Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH:13]([CH:14]=O)[CH:12]2[CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9]3)=[CH:4][CH:3]=1.C1(=O)NC(=O)C=C1.ClC1C=CC(N)=CC=1.N1C=CC=CC=1.Cl.[CH3:45][O:46][NH2:47]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[CH:13]([CH:14]=[N:47][O:46][CH3:45])[CH:12]2[CH2:11][N:10]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:9]3)=[CH:6][CH:7]=1
Reactant: CON
Reactant: CC(C)(C)OC(=O)N1CC2C(C=O)C2(c2ccc(Cl)cc2)C1
Agent: Cl
Agent: Nc1ccc(Cl)cc1
Agent: O=C1C=CC(=O)N1
Solvent: c1ccncc1
Solvent: CCO
Product: CON=CC1C2CN(C(=O)OC(C)(C)C)CC12c1ccc(Cl)cc1
Yield: 63 %

Procedure:
To a solution of tert-butyl 1-(4-chlorophenyl)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (609 mg, 1.99 mmol, prepared from maleimide and 4-chloroaniline according to the methods described in WO 2009141412 and WO 2008074716), in ethanol (10 mL) under nitrogen atmosphere, were added pyridine (0.8 mL, 9.9 mmol) and O-methylhydroxylamine hydrochloride (332.4 mg, 3.98 mmol). The reaction mixture was refluxed for 5 h. After completion of the reaction as confirmed by TLC, the solvent was evaporated. The crude compound was extracted with ethyl acetate (20 mL). The organic layer was separated, washed with 5% HCl (5 mL), water (10 mL), dried over Na2SO4 and concentrated in vacuo to afford crude product which was purified by column chromatography (silica gel, 2:3 EtOAc:Pet Ether) to afford pure tert-butyl 1-(4-chlorophenyl)-6-((methoxyimino)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (430 mg, 63%) as a viscous oil as mixture of isomers.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[C:24](Cl)(=[O:26])[CH3:25].[NH4+].[Cl-]>C1COCC1>[C:24]([N:8]1[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][O:10][C:9]1=[O:12])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: O=C1N[C@H](c2ccccc2)CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)N1C(=O)OC[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a stirred suspension of 5.000 g (4R)-(−)-4-phenyl-2-oxazolidinone (30.03 mmol) in 100 mL THF, were added 21.0 mL n-butyllithium in hexane (1.5 M, 31.53 mmol, 1.05 eq) at 0° C. within 10 min. The resulting colorless solution was stirred for additional 50 min at 0° C. 2.57 mL acetyl chloride (36.04 mmol, 1.2 eq) were then added within 1 min. After 3.5 h the reaction was stopped by addition of 25 mL saturated aqueous NH4Cl and the mixture was extracted with 75 mL ethyl acetate. The organic phase was washed with 50 mL saturated aqueous NaHCO3 and with 50 mL brine. The solution was dried for 30 minutes over 5 g Na2SO4 and filtered. The filter cake was washed with 10 mL ethyl acetate. After removal of solvent in a rotary evaporator (40° C., 18 mbar), the crude product was obtained as white crystals (6.13 g, 100% w/w; HPLC purity 88.3% area). Further purification was achieved by dissolving in 10.6 mL ethyl acetate at reflux temperature and subsequent dropwise addition of 26.6 mL heptane. The resulting suspension was allowed to slowly cool down to 5° C. and after standing overnight, the precipitate was collected by filtration. After washing with 3 mL heptane, the title compound was obtained as white crystals (5.26 g, 25.6 mmol, 85% by weight) and in high purity (HPLC purity 96.6% area).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl.C(N(CC)CC)C.Cl.[CH2:39]([C:41]1[C:42]([NH:51][C@H:52]2[CH2:56][CH2:55][CH2:54][C@@H:53]2[NH2:57])=[N:43][CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[N:46]=1)[CH3:40]>C(Cl)Cl>[CH2:39]([C:41]1[C:42]([NH:51][C@H:52]2[CH2:56][CH2:55][CH2:54][C@@H:53]2[NH:57][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:43][CH:44]=[C:45]([C:47]([F:50])([F:48])[F:49])[N:46]=1)[CH3:40]
Reactant: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1N
Reactant: O=C(O)c1cc(F)ccc1-c1ncccn1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1cc(F)ccc1-c1ncccn1
Temperature: 25 °C
Reaction time: 88 h

