Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=O.[CH:12]([NH:14][NH2:15])=[O:13]>C(O)C.Cl>[CH:12]([NH:14][N:15]=[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:13]
Reactant: O=C1CCc2ccccc2C1
Reactant: NNC=O
Agent: Cl
Solvent: CCO
Product: O=CNN=C1CCCc2ccccc21
Temperature: 70 °C
Yield: 36.3 %

Procedure:
A mixture of 1,2,3,4-tetrahydronaphthalen-2-one (3.5 g, 24.0 mmol) and formic hydrazide (1.56 g, 26.0 mmol) in 25 mL of ethanol and 1 drop of concentrated hydrochloric acid was heated at 70° C. for 1 hour. The mixture was cooled to room temperature giving a crystalline material. The material was isolated by filtration and washed with ethanol. Drying gave 2-formylhydrazono-1,2,3,4-tetrahydronaphthalene (3.5 g, 8.7 mmol).
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH:20]3[CH3:24])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.C(OCC)(=O)C.[ClH:31]>CO.[OH-].[OH-].[Pd+2]>[ClH:31].[CH3:24][CH:20]1[CH2:21][CH2:22][CH2:23][N:19]1[C:17]1[CH:16]=[N:15][C:13]2[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=2[N:18]=1
Reactant: CC1CCCN1c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1CCCN1c1cnc2c(n1)OCCNC2
Temperature: 50 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
To a solution of 8-benzyl-3-(2-methylpyrrolidin-1-yl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepine (0.51 g) in methanol (15 mL) was added 20% Pd(OH)2/C (0.08 g), and the mixture was stirred under a hydrogen atmosphere at 50° C. for 1 hr. The reaction mixture was filtered, and the filtrate was concentrated. To a solution of the obtained crude product in ethyl acetate (15 mL) was added a 4 N hydrogen chloride-ethyl acetate solution (430 μL) and the mixture was stirred for 30 min. The reaction mixture was filtered, and the obtained crystals were purified by recrystallization (methanol-ethyl acetate) to give the title compound (0.30 g, 71%) as a colorless powder.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([C:21]([C:24]2[CH:29]=[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]3[CH3:36])[N:27]=[C:26]([C:37]3[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=3)[N:25]=2)([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(=O)([O-])O.[Na+]>O1CCOCC1.C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([C:21]([C:24]2[CH:29]=[C:28]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]3[CH3:36])[N:27]=[C:26]([C:37]3[CH:38]=[CH:39][C:40]([NH:41][C:2](=[O:3])[O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)=[CH:42][CH:43]=3)[N:25]=2)([CH3:22])[CH3:23])(=[O:19])=[O:20])=[CH:14][CH:13]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccc(Cl)cc2)nc(-c2ccc(N)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(=O)(=O)c2ccc(Cl)cc2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
Phenyl chloroformate (0.256 mL, 2.04 mmol) was added dropwise to 4-[4-[2-(4-chlorophenyl)sulfonylpropan-2-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl]aniline (850 mg, 1.85 mmol) and sodium hydrogencarbonate (233 mg, 2.78 mmol) in dioxane (20 mL) at RT. The resulting suspension was stirred at RT for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (2×100 mL) and saturated brine (50 mL). The organic layer was dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 30 to 50% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the desired material as a white solid (955 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[OH:31])[C:5]2=[CH:4][CH:3]=1.[CH3:33][Si:34]([C:37]#[CH:38])([CH3:36])[CH3:35].CCN(CC)CC>CN(C=O)C.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.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:38]#[C:37][Si:34]([CH3:36])([CH3:35])[CH3:33])[CH:27]=[CH:26][C:25]=3[OH:31])[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2O)N1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(O)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 83 °C

