Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[C:4]([F:16])[C:3]=1[O:17][CH3:18].Cl[C:20]1[N:25]=[C:24]([NH:26][CH3:27])[C:23]([C:28]([F:31])([F:30])[F:29])=[CH:22][N:21]=1.C(O)(C(F)(F)F)=O>COCCO>[F:16][C:4]1[C:3]([O:17][CH3:18])=[C:2]([NH:1][C:20]2[N:25]=[C:24]([NH:26][CH3:27])[C:23]([C:28]([F:31])([F:29])[F:30])=[CH:22][N:21]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)=[O:9]
Reactant: COc1c(N)ccc(C(=O)N2CCOCC2)c1F
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Solvent: COCCO
Solvent: O=C(O)C(F)(F)F
Product: CNc1nc(Nc2ccc(C(=O)N3CCOCC3)c(F)c2OC)ncc1C(F)(F)F
Temperature: 95 °C
Reaction time: 2 h

Procedure:
A mixture of (4-amino-2-fluoro-3-methoxyphenyl)(morpholino)methanone (0.18 g, 0.72 mmol) and 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (0.10 g, 0.47 mmol) in a solution of 2-methoxyethanol (2 mL) and TFA (0.055 mL) was stirred at 95° C. for 2 hours. The reaction was concentrated and purified by reverse phase HPLC to give the title compound. Additional compounds made using the above procedure are shown in Table 6 below.
Reaction SMILES: S(Cl)([Cl:3])=O.[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:17]2[CH2:22][CH2:21][CH:20]([C:23]([OH:25])=O)[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)([O-:7])=[O:6]>C1(C)C=CC=CC=1>[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([N:17]2[CH2:22][CH2:21][CH:20]([C:23]([Cl:3])=[O:25])[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)([O-:7])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Solvent: Cc1ccccc1
Product: O=C(Cl)C1CCN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C

Procedure:
Thionyl chloride (4.0 ml, 55.0 mmol) was added dropwise to a stirred solution of 1-(4-nitro-benzenesulfonyl)-piperidine-4-carboxylic acid (1.25 g, 3.98 mmol) in toluene (12 ml) and the mixture was heated at 80° C. for 2 hours. After this time, the reaction mixture was concentrated under vacuum to afford the title compound as a white solid which was used without further purification.
Reaction SMILES: [CH3:1][C:2](=[CH2:17])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[O:25]=[C:26]([C:30]1[N:38]2[C:33]([CH2:34][CH2:35][CH2:36][CH2:37]2)=[CH:32][C:31]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:27](Cl)=[O:28]>C(Cl)Cl>[CH3:17][C:2](=[CH2:1])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:27](=[O:28])[C:26](=[O:25])[C:30]3[N:38]4[C:33]([CH2:34][CH2:35][CH2:36][CH2:37]4)=[CH:32][C:31]=3[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: O=C(Cl)C(=O)c1c(-c2ccccc2)cc2n1CCCC2
Reactant: C=C(C)CN1CCN(c2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)CN1CCN(c2ccc(NC(=O)C(=O)c3c(-c4ccccc4)cc4n3CCCC4)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.1 %

Procedure:
To an ice-cold solution of 4-[4-(2-methyl-allyl)-piperazin-1-yl]-phenylamine (prepared as described in Reference Example 89, 500 mg, 2.16 mmol) and triethylamine (0.6 mL, 4.32 mmol) in dry DCM (12 mL) was added a solution of oxo-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetyl chloride (prepared as described in Reference Example 21, 726 mg, 2.52 mmol) in DCM (5 mL). The mixture was warmed to room temperature and stirred for 30 min then diluted with DCM, washed successively with water, sodium bicarbonate solution and brine, then dried over sodium sulfate. Concentration gave a residue which was purified by preparative TLC using ethyl acetate and hexane (3:7) as eluent to afford N-{4-[4-(2-methyl-allyl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetamide (220 mg, 21%) as a yellow powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]=[C:9]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:8]=[C:7]2[N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=3)[N:29]([CH3:39])[C:28]2=[O:40])[CH2:23][CH2:22]1)[CH3:2].Br[CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])[N:10]=[C:9]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:8]=[C:7]2[N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=3)[N:29]([CH3:39])[C:28]2=[O:40])[CH2:23][CH2:22]1)[CH3:2]
Reactant: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1O
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1cc2nc(N3CCOCC3)nc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OCC
Yield: 62 %

