Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[N:12]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=3)=[O:10])=[CH:4][CH:3]=1.[CH:29]12[CH2:35][CH2:34][CH:33]1[CH2:32][NH:31][CH2:30]2.[OH-].[K+].O>CN1CCCC1=O>[CH:29]12[CH2:35][CH2:34][CH:33]1[CH2:32][N:31]([C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[N:12]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([F:20])=[CH:15][CH:14]=4)=[O:10])=[CH:4][CH:3]=1)[CH2:30]2
Reactant: O=C(Nc1ccc(Cl)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: C1CC2CNCC12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(N2CC3CCC3C2)nc1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Yield: 15.3 %

Procedure:
A mixture of 0.2 g (0.5 mmol) of N-[6-chloropyridin-3-yl]-5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxamide, prepared in step 3.1, of 0.0806 g (0.6 mmol) of 3-azabicyclo[3.2.0]heptane (J. Med. Chem. 1967, 10(4), 621) and of 0.0564 g (1.01 mmol) of potassium hydroxide in 0.5 ml of N-methylpyrrolidinone is heated for 90 minutes in a microwave oven regulated at 150° C. under 150 watts. The reaction mixture is subsequently poured into 20 ml of water. The mixture is extracted with three times 30 ml of ethyl acetate. The combined organic phases are washed with 30 ml of water, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting solid is subsequently purified by silica column chromatography, elution being carried out with a mixture of n-heptane and ethyl acetate. 35 mg of the expected product are thus isolated.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:25](=[C:26]([CH3:28])[CH:27]=1)[NH:24][CH2:23][CH2:22]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:18][CH3:17])=[CH:27][C:26]=3[CH3:28])[CH2:22][CH2:23]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=1
Reactant: CC[C@H](COC)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(C)c2c(c1)CCN2
Agent: Cl
Product: CC[C@H](COC)n1cc(Cl)nc(N2CCc3cc(OC)cc(C)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-(methoxymethyl)propyl]-2(1 H)-pyrazinone and 5-methoxy-7-methylindoline hydrochloride as the starting materials. mp 62-64° C.; 1H NMR (300 MHz, CDCl3): δ 6.92 (s, 1 H), 6.67 (s, 1 H), 6.59 (d, J=2.2 Hz, 1 H), 5.02-4.92 (m, 1 H), 4.38 (t, J=7.7 Hz, 2 H), 3.79 (s, 3 H), 3.66 (dd, J=10.3, 5.5 Hz, 1 H), 3.56 (dd, J=10.6, 3.6 Hz, 1 H), 3.36 (s, 3 H), 3.04 (t, J=7.7 Hz, 2 H), 2.06 (s, 3 H), 1.90-1.70 (m, 2 H), 0.94 (t, J=7.3 Hz, 3 H); HRMS (ESI) calcd for C19H25N3O3Cl (M+H)+: 378.1584; Found m/z 378.1604.
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][N:18](COCC[Si](C)(C)C)[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1>>[C:1]([NH:5][C:6]([C:17]1[NH:18][C:19]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=2)[N:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N=C=O
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Product: CC(C)(C)NC(=O)c1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)[nH]1

Procedure:
Using essentially the same procedure as Example 25, Step B–C, but using t-butyl isocyanate (0.016 mL, 0.14 mmol) in Step B, 4,5-di-(4-chlorophenyl)-1-(2-(trimethylsilyl)ethoxymethyl)imidazole (23 mg, 0.055 mmol) from Example 25, Step A was converted to the SEM intermediate and then to the title compound with TBAF. HPLC/MS: 388 (M+1), 390 (M+3); Rt=2.45 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19](OS(C(F)(F)F)(=O)=O)[CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32]([Mg]Br)=[CH2:33]>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH:32]=[CH2:33])[CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[Mg]Br
Reactant: O=S(=O)(Oc1ccc2cc(C3CCN(Cc4ccccc4)CC3)ccc2c1)C(F)(F)F
Product: C=Cc1ccc2cc(C3CCN(Cc4ccccc4)CC3)ccc2c1
Yield: 63.3 %

Procedure:
Beginning with 0.839 gm (1.9 mMol) 1-benzyl-4-(6-trifluoromethanesulfonyloxynaphth-2-yl)piperidine and 3.73 mL (3.7 mMol) vinylmagnesium bromide (1M in tetrahydrofuran), 0.394 gm (65%) of the desired compound were prepared as a waxy white solid substantially by the procedure of EXAMPLE 7.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([C:18]2[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25])[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH2:46])[CH:31]=[C:32]([O:44][CH3:45])[C:33]=1[O:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1.[OH-].[Na+]>CC(O)=O>[NH:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[N:8]([C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:25])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:46][C:30]2[CH:29]=[C:28]([O:27][CH3:26])[C:33]([O:34][CH2:35][CH2:36][N:37]3[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]3)=[C:32]([O:44][CH3:45])[CH:31]=2)[N:7]=1
Reactant: COc1cc(N)cc(OC)c1OCCN1CCN(C)CC1
Reactant: Cc1cccc(C)c1N(c1ccnc(Cl)n1)c1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc(Nc2nccc(N(c3nc4ccccc4[nH]3)c3c(C)cccc3C)n2)cc(OC)c1OCCN1CCN(C)CC1
Temperature: 100 °C

Procedure:
A pressure tube was charged with a solution of 2-(N-(2-chloropyrimid-4-yl)-2,6-dimethylphenylamino)-1H-benzimidazole (50 mg, 0.14 mmol), 3,5-dimethoxy-4-[2-(4-methylpiperazin-1-yl)-ethoxy]phenylamine (42 mg, 0.14 mmol) in glacial AcOH (2 mL). The reaction, a dark brown solution, was heated to 100° C. for 18 h. The reaction was cooled to RT and then basified by careful addition of 5M NaOH (15 mL). The aqueous solution was extracted with CH2Cl2. The combined organic extracts were dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by column chromatography (silica; CH2Cl2:MeOH; 8:2) to afford the title compound as a light purple solid. MS m/z=609 (M+H). Calc'd for C34H40N8O3=608.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[C:4](=O)[C:3]1=O.[CH:13]1([NH2:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[NH2:19].O>C(O)(=O)C>[CH3:1][C:2]1([CH3:12])[C:3]2[C:4](=[N:19][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=3[N:20]=2)[C:5]([CH3:9])([CH3:8])[CH2:6][CH2:7]1
Reactant: NC1CCCCC1N
Reactant: CC1(C)CCC(C)(C)C(=O)C1=O
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)CCC(C)(C)c2nc3c(nc21)CCCC3

Procedure:
20.0 g of 3,3,6,6-tetramethyl-1,2-cyclohexanedione and 20 ml of 1,2-cyclohexanediamine were dissolved in 20 ml of acetic acid. The obtained solution was heated under reflux for 6 hours, cooled by allowing to stand, and poured