Procedure:
To a stirred solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-hydroxy-5-iodo-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione (100 mg) in DMF (2 mL) were added PdCl2(PPh3)2 (18 mg), CuI (4 mg), trimethylsilyl acetylene (Aldrich, 0.40 mL) and Et3N (Aldrich, 0.62 mL) and the mixture was purged with nitrogen and then heated at 83° C. for 3 hrs. The solvent was removed and the crude was directly used for next step. MS (H+), 549.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][CH3:16])=[CH:14][C:9]=2[C:8](=[O:17])[NH:7][C:6]2[CH:18]=[CH:19][CH:20]=[N:21][C:5]1=2)=[O:3].[CH2:22]([N:24]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][NH2:36])[CH2:25][CH3:26])[CH3:23].C(OC(C)C)(C)C>>[CH2:22]([N:24]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][NH:36][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][CH3:16])=[CH:14][C:9]=2[C:8](=[O:17])[NH:7][C:6]2[CH:18]=[CH:19][CH:20]=[N:21][C:5]1=2)=[O:3])[CH2:25][CH3:26])[CH3:23]
Reactant: CCc1ccc2c(c1)C(=O)Nc1cccnc1N2C(=O)Cl
Reactant: CCN(CC)CC1CCCCN1CCN
Solvent: CC(C)OC(C)C
Product: CCc1ccc2c(c1)C(=O)Nc1cccnc1N2C(=O)NCCN1CCCCC1CN(CC)CC
Yield: 70 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-8-ethyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[(diethylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 70% of theory. Colourless crystals, m.p. 124°-126° C. (diisopropylether).
Reaction SMILES: Br[CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH:19]12[O:26][CH:23]([CH2:24][CH2:25]1)[CH2:22][NH:21][CH2:20]2>C(#N)C>[CH:23]12[O:26][CH:19]([CH2:25][CH2:24]1)[CH2:20][N:21]([CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:22]2
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: C1CC2CNCC1O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)N1CC2CCC(C1)O2
Temperature: 50 °C
Reaction time: 8 h

Procedure:
4.72 g (19.8 mmol) of diethyl 2-bromomalonate are introduced into 30 ml of acetonitrile. Then 3.82 g (27.7 mmol) of potassium carbonate and 2.46 g (21.7 mmol) of 8-oxa-3-azabicyclo[3.2.1]octane from step 4 are added. The suspension is stirred at 50° C. overnight. This is followed by filtration with suction and evaporation of the filtrate to dryness in a rotary evaporator. The residue is employed without further purification in the next stage.
Reaction SMILES: [CH3:1][C@H:2]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.C(O)C>C(O)(=O)C.[Pt]=O>[CH3:1][C@H:2]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: C[C@@H](COc1ccncc1)NC(=O)OC(C)(C)C
Agent: O=[Pt]
Solvent: CCO
Solvent: CC(=O)O
Product: C[C@@H](COC1CCNCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.3 %