Procedure:
The same procedure as in Example 48 was repeated, using 3.90 g (7.13 mmol) of Compound 47 obtained in Example 47, except that ethyl bromoacetate was used in place of methyl iodide, to give 2.81 g (yield: 62%) of Compound 54 as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][N:5]([CH:7]([F:9])[F:8])[CH:6]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[CH3:17][O:16][N:15]([CH3:14])[C:10]([C:3]1[C:2]([Cl:1])=[CH:6][N:5]([CH:7]([F:9])[F:8])[N:4]=1)=[O:12]
Reactant: O=C(O)c1nn(C(F)F)cc1Cl
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1nn(C(F)F)cc1Cl
Reaction time: 16 h
Yield: 90.1 %

Procedure:
A solution of 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid (150 mg, 0.76 mmole) in dichloromethane (5 ml) was subsequently treated at 22° C. with N,O-dimethylhydroxylamine hydrochloride (78 mg, 0.80 mmole), N-methylmorpholine (0.09 ml, 0.8 mmole) and EDCI.HCl (154 mg, 0.8 mmole) and stirring was continued for 16 h. The mixture was washed with 1 M aqueous HCl and H2O, the organic layer was dried, evaporated and the residue purified by chromatography on silica gel using cyclohexane/AcOEt (2:1) to give the title compound (164 mg) as a colorless oil. MS: m/z=240.1 [M]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][N:3]=1.[CH2:10]([Mg]Cl)[CH3:11].CCOCC>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:9])[CH2:10][CH3:11])[CH:5]=[CH:4][N:3]=1
Reactant: CC[Mg]Cl
Reactant: O=Cc1ccnc(Br)c1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a chilled (−78° C.) solution of 2-bromo-pyridine-4-carbaldehyde (7.0 g, 38 mmol) in THF (200 mL) was added a 2 M solution of ethylmagnesium chloride in ether (23.5 mL, 47.0 mmol) over a 10 minute period. After 15 minutes, the mixture was gradually warmed to room temperature over 1 hour. The reaction was quenched by the slow addition of saturated aqueous NH4Cl (100 mL) and extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to afford a brown oil. The crude material was purified by silica gel chromatography eluting with a gradient of 20-40% EtOAc in hexanes to afford 1-(2-bromo-pyridin-4-yl)-propan-1-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]#[N:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13](=[N:16][OH:17])[NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(-c2ccc(Cl)cc2)o1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NC(=NO)c1ccc(-c2ccc(Cl)cc2)o1

Procedure:
A mixture of 51 g (0.25 mole) of 5-(p-chlorophenyl)-2-furonitrile, 19 g (0.27 mole) of hydroxylamine hydrochloride, 18 g (0.27 mole) of potassium hydroxide and 750 ml of absolute ethanol was heated under reflux for 1 hour. The reaction mixture was concentrated on a rotary evaporator and cooled in ice overnight. The solid was collected by filtration and washed with anhydrous ether to give 43 g (73%). Two recrystallizations from absolute ethanol gave an analytical sample, m.p. 167°-169°.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][CH:3]=1.[N:8](OCCC(C)C)=[O:9].C(OC(C)C)(C)C>C(O)C.Cl>[NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N:8]=[O:9]
Reactant: CC(C)CCON=O
Reactant: Cn1nccc1N
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: Cn1ncc(N=O)c1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-amino-1-methylpyrazole (5 g) in ethanol (50 ml) was added isoamyl nitrite (6.92 ml), and then 20% hydrochloric acid (5 drops) was added at 4° C. The reaction mixture was refluxed for 2 hours and cooled to room temperature. To the reaction mixture was added diisopropyl ether (50 ml), and the mixture was stirred for 0.5 hour. The resulting precipitate was collected by filtration and dried in vacuo to give 5-amino-1-methyl-4-nitrosopyrazole (3.53 g).
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[C:14]2[O:13][CH2:12][O:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[O:11]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:5][CH2:4][NH2:1])[C:14]=2[O:13][CH2:12]1
Reactant: O=[N+]([O-])C=Cc1cccc2c1OCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCCc1cccc2c1OCO2