Procedure:
To a solution of 5-fluoro-2-(pyrimidin-2-yl)benzoic acid (CAS number 1293284-57-7; 53 mg, 0.24 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (33 mg, 0.24 mmol), EDC (46.3 mg, 0.241 mmol) and triethylamine (0.067 ml, 0.48 mmol) in DCM (5 ml) was added (1S,2S)-1-N-[3-ethyl-5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 41; 50 mg, 0.161 mmol). The reaction mixture was stirred at room temperature for 88 hours and then partitioned between DCM and a saturated solution of sodium bicarbonate, passing through a hydrophobic frit. The organics were loaded directly on to a cation/anion mixed mode cartridge, eluted with DCM and concentrated in vacuo. This was then purified by reverse phase chromatography (C18 silica, 0-100% acetonitrile/water with 0.1% ammonia). The resulting aqueous was concentrated in vacuo and extracted with DCM. The organics were concentrated in vacuo to afford the title compound.
Reaction SMILES: Br[C:2]([CH3:16])([CH3:15])[C:3]([NH:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[O:8][N:7]=1)=[O:4].[C:17]([O-:20])(=[S:19])[CH3:18].[K+]>CN(C=O)C.C(OCC)C>[C:11]([C:9]1[O:8][N:7]=[C:6]([NH:5][C:3]([C:2]([S:19][C:17](=[O:20])[CH3:18])([CH3:16])[CH3:15])=[O:4])[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC([O-])=S
Reactant: CC(C)(Br)C(=O)Nc1cc(C(C)(C)C)on1
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)SC(C)(C)C(=O)Nc1cc(C(C)(C)C)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of 200 mg (0.69 mmol) of 2-bromo-N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-propionamide (prepared as described in Method B, step 2) in DMF (3 mL) were added 157 mg (1.4 mmol) of potassium thioacetate. The reaction was stirred at room temperature for 3 h. The reaction mixture was diluted with diethyl ether (5 mL) and washed with 2M aqueous HCl solution (5 mL). The organic layer was dried over Na2SO4. Filtration and concentration under reduced pressure afforded 151 mg of thioacetic acid S-[1-(5-tert-butyl-isoxazol-3-ylcarbamoyl)-1-methyl-ethyl]ester.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:11][C:12]1[CH:35]=[CH:34][C:15]([CH2:16][C@@:17]2(CC)[NH:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[C:27]([Cl:29])[N:26]=[C:25]([Cl:30])[CH:24]=3)[C:18]2=[O:31])=[CH:14][CH:13]=1.I[CH2:37][CH3:38].[CH2:39]1COCC1>C1(C)C=CC=CC=1>[Br:11][C:12]1[CH:35]=[CH:34][C:15]([CH2:16][C@@:17]2([CH3:39])[N:21]([CH2:37][CH3:38])[C:20](=[O:22])[N:19]([C:23]3[CH:28]=[C:27]([Cl:29])[N:26]=[C:25]([Cl:30])[CH:24]=3)[C:18]2=[O:31])=[CH:14][CH:13]=1
Reactant: CCI
Reactant: C1CCOC1
Reactant: CC[C@]1(Cc2ccc(Br)cc2)NC(=O)N(c2cc(Cl)nc(Cl)c2)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCN1C(=O)N(c2cc(Cl)nc(Cl)c2)C(=O)[C@@]1(C)Cc1ccc(Br)cc1
Yield: 83.9 %