Procedure:
To a solution of tert-butyl [(1S)-1-methyl-2-(pyridin-4-yloxy)ethyl]carbamate (1.03 g) in acetic acid (10 mL)/ethanol (10 mL) was added platinum oxide (500 mg), and the reaction mixture was stirred at room temperature for 5 hr under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated. The obtained residue was dissolved in 0.5 M hydrochloric acid, and the solution was washed with ethyl acetate, basified with potassium carbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give the title compound (805 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=1)(=O)=O.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Li+].[Cl-].C([Sn]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=1)(CCCC)CCCC)CCC>CN1C(=O)CCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:57]1[CH:58]=[CH:59][CH:60]=[C:61]([C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH:12]=2)[CH:56]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cccnc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate (prepared according to Wustrow, D. J., Wise, L. D., Synthesis, (1991), 993-995; 2.73 g, 8.22 mmol) was dissolved in 80 mL of NMP. Triphenylarsine (220 mg, 0.66 mmol), LiCl (1.09 g, 24.7 mmol), and tris(dibenzylideneacetone)-dipalladium(0) (156 mg, 0.160 mmol) were then added to the reaction vessel. After 10 min of constant stirring, tributylstannyl pyridine (4.0 g, 9.7 mmol) in 10 mL of NMP was added using a syringe. The reaction vessel was repeatedly evacuated and flushed with N2 (g) (4×). The reaction mixture was then stirred at rt for 30 min, then at 80° C. for 2.5 h, and then at 65° C. for 16 h. Afterwards, 20 mL of 1M KF solution was added. The mixture was stirred for 1.5 h and then diluted with ethyl acetate (100 mL) and filtered. The filtrate was further diluted with 200 mL of 1M KF solution and 200 mL of ethyl acetate. The organic and aqueous layers were separated, and the aqueous layer was extracted once again with ethyl acetate (200 mL). The organic layers were combined, washed with water (6×200 mL) and then with brine (1×300 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Tert-Butyl 3′,6′-dihydro-3,4′-bipyridine-1′(2′H)-carboxylate was obtained through silica gel flash column chromatography (1% MeOH in EtOAc). ESI-MS calculated for C15H20N2O2: 260.35, found 261 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([C:14]2[N:18]([CH:19]([CH3:21])[CH3:20])[C:17]3[CH:22]([C:35]4[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=4)[N:23]([C:26]4[CH:31]=[C:30]([Cl:32])[C:29](=[O:33])[N:28]([CH3:34])[CH:27]=4)[C:24](=[O:25])[C:16]=3[CH:15]=2)[CH:7]=1)C.[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O>[Cl:32][C:30]1[C:29](=[O:33])[N:28]([CH3:34])[CH:27]=[C:26]([N:23]2[C:24](=[O:25])[C:16]3[CH:15]=[C:14]([C:8]4[CH:7]=[C:6]([CH2:5][C:4]([OH:42])=[O:3])[CH:11]=[CH:10][C:9]=4[O:12][CH3:13])[N:18]([CH:19]([CH3:21])[CH3:20])[C:17]=3[CH:22]2[C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH:31]=1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2cc3c(n2C(C)C)C(c2ccc(Cl)cc2)N(c2cc(Cl)c(=O)n(C)c2)C3=O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(CC(=O)O)cc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of {3-[5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrol-2-yl]-4-methoxy-phenyl}-acetic acid ethyl ester (Step 118.1) (0.338 mmol) and LiOH (0.675 mmol) in MeOH (1.6 mL) and H2O (0.4 mL) was stirred at rt. After 4 h, the reaction mixture was acidified to pH 4 with 10% aqueous citric acid and extracted with EtOAc (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated. The residue was purified using a RediSep® silica gel column to afford the title compound as a white solid. tR: 6.18 min (HPLC 2); ESI-MS: tR=0.98 min, [M]+ 580/582/584 (LC-MS 1); TLC: Rf=0.24 (9:1 CH2Cl2/MeOH).
Reaction SMILES: [CH3:1][C:2](=[CH2:19])[C:3]([O:5][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][CH2:13][O:14][C:15](=[O:18])[CH:16]=[CH2:17])=[O:10])=[O:4].[CH3:20][CH:21]1[CH2:23][NH:22]1>>[CH3:19][C:2](=[CH2:1])[C:3]([O:5][CH2:6][CH2:7][NH:8][C:9]([O:11][CH2:12][CH2:13][O:14][C:15](=[O:18])[CH2:16][CH2:17][N:22]1[CH2:23][CH:21]1[CH3:20])=[O:10])=[O:4]
Reactant: CC1CN1
Reactant: C=CC(=O)OCCOC(=O)NCCOC(=O)C(=C)C
Product: C=C(C)C(=O)OCCNC(=O)OCCOC(=O)CCN1CC1C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
The product of Step 1 (2-({[2-(acryloyloxy)ethoxy]carbonyl}amino)ethyl 2-methylacrylate, 10.0 g, 37 mmol) was mixed with 2-methylaziridine (2.8 g, about 44 mmol, 90% pure, available from Aldrich) to cause a slight exotherm. The reaction mixture was allowed to stand at room temperature overnight. Excess 2-methylaziridine was removed at reduced pressure to leave the desired product (12.0 g) as a colorless liquid. NMR and IR spectral analyses confirmed the structure of the product.
Reaction SMILES: [OH-].[Li+].O.C([O:6][C:7](=[O:19])[C:8]1[C:13]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:12][CH:11]=[CH:10][CH:9]=1)C.[OH-].[Na+]>C1COCC1>[CH:14]1([C:13]2[C:8]([C:7]([OH:19])=[O:6])=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: CCOC(=O)c1ccccc1C1CCCC1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccccc1C1CCCC1
Reaction time: 5 h