Procedure:
In close analogy to the procedure described above, 4-(2-Nitro-vinyl)-benzo[1,3]dioxole is reacted with lithium aluminium hydride to provide the title compound.
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([C:15](O)=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O[N:26]1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1>[NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([C:15]([NH2:26])=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCC(=O)OCc1ccccc1)C(N)=O
Reaction time: 5 h
Yield: 75 %

Procedure:
48.6 g (1.0 eq) Boc-D-Glu(OBzl)-OH was dissolved in tetrahydrofuran, 24.8 g (1.5 eq) HOSu and 44.5 g (1.5 eq) DCC were added sequentially. After stirring for 5 hours in ice bath, the reaction was warmed to r.t and stirred for another 20 hours. A large number of white precipitate (DCU) precipitated, the precipitate was filtered out and washed with little tetrahydrofuran. The filtrate was stirred in ice-salt bath, and anhydrous ammonia was introduced to the solution. After 15 minutes, a large number of white precipitate precipitated, and stirred the mixture for another 1.5 hours, no more white solid precipitated out, and the reaction was completed. The precipitate was filtered and washed with tetrahydrofuran, and yellow oil was obtained after removing the tetrahydrofuran filtrate under vacuum. The yellow oil was diluted with AcOEt; and the pH of the solution was adjusted to 7 with 2N HCl aqueous solution in ice bath, and the solution was allowed to stand for 30 minutes. The AcOEt layer was separated, and successively washed with diluted hydrochloric acid, saturated sodium bicarbonate and water. After that, the AcOEt layer was dried with MgSO4 overnight. The mixture was filtered and the filtrate was evaporated to dryness under vacuum, and the residue was recrystallized with ethyl acetate-cyclo hexane to yield 34.2 g target compound with the yield of 75%, m.p.=122˜123° C., [α]=−1.8° (C=9.8 mg/mL, DMF)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[N:17]=[CH:16][N:15]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=4OS(C(F)(F)F)(=O)=O)[CH:13]=3)[CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Li+].[Cl-].[C:38](C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)[CH3:39]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:26][C:24]([F:25])([F:27])[C:21]1[CH:22]=[CH:23][C:18]([C:14]2[N:15]=[CH:16][N:17]=[C:12]([O:11][C:8]3[CH:9]=[C:10]4[C:5]([CH:4]=[CH:3][CH:2]=[N:1]4)=[CH:6][CH:7]=3)[CH:13]=2)=[C:19]([CH:38]=[CH2:39])[CH:20]=1
Reactant: O=S(=O)(Oc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1)C(F)(F)F
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1cc(C(F)(F)F)ccc1-c1cc(Oc2ccc3cccnc3c2)ncn1
Temperature: 25 °C

Procedure:
To a solution of trifluoromethanesulfonic acid 2-[6-(quinolin-7-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenyl ester, (Example 192(a)), (600 mg, 1.2 mmol) in dioxane (6.0 mL) was added vinyltributylstannate (370 μL, 1.6 mmol, Fluka), LiCl (150 mg, 3.5 mmol, Aldrich), Pd(PPh3)4 (27 mg, 0.02 mmol, Strem) and a few crystals of 2,6-di-tert-butyl-4-methylphenol (Aldrich). The reaction mixture was stirred at reflux for 21 h. The resulting mixture was allowed to cool to room temperature and concentrated in vacuum. Purification by silica gel chromatography (1% MeOH/CH2Cl2) provided the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 394 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:12])=[CH:4][CH:3]=1.[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1.C(Cl)Cl>[Br:11][C:10]1[C:2]([NH:1][S:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])=[CH:3][CH:4]=[C:5]2[C:9]=1[C:8](=[O:12])[CH2:7][CH2:6]2
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc2c(c1Br)C(=O)CC2
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1CCc2ccc(NS(=O)(=O)c3ccccc3)c(Br)c21
Reaction time: 2 h
Yield: 34.9 %