Procedure:
A solution of 1.12 mL (0.559 mmol) of 0.5 M potassium bis(trimethylsilyl)amide in toluene was added to a solution of 0.16 g (0.373 mmol) of the product of Example 1 and 0.149 mL (1.86 mmol) iodoethane in 3.5 mL dry THF+0.13 mL (0.746 mmol) HMPA. The reaction was refluxed overnight, quenched with aqueous NH4Cl, extracted 4× with ether, washed 3× with H2O, dried and concentrated in vacuo to an oil. Purification on Analtech 2 mm prep plates, developed in 15% acetone-petroleum ether, afforded 143 mg (84%) of sticky glassy resin. (−)-Electrospray mass spec (M+35 490) was consistent with the structure.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][CH2:10][NH2:11])[N:8]=1)[CH3:2].[C:12](O)(=O)C.C=O>CO>[CH2:1]([NH:3][C:4]1[S:5][C:6]2[CH2:12][NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1)[CH3:2]
Reactant: CC(=O)O
Reactant: CCNc1nc(CCN)cs1
Agent: C=O
Solvent: CO
Product: CCNc1nc2c(s1)CNCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 162.9 %

Procedure:
2-Ethylamino-4-(2-aminoethyl)thiazole (0.20 g, 1.17 mmol) and acetic acid (0.02 ml, 0.35 mmol) were dissolved in methanol (15 ml) and treated with formaldehyde (0.095 ml of a 37% aqueous solution, 1.17 mmol). The reaction was allowed to stir at room temperature for 15 minutes; it was then concentrated in vacuo and subjected to column chromatography (eluant: 89:10:1 chloroform: methanol: concentrated aqueous ammonium hydroxide). This provided the title product as a yellow solid (0.105 g, 0.57 mmol, 49% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[NH:9][C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH:22]1[O:26][CH2:25][CH2:24][O:23]1.O>CN(C)C=O.C(OCC)(=O)C>[O:23]1[CH2:24][CH2:25][O:26][CH:22]1[CH2:21][N:9]1[C:7]2=[N:8][C:3]([O:2][CH3:1])=[CH:4][N:5]=[C:6]2[CH:12]=[CH:11][C:10]1=[O:13]
Reactant: COc1cnc2ccc(=O)[nH]c2n1
Reactant: BrCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cnc2ccc(=O)n(CC3OCCO3)c2n1
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
To a solution of 0.30 g of 3-methoxypyrido(2,3-b)pyrazin-6(5H)-one in 6 mL of N,N-dimethylformamide, 0.35 g of potassium carbonate was added, and the mixture was stirred at 65 to 75° C. for 10 minutes. Thereto was added 0.21 mL of 2-bromomethyl-1,3-dioxolan, and the mixture was stirred at 95 to 100° C. for 1 hour 30 minutes. Thereto were further added 0.05 mL of 2-bromomethyl-1,3-dioxolan and 120 mg of potassium carbonate, and the mixture was stirred at 95 to 100° C. for 2 hours 15 minutes. The reaction mixture was cooled to room temperature, and water and ethyl acetate were then added thereto, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, and the resultant solution was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of hexane:ethyl acetate=2:1 to obtain 0.13 g of 5-(1,3-dioxolan-2-ylmethyl)-3-methoxypyrido(2,3-b)pyrazin-6(5H)-one as a yellow solid.
Reaction SMILES: [C:1](=[O:6])([O:4]C)[O:2]C.[CH2:7]([N:11]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10].O>CO>[C:1](=[O:2])([O-:6])[OH:4].[CH2:16]([NH+:11]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN(CCCC)CCCC
Reactant: COC(=O)OC
Solvent: O
Solvent: CO
Product: CCCC[NH+](CCCC)CCCC
Product: O=C([O-])O
Reaction time: 7 h

