (10 g) in methylene chloride (100 ml) was added a solution of hydrazine hydrate (6.08 g) in methanol (7 ml). The reaction mixture was stirred at ambient temperature for an hour. The precipitates were collected by filtration and washed with methylene chloride. The filtrate and the washings were combined, adjusted to pH 7.0 with conc. hydrochloric acid, and washed with a saturated aqueous sodium chloride, and then dried over magnesium sulfate. The solution was evaporated in vacuo to give benzhydryl 2-aminooxyacetate (6.0 g).
Reaction SMILES: C[Mg]Br.[NH:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[C:7]=2[CH:6]=[CH:5]1.[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1[CH2:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>C(OCCCC)CCC.CN(C)C=O>[CH3:16][O:15][C:13]([C:8]1[C:7]2[C:6]([CH2:33][C:32]3[CH:31]=[CH:30][C:29]([O:28][CH2:27][C:18]4[CH:19]=[CH:20][C:21]5[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:17]=4)=[CH:36][CH:35]=3)=[CH:5][NH:4][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:14]
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: ClCc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: C[Mg]Br
Solvent: CN(C)C=O
Solvent: CCCCOCCCC
Product: COC(=O)c1cccc2[nH]cc(Cc3ccc(OCc4ccc5ccccc5n4)cc3)c12
Temperature: 25 °C

Procedure:
A solution of methyl magnesium bromide in n-butyl ether (1.0M, 10.3 ml) was added dropwise to a solution of methyl indole-4-carboxylate (1.5 g) in dry dimethylformamide (15 ml) stirred under an atmosphere of nitrogen at room temperature. The mixture was stirred at room temperature for 20 minutes then a solution of 4-(quinolin-2-ylmethoxy)benzyl chloride (Example 1a) (2.35 g) in dry dimethylformamide (10 ml) added dropwise. The mixture was stirred at room temperature overnight, concentrated in vacuo, diluted with ethyl acetate and washed with water and a saturated solution of ammonium chloride; the organic phase was dried, filtered and evaporated. The residue was purified by chromatography on flash silica, eluting with petroleum spirit 40°-60° C.--diethyl ether (1:1) to give the product as a white solid. A small quantity was crystallised from petroleum spirit 40°-60° C.--diethyl ether (1:1), m.p. 148°-150° C.
Reaction SMILES: O1C[CH2:5][CH:4]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:16]=[CH:17][C:18]4[N:19]([C:21]([C:24]([F:27])([F:26])[F:25])=[N:22][N:23]=4)[N:20]=3)[CH2:11][CH2:10]2)[CH2:3]C1.O.[C:29]1(C)C=CC(S(O)(=O)=O)=CC=1.CC(C)=C>C(Cl)Cl>[C:4]([O:7][CH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([C:24]([F:27])([F:25])[F:26])=[N:22][N:23]=3)[N:20]=2)[CH2:13][CH2:14]1)([CH3:5])([CH3:29])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCC(COC4CCOCC4)CC3)nn12
Agent: C=C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OCC1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.8 %

Procedure:
A stirred solution of [1-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]methanol (obtained as described in Example 294, preparation of starting materials) (151 mg, 0.5 mmol) and p-toluenesulfonic acid monohydrate (190 mg, 1.0 mmol) in DCM (2 mL) was cooled to −70° C. and 2-methylpropene (1 mL, 10.48 mmol) was condensed in from a cylinder. The mixture was stirred for 2 days at ambient temperature in a sealed tube. The tube was re-cooled to open then allowed to warm to ambient temperature with stirring. The solution was diluted with DCM and washed with 2M aqueous K2CO3. The organic phase was dried over MgSO4 and evaporated. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-(4-(tert-butoxymethyl)piperidin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (98 mg, 54%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][CH:19]2[CH2:23][CH2:22][C:21]3(OCCC[O:24]3)[CH2:20]2)[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:18][CH:19]2[CH2:23][CH2:22][C:21](=[O:24])[CH2:20]2)[C:10]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1nccs1)C(CC1CCC2(C1)OCCCO2)c1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(CC(C(=O)Nc2nccs2)c2ccc(Cl)c(Cl)c2)C1
Yield: 72.3 %

Procedure:
A solution of crude 2-(3,4-dichloro-phenyl)-3-(6,10-dioxa-spiro[4.5]dec-2-yl)-N-thiazol-2-yl-propionamide (768.5 mg, 1.74 mmol) in tetrahydrofuran (8.7 mL) and a 5% aqueous hydrochloric acid solution (3.9 mL) was stirred at 25° C. for 64 h. The resulting reaction solution was concentrated in vacuo to remove tetrahydrofuran and then diluted with ethyl acetate (100 mL). The organic layer was washed with a 1% aqueous hydrochloric acid solution (50 mL), water (50 mL) and a saturated aqueous sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50% ethyl acetate/hexanes) afforded 2-(3,4-dichloro-phenyl)-3-(3-oxo-cyclopentyl)-N-thiazol-2-yl-propionamide (481.9 mg, 47% over 2 steps) as a white solid: mp 146-148° C.; (ES)+-HRMS m/e calcd for C17H16C12N2O2S (M+H)+ 383.0383. found 383.0385.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:10]1([NH2:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(#N)C>[CH:10]1([NH:16][C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)NC1CCCCC1
Temperature: 90 °C
Yield: 20.2 %