Procedure:
A solution of Example 129C (1.0808 g, 3.52 mmol) in pyridine (17.5 mL) was treated with phenylsulfonyl chloride (0.58 mL, 4.58 mmol), stirred for 2 hours, diluted with CH2Cl2, washed with 1N HCl (3×50 mL) and brine (50 mL), dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 9:1 hexanes/ethyl acetate to provide the desired product (450 mg, 35%); MS (ESI(+)) m/e 368 (M+H)+; MS (ESI(−)) m/e 364, 366 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.70 (m, 2H), 7.63 (m, 1H), 7.56 (m, 2H), 7.51 (m, 1H), 7.42 (m, 1H), 3.00 (m, 2H), 2.66 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Cl.N([O-])=O.[Na+].[N-:14]=[N+:15]=[N-].[Na+]>O>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]=[N+:14]=[N-:15]
Reactant: Nc1ccccc1F
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1ccccc1F

Procedure:
A mixture of 4.44g. (0.04 mole) of 2-fluoroaniline in 16 ml. of water and 9 ml. of concentrated HCl, kept at 0°-5° C., was treated with a solution of 2.90g. (0.04 mole) of NaNO2 in 10 ml. of water. The reaction mixture was aged for one-half hour at 0°-5° C. and there was then added slowly to the mixture a solution of 2.6g. (0.04 mole) of NaN3 in 10 ml. of water. The reaction mixture was then allowed to slowly reach room temperature, and it was noted that a gas was evolved. There was then added 40 ml. of petroleum ether, and the reaction mixture was shaken well, after which it was observed to separate into two separate layers. The yellow petroleum ether layer was separated, dried over MgSO4, and concentrated under reduced pressure at a temperature of about 30° C. There was produced 5.5g. of a yellow oil and the structure of the final product was confirmed by IR.
Reaction SMILES: Br[C:2]1[C:3]([CH2:11][CH3:12])=[N:4][N:5]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=12.[Li]C(C)(C)C.[O:18]=[C:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>C1COCC1>[C:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][C:19]([OH:18])([C:2]2[C:3]([CH2:11][CH3:12])=[N:4][N:5]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=23)[CH2:20][CH2:21]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CCc1nn2c(c1Br)CCCC2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCc1nn2c(c1C1(O)CCN(C(=O)OC(C)(C)C)CC1)CCCC2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-bromo-2-ethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (4.01 g, 17.6 mmol, from Step C) in THF (20 mL) was added tert-BuLi (1.7 M in pentane, 22.8 mL, 38.7 mmol) dropwise at −78° C. After stirring at −78° C. for 30 min., was added tert-butyl 4-oxo-1-piperidinecarboxylate (3.51 g, 17.6 mmol) in THF (10 mL) dropwise at −78° C. The mixture was stirred at −78° C. for 10 min. and at rt for 4 h. After the reaction was quenched with aqueous NH4Cl, the mixture was partitioned between EtOAc and water. Aqueous layer was extracted with EtOAc (3×). Combined organic phase was washed with brine and dried over anhydrous MgSO4. Concentration was followed by purification by flash chromatography (hexanes:EtOAc=1:1, then 100% EtOAc) to give the title compound as a foamy solid. 1HNMR (500 MHz, CDCl3) δ 1.26 (t, 3H, J=7.4 Hz), 1.49 (s, 9H), 1.75–1.90 (m, 4H), 1.90–2.10 (m, 4H), 2.76 (q, 2H, J=7.6 Hz), 2.89 (t, 2H, J=6.4 Hz), 3.10–3.20 (br, 2H), 3.85–4.05 (br, 2H), 4.09 (t, 2H, J=6.2 Hz). ESI-MS 276 (M-tert-Bu-H2O+H); HPLC A 2.05 min.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)[OH:4].[C:26]1([C:37](O)=[O:38])[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[OH:4][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)[CH:2]([NH:1][C:37]([C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12)=[O:38])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:24])([F:25])[CH:21]([F:22])[F:23])[CH:14]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(O)c1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{(1RS,2SR)-2-amino-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl}phenol (2.89 g, 8.04 mmol) in acetonitrile (50 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (1.51 g, 8.04 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.31 g, 12.06 mmol) and 1-hydroxybenzotriazole hydrate (1.23 g, 8.04 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (200 ml) and extracted with ethyl acetate (200 ml×2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:1) to give the objective substance (2.75 g, 65%) as an amorphous compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1.C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>C(Cl)Cl>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([CH2:27][NH:1][C:2]2[CH:3]=[C:4]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[O:18])=[CH:16][C:11]=4[N:10]=[CH:9]3)[CH:5]=[CH:6][CH:7]=2)[CH:29]=1
Reactant: O=Cc1cccnc1
Reactant: Nc1cccc(-n2cnc3cc(C(=O)NCc4cccnc4)ccc32)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1cccc(NCc2cccnc2)c1