Procedure:
30.2 g of dimethyl carbonate, 62.1 g of tri-n-butylamine, 30.5 g of water and 15.0 g of methanol were introduced in the same reactor as used in Preparation Example 1 and heated with stirring. After the temperature in the reactor reached 140° C., the reaction was continued for 7 hours at 140° C. Tributylammonium hydrogencarbonate was obtained in a yield of 84.3 mol % (based on tri-n-butylamine).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[CH:16]=[C:15]([Cl:17])[C:14]([S:18](Cl)(=[O:20])=[O:19])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[OH-].[Na+]>O>[Cl:7][C:8]1[CH:16]=[C:15]([Cl:17])[C:14]([S:18]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:20])=[O:19])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(S(=O)(=O)N2CCCCC2)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred suspension of 1.7 g. (0.02 mole) of piperidine and 5.8 g. (0.02 mole) of 2,4-dichloro-5-chlorosulfonylbenzoic acid (Sturm, et al., Ber., 99, 328 (1966) in 70 ml. of water and cooled to 15° C. is treated dropwise with 50 ml. of 1N sodium hydroxide. When the addition is complete, the mixture is allowed to warm to room temperature and remain for 1 hr. The hazy suspension is filtered and the clear filtrate acidified with 12N hydrochloric acid. The precipitated solids are filtered and dried, 7.7 g., m.p. 200°-205° C. A sample is recrystallized from acetonitrile, m.p. 205°-206° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[CH:6]=[O:7])[CH3:2].[O-:13]Cl=O.[Na+].Cl>CS(C)=O.O>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:6]([OH:13])=[O:7])[CH3:2]
Reactant: CCc1cc(C=O)cc(C)c1O
Reactant: [O-][Cl+][O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCc1cc(C(=O)O)cc(C)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.8 %

Procedure:
To a solution of 3-ethyl-4-hydroxy-5-methyl-benzaldehyde (78.8 g, 0.48 mol) in DMSO (585 mL), a solution of NaH2PO4 dihydrate (17.3 g, 0.144 mol) in water (160 mL) is added over a period of 13 min. The mixture is stirred at rt an a solution of NaClO2 (65.17 g, 0.577 mol) in water (160 mL) is added while the mixture is cooled with an ice-bath. The mixture is stirred for 1 h before a second portion of NaClO2 (43.44 g, 0.480 mol) in water (100 mL) is added while the temperature is kept between 25 and 40° C. with an ice-bath. Th yellow suspension is stirred at rt for 24 h before it is acidified with 32% aq. HCl to pH 2-3. The mixture is extracted with TBME (250 mL), the org. extract is washed with water, and the washings are extracted back with TBME. The solvent of the combined org. extracts is evaporated to give crude 3-ethyl-4-hydroxy-5-methyl-benzoic acid (80.3 g) as a yellow solid.
Reaction SMILES: [NH:1]([C:65]([O:67][CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)=[O:66])[C@@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@@H:29]([C:37]([NH:39][C@H:40]([C:51]([N:53]1[CH2:64][CH2:63][CH2:62][C@H:54]1[C:55]([O:57]C(C)(C)C)=[O:56])=[O:52])[CH2:41][C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:44][CH:43]=1)=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[NH:25])[NH2:24])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OC(C)(C)C)=O>FC(F)(F)C(O)=O.C(S)C>[NH:1]([C:65]([O:67][CH2:68][C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1)=[O:66])[C@@H:2]([C:15]([NH:17][C@H:18]([C:26]([NH:28][C@@H:29]([C:37]([NH:39][C@H:40]([C:51]([N:53]1[CH2:64][CH2:63][CH2:62][C@H:54]1[C:55]([OH:57])=[O:56])=[O:52])[CH2:41][C:42]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[NH:44][CH:43]=1)=[O:38])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:27])[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[NH:24])[NH2:25])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCS
Product: N=C(N)NCCC[C@H](NC(=O)[C@@H](CCCCN)NC(=O)OCc1ccccc1)C(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 1 h

Procedure:
1.55 g of Z-D-Lys(Boc)-Arg-D-Phe-Trp-Pro-OBut are dissolved in 14.5 ml of 90 percent strength trifluoroacetic acid and 1.5 ml of ethyl mercaptan. The solution is left to stand for 1 hour at room temperature and is concentrated. The residue is dissolved in water and chromatographed over a weakly basic ion exchanger (acetate form). The eluate is freeze-dried. Yield 883 mg. The peptide is purified by being chromatographed in 90 percent strength methanol over a crosslinked, hydroxypropylated dextran gel. Yield 570 mg, [α]D22 =-24.6° (c=1, methanol).
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.Cl[CH2:26][CH2:27][CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1>>[F:1][C:2]1[CH:21]=[C:20]([CH:19]=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1)[NH2:22]
Reactant: CN1CCN(CCCCl)CC1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1O
Product: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCCCN1CCN(C)CC1