Procedure:
A stirred suspension of ethyl 2-bromo-2-methylpropanoate (0.975 g, 5 mmol), cyclohexanamine (0.496 g, 5.00 mmol), potassium carbonate (1.382 g, 10.00 mmol) and sodium iodide (0.600 g, 4.00 mmol) in acetonitrile (10 ml) was heated at 90° C. overnight under nitrogen. The reaction mixture was cooled, filtered and evaporated to dryness and then purified by silica gel FCC (5% EtOAc in DCM) to afford ethyl 2-(cyclohexylamino)-2-methylpropanoate as a clear oil (215 mg, ˜20%). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 4.16 (q, J=7.2 Hz, 2H), 2.38-2.29 (m, 1H), 1.86-1.78 (m, 2H), 1.74-1.67 (m, J=13.5, 3.4, 3.4 Hz, 2H), 1.66-1.55 (m, 2H), 1.31 (s, 6H), 1.30-1.27 (m, 3H), 1.27-1.19 (m, 2H), 1.15-1.04 (m, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[C:24]1([N:30]2[CH:34]=[C:33]([CH2:35][CH2:36][C:37]3[N:38]=[CH:39][S:40][CH:41]=3)[C:32]([OH:42])=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C)C=O.[H-].[Na+]>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:42][C:32]3[C:33]([CH2:35][CH2:36][C:37]4[N:38]=[CH:39][S:40][CH:41]=4)=[CH:34][N:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:31]=3)=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: Oc1nn(-c2ccccc2)cc1CCc1cscn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(-c3ccccc3)cc2CCc2cscn2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.6 %

Procedure:
To a mixture of 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-5-methyl-1,3-oxazole (0.57 g), 1-phenyl-4-[2-(1,3-thiazol-4-yl)ethyl]-1H-pyrazol-3-ol (0.38 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.060 g) at room temperature, and the mixture was stirred at room temperature for 4 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-(2-furyl)-4-({2-methoxy-4-[({1-phenyl-4-[2-(1,3-thiazol-4-yl)ethyl]-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole as colorless crystals (0.53 g, yield 66%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 127-128° C.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:39])=[C:5]([C:30]([O:37]C)=[C:31]([O:35][CH3:36])[C:32]=1[O:33][CH3:34])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:34][O:33][C:32]1[C:3](=[O:2])[C:4]([CH3:39])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:21][CH2:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])=[C:11]([CH:20]=2)[C:12]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[O:13])[C:30](=[O:37])[C:31]=1[O:35][CH3:36]
Reactant: COc1c(C)c(Cc2ccc(OCC(=O)OC(C)(C)C)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCC(=O)OC(C)(C)C)c(C(=O)N3CCCCC3)c2)=C(C)C1=O
Yield: 63.4 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(tert-butoxycarbonylmethyloxy)benzoyl]piperidine (0.292 g, 0.538 mmol) was dissolved in a mixed solution of acetonitrile (12 ml) and water (4 ml) and after adding thereto CAN (0.737 g, 1.34 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=2:1) to obtain the titled compound (0.175 g, 0.341 mmol, 63%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-])=O)=[C:7]([CH3:15])[CH:6]=1)[CH3:2].Cl>C(O)C.[Fe]>[CH2:1]([O:3][CH2:4][C:5]1[CH:6]=[C:7]([CH3:15])[C:8]([NH2:12])=[C:9]([CH3:11])[CH:10]=1)[CH3:2]
Reactant: CCOCc1cc(C)c([N+](=O)[O-])c(C)c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CCOCc1cc(C)c(N)c(C)c1

Procedure:
To a solution of the product from Step B (10.0 g) in 50% aqueous ethanol (150 ml) is added iron powder (7.5 g) and concentrated hydrochloric acid (2.0 ml in 10 ml ethanol). The mixture is stirred mechanically at reflux for 2 hours. The solids are filtered hot, washed with ethanol and discarded. The filtrate is neutralized with sodium bicarbonate, evaporated to a residue and extracted with dichloromethane. The organic phase is treated with charcoal and a small amount of silica gel, dried, and evaporated to afford crude, syrupy 4-ethoxymethyl-2,6-dimethylaniline. The product could be purified further by silica gel chromatography [cyclohexane/ethyl acetate (19:1)] or used directly in the next step. Yield after chromatography is 4.8 g.