Procedure:
A solution of 1-(3-aminophenyl)-N-(pyridin-3-ylmethyl)-1H-benzimidazole-5-carboxamide (prepared in Steps (a)-(d) of the procedure used for the synthesis of EXAMPLE I1, 70.2 mg, 0.205 mmol) and nicotinaldehyde (20 μL, 0.21 mmol) in DCM (1 mL) under N2 was treated with TFA (1 mL) and after 5 min was heated at reflux for 2 h. The cooled reaction mixture was then treated with Et3SiH (70 μL, 0.44 mmol) and the mixture re-heated to reflux for 19 h. After this time the solvents and excess reagents were removed by concentration in vacuo and the crude residue purified by column chromatography over silica gel eluting with 0.7-15% MeOH/DCM to provide the title compound; MS (ES+): m/z 435 [MH+]
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:8]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:3][CH:2]=1.[H-].[Na+].[CH3:30][O:31][CH2:32][CH2:33]I>CN(C)C=O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:33][CH2:32][O:31][CH3:30])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH:10]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:8]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:3][CH:2]=1
Reactant: COC(=O)c1cc2cc(O)c(OC)cc2c(-c2ccncc2)c1C(=O)OC
Reactant: COCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cc2cc(C(=O)OC)c(C(=O)OC)c(-c3ccncc3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.2 %

Procedure:
To a solution of 1-(4-pyridyl)-2,3-bis(methoxycarbonyl)-6-hydroxy-7-methoxynaphthalene (17 g) in dimethylformamide (50 ml) is added gradually sodium hydride (60% dispersion-type) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. The mixture is cooled with ice, and thereto is added 2-methoxyethyl iodide (10.3 g). The mixture is stirred at room temperature for 2 hours, and heated to 80° C. One hour thereafter, the reaction solution is allowed to cool, and concentrated. The resulting residue is dissolved in ethyl acetate, washed with water, dried, and concentrated. The precipitated crystal is washed with diethyl ether to give 1-(4-pyridyl)-2,3-bis(methoxycarbonyl)-6-(2-methoxyethyloxy)-7-methoxynaphthalene (8.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C@@H:18]3[CH2:30][CH3:31])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Cl.O1CCOCC1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C@@H:18]3[CH2:30][CH3:31])=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC[C@H]1CNCCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 65.7 %

Procedure:
A mixture of 114c (502 mg, 1.02 mmol), dichloromethane (2 mL), and 4.0 M HCl/dioxane (4 mL) was stirred at room temperature for 5 h. It was then concentrated under reduced pressure to afford crude 114d as a yellow solid (263 mg, 66%), which was used in the next step without further purification. MS: [M+H]+ 392.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[O:5](C(OC(C)(C)C)=O)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=O>C(Cl)(Cl)Cl>[C:6]([NH:3][CH2:2][CH2:1][NH2:4])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:5]
Reactant: NCCN
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCN
Reaction time: 16 h

Procedure:
Ethylenediamine (16-1) (Aldrich) (18.04 g, 0.50 mol) in CHCl3 (200 ml) was treated with a solution of BOC2O (13.1 g, 0.06 moles) in CHCl3 (100 ml) at room temperature over 1 h. This was stirred for 16 h, filtered, and concentrated to give 16-2 as a clear oil.