Procedure:
S1 was prepared from 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-quinolin-7-ol and 1-(3-chloropropyl)-4-methylpiperazine following the general procedure reported in Preparative Example 54 Step 1-2. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.95 (quint., J=6.8 Hz, 2H), 2.14 (s, 3H), 2.22-2.47 (m, 10H), 3.94 (s, 3H), 4.17 (t, J=6.5 Hz, 2H), 5.48 (br.s, 2H), 6.38 (d, J=5.2 Hz, 1H), 6.46 (dd, J=8.7 Hz, J=2.4 Hz, 1H), 6.55 (dd, J=13.2 Hz, J=2.4 Hz, 1H), 7.07 (t, J=9.0 Hz, 1H), 7.36 (s, 1H), 7.50 (s, 1H), 8.44 (d, J=5.2 Hz, 1H). MS (ES) C24H29FN4O3 requires: 440. Found: 441 (M+H)+.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]([F:16])([F:15])[C:6]([C:8]1[C:9](F)=[N:10][CH:11]=[CH:12][CH:13]=1)=O>C(O)C>[F:4][C:5]([F:16])([F:15])[C:6]1[C:8]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[NH:3][N:2]=1
Reactant: NN
Reactant: O=C(c1cccnc1F)C(F)(F)F
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1n[nH]c2ncccc12
Yield: 84.9 %

Procedure:
Hydrazine hydrate (3.06 mL, 63.0 mmol) was added to 2,2,2-trifluoro-1-(2-fluoropyridin-3-yl)ethanone (1.9 g, 9.0 mmol) in absolute ethanol (50 mL), and the mixture was heated to reflux overnight. The cooled reaction mixture was evaporated to afford a solid, which was partitioned between water and ethyl acetate. The aqueous layer was extracted with another portion of ethyl acetate. The combined ethyl acetate extracts were washed twice with brine, dried over magnesium sulfate, filtered, and evaporated to yield 3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (1.43 g, 85%) as a solid.
Reaction SMILES: [ClH:1].[CH2:2]([NH:4][CH2:5][CH3:6])[CH3:3].[CH2:7]=O.[CH3:9][C:10]1[C:11]2[CH2:24][CH2:23][CH2:22][C:21](=[O:25])[C:12]=2[C:13]2[CH2:14][CH2:15][C:16](=[O:20])[NH:17][C:18]=2[CH:19]=1>C(OC(=O)C)(=O)C>[ClH:1].[CH2:2]([N:4]([CH2:7][CH:22]1[C:21](=[O:25])[C:12]2[C:13]3[CH2:14][CH2:15][C:16](=[O:20])[NH:17][C:18]=3[CH:19]=[C:10]([CH3:9])[C:11]=2[CH2:24][CH2:23]1)[CH2:5][CH3:6])[CH3:3]
Reactant: C=O
Reactant: Cc1cc2c(c3c1CCCC3=O)CCC(=O)N2
Reactant: CCNCC
Agent: Cl
Solvent: CC(=O)OC(C)=O
Product: CCN(CC)CC1CCc2c(C)cc3c(c2C1=O)CCC(=O)N3
Reaction time: 3 h