Procedure:
0.200 g (8.35 mmol) lithium hydroxide and 15 mL water were added to a solution of 1.10 g (5.04 mmol) 6-cyclopentyl-benzoic acid ethyl ester in 20 mL THF at RT, and the resulting mixture was stirred over night. 5.00 mL (20.0 mmol) 4 M aqueous NaOH solution were added and stirring was continued at 50° C. for 5 h. THF was removed by distillation. The residue was acidified with 4 M aqueous hydrochlorid and the precipitate was filtered off, washed with water and dried.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[C:3]#[CH:4]>ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:2]([CH3:14])([CH3:1])[CH:3]=[CH:4][C:7]=2[CH:8]=1
Reactant: C#CC(C)(C)Oc1ccc(OC)cc1
Solvent: Clc1ccccc1Cl
Product: COc1ccc2c(c1)C=CC(C)(C)O2
Yield: 61 %

Procedure:
A solution of 4-(1,1-dimethyl-2-propynyloxy)anisole in 1,2-dichlorobenzene (50 mL) was stirred at 190° C. for 2 hours. Upon the completion of the reaction, the solvent was distilled off under a reduced pressure. The residue was purified by column chromatography (hexane/chloroform=3/1) and the aimed product was obtained as red oily substance (2-step, yield: 61%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6](=[O:17])[CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCSc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCSc1ccc(OCc2ccccc2)cc1

Procedure:
A mixture solution of the compound prepared in Example 1(1) (3.29 g), benzyl bromide (2.3 ml), potassium carbonate (3.58 g) and dimethylformamide (15 ml) was stirred overnight at room temperature. The reaction solution was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the title compound (2.20 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([NH:18][CH3:19])=[C:16]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[C:15]([C:27](=[N:29][OH:30])[NH2:28])=[N:14]1.O.[C:32]1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC)(OC)OC>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[C:17]([NH:18][CH3:19])=[C:16]([S:20]([C:23]([F:25])([F:26])[F:24])(=[O:21])=[O:22])[C:15]([C:27]2[N:28]=[CH:32][O:30][N:29]=2)=[N:14]1
Reactant: CNc1c(S(=O)(=O)C(F)(F)F)c(C(N)=NO)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(OC)OC
Product: CNc1c(S(=O)(=O)C(F)(F)F)c(-c2ncon2)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 2396.7 %

Procedure:
1-(2,6-dichloro-4-trifluoromethylphenyl)-5-methylamino-4-trifluoromethylsulfonyl-3-pyrazolecarboxamide oxime 500 mg (1.00 mmol) was dissolved in 5 ml of trimethyl orthoformate, and then 5 mg of p-toluenesulfonic acid monohydrate was added. After the mixture was was stirred at room temperature for 6hrs, trimethyl orthoformate was distilled off in vacuo, and then added 20 ml of ethyl acetate. The ethyl acetate solution was washed once with 30 ml of aqueous saturated sodium hydrogencarbonate solution, and then four times with 30 ml of aqueous saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off. The resulting concentrated residue was purified by silica gel column chromatography [eluent: chloroform] to obtain 320 mg (0.63 mmol) of the title compound as a colorless crystal. Yield 63%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([N:12]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][OH:11])=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl>[CH2:24]([N:12]([C@H:9]([CH2:10][OH:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:3][CH:4]=1)[CH2:13][C@H:14]([OH:23])[CH2:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(C[C@@H](CO)N(Cc2ccccc2)C[C@H](O)COc2ccccc2)cc1)c1ccccc1
Temperature: 25 °C

Procedure:
To an ice-cooled mixture of (2S)-3-(4-aminophenyl)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-1-propanol (63 mg) and pyridine (25 μl) in dichloromethane (0.6 ml) was added dropwise benzoyl chloride (22 μl), and the mixture was stirred at room temperature for more than 2 hours. The mixture was partitioned between chloroform-methanol and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, chloroform/methanol) to give N-[4-[(2S)-2-[N-benzyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-3-hydroxypropyl]phenyl]benzamide (80 mg) as a white amorphous powder.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH:12]1([CH2:17][NH2:18])[CH2:16][CH2:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:2]([NH:18][CH2:17][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: NCC1CCCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCCC1)OCc1ccccc1
Reaction time: 8 h
Yield: 121.7 %