Procedure:
Diethylamine hydrochloride (8.3 g) is mixed with 6 ml of 37% formalin at room temperature for 30 minutes whereupon 40 ml of acetic anhydride is added dropwise at 60°-70° C. with stirring. After about 1 hour 11.5 g of 6-methyl-1,2,3,4,7,8,9,10-octahydro-benzo[f]quinoline-3,10-dione is added, and the resulting mixture is kept at 60°-70° C. for 3 hours. The reaction mixture is then concentrated under reduced pressure. To the residue is added 200 ml of acetone, and the mixture is heated under reflux for 10 minutes and then allowed to stand at room temperature. The precipitated crystals are collected by filtration and recrystallized from ethanol to give 7.0 g of 9-diethylaminomethyl-6-methyl-1,2,3,4,7,8,9,10-octahydro-benzo[f]quinoline-3,10-dione hydrochloride as colorless needles, melting at 196°-197° C.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13]1[CH:51]=[CH:50][C:16]([CH2:17][O:18][CH2:19][C@H:20]([CH3:49])[C@H:21]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C@@H:22]([CH3:40])[CH2:23][CH2:24][C:25]([N:27]2[C@H:31]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:30][O:29][C:28]2=[O:39])=[O:26])=[CH:15][CH:14]=1.CI>C1COCC1>[CH3:11][O:12][C:13]1[CH:51]=[CH:50][C:16]([CH2:17][O:18][CH2:19][C@H:20]([CH3:49])[C@H:21]([O:41][Si:42]([C:45]([CH3:46])([CH3:48])[CH3:47])([CH3:44])[CH3:43])[C@@H:22]([CH3:40])[CH2:23][C@@H:24]([CH3:1])[C:25]([N:27]2[C@H:31]([CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:30][O:29][C:28]2=[O:39])=[O:26])=[CH:15][CH:14]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1ccc(COC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)CCC(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(COC[C@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C[C@@H](C)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.4 %

Procedure:
NaHMDS (1 M in THF, 14.9 mL, 14.9 mmol) was added dropwise over a 30 min period to a cooled (−78° C.) suspension of the imide 25 (7.91 g, 13.6 mmol) in THF (45 mL). After 15 min of stirring, the resulting cold solution was treated with MeI (2.53 mL, 40.8 mmol) and allowed to stir at −78° C. for 3 h before being warmed to 25° C. overnight (12 h) The reaction was quenched with H2O (100 mL), and the aqueous layer was extracted with Et2O (3×150 mL). The combined organic extracts were dried (MgSO4), concentrated in vacuo and chromatographed (EtOAc/hexane 1:9) to provide 5.97 g (74%) of 26 as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.42-7.26 (m, 7H), 6.95-6.92 (m, 2H), 4.71 (m, 1H), 4.51 (m, 2H), 4.18 (m, 2H), 3.95 (m, 1H), 3.84 (s, 3H), 3.63 (dd, J=8.9, 3.8 Hz, 1H), 3.57 (dd, J=6.4, 2.7 Hz, 1H), 3.35 (t, J=8.5 Hz, 1H), 3.28 (dd, J=13.3, 3.1 Hz, 1H), 2.83 (dd, J=13.3, 9.4 Hz, 1H), 2.10-1.95 (m, 2H), 1.68 (m, 1H), 1.38 (ddd, J=14.1, 9.8, 4.9 Hz, 1H), 1.31 (d, J=6.8 Hz, 3H), 1.04 (d, J=6.9 Hz, 3H), 0.98 (s, 9H), 0.95 (d, J=6.7 Hz, 3H), 0.14 (s, 3H), 0.13 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 176.8, 158.8, 152.8, 135.1, 130.8, 129.3, 128.9, 128.7, 127.1, 113.5, 77.6, 72.6, 72.4, 65.7, 55.0, 38.9, 38.0, 37.6, 35.3, 33.8, 26.0, 18.8, 18.3, 14.9, 13.8, −3.8, −4.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([NH2:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[C@H:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: NC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 51.5 %

Procedure:
To a solution of rac-(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylamine (0.54 g, 1.68 mmol) in THF (5 mL) was added a solution of K2CO3 (0.46 g, 3.36 mmol) in H2O (3 mL). After 10 minutes, ethyl chloroformate (0.18 mL, 1.85 mmol) was added and stirring was continued at ambient temperature for an additional 2 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (5 mL) and a solution of borane in THF (1M) was added (6.7 mL). The reaction mixture was then heated at 65° C. over night, cooled to ambient temperature and carefully quenched with conc. HCl (5 mL). The mixture was then heated at 80° C. for 2 h, cooled to ambient temperature, concentrated under vacuo, diluted with Et2O (20 mL) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 0.29 g (51%) of rac-[(3S,4R)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-amine as a colorless oil. ES-MS m/e: 335.3 (M+H+).