Procedure:
Benzyl chloroformate (0.919 g, 5.38 mmol) was added to a solution of cyclopentylmethylamine (0.445 g, 4.49 mmol) and DIEA (1.74 g, 13.5 mmol) in 50 mL of CH2Cl2 and the mixture was strried overnight at R.T. The mixture was concentrated in vacuo and the residue was taken up in EtOAc, washed with water, sat. aq. NaHCO3, brine, dried over MgSO4 and concentrated to give the crude N-Cbz-cyclopentylmethylamine (1.275 g) which was used without further purification. 1H NMR consistent with structure.
Reaction SMILES: [CH3:1][C:2]1([C:17]([O:19]C)=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].CO.O.[OH-].[Li+].Cl>O>[CH2:10]([O:9][C:7]([N:3]1[CH2:4][CH2:5][CH2:6][C:2]1([CH3:1])[C:17]([OH:19])=[O:18])=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)C1(C)CCCN1C(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C(=O)O)CCCN1C(=O)OCc1ccccc1
Temperature: 30 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
To the solution of 1-benzyl 2-methyl 2-methylpyrrolidine-1,2-dicarboxylate (3.1 g, 10.8 mmol) in the mixture of Methanol (20 mL) and water (20 mL) was added lithium hydroxide monohydrate (0.9 g, 21.6 mmol). The mixture was stirred at 30° C. for 3 h. The resulting mixture was treated with 5N hydrochloric acid to pH=2 and filtrated, washed with water, dried in vacuum at 45° C. 1.9 g of 1-(benzyloxycarbonyl)-2-methylpyrrolidine-2-carboxylic acid was obtained. Yield: 67%. LC-MS (ESI) m/z: 264 (M+1)+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:17])=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[N:18]1([C:22]([C:24]2[CH:25]=[N:26][N:27]([CH3:32])[C:28]=2[C:29](O)=[O:30])=[O:23])[CH2:21][CH2:20][CH2:19]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[F:1][C:2]1[C:3]([NH:17][C:29]([C:28]2[N:27]([CH3:32])[N:26]=[CH:25][C:24]=2[C:22]([N:18]2[CH2:21][CH2:20][CH2:19]2)=[O:23])=[O:30])=[CH:4][C:5]2[N:6]([N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)O
Reactant: Nc1cc2nc(-c3ccccc3)nn2cc1F
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1cc2nc(-c3ccccc3)nn2cc1F
Yield: 43.5 %

Procedure:
A mixture of 6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine (50 mg, 219 μmol), 4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (45.8 mg, 219 μmol), propylphosphonic anhydride (50% in ethyl acetate, 323 μl, 548 μmol) and diisopropylethyl amine (115 μl, 657 μmol) in tetrahydrofuran (5 ml) was refluxed for 18 hours. The crude material is loaded on silica and purified by flash chromatography on a 20 g silica column using heptane/ethyl acetate 20-100% as eluent, affording 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (40 mg: 43.5%) as white solid. Mp.: >250° C. MS: m/z=420.3 (M+H+).
Reaction SMILES: [CH3:1][C:2]12[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][C:8]1=[CH:7][C:5](=O)[CH2:4][CH2:3]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:25]([SH:28])[CH2:26][SH:27].O>C(O)(=O)C>[CH3:1][C:2]12[C:12](=[O:13])[CH2:11][CH2:10][CH:9]=[C:8]1[CH2:7][C:5]1([S:28][CH2:25][CH2:26][S:27]1)[CH2:4][CH2:3]2
Reactant: SCCS
Reactant: CC12CCC(=O)C=C1CCCC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC12CCC3(CC1=CCCC2=O)SCCS3
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.3 %

Procedure:
To a solution of Wieland-Miescher ketone (5.87 g, 33.0 mmol) in glacial acetic acid (40 mL) was added p-toluenesulfonic acid (2.94 g) followed by dropwise addition of 1,2-ethanedithiol over a 1 hour period. The reaction mixture was stirred at room temperature for another 4 hours, poured into 30 mL water, and stirred for 15 minutes. The white solid was filtered off, washed successively with water, diluted with NaHCO3 solution and water, and then dried to yield thioketal 239 (7.33 g, 87.3 %) as a white solid. 1H NMR (CDCl3) δ 1.50-2.70 (m, 10H), 3.20-3.40 (m, 4H), 5.67 (s, 1H); 13C NMR (CDCl3) 212.92, 141.23, 128.04, 64.81, 49.43, 40.11, 39.62, 37.92, 37.57, 30.81, 30.69, 24.73, 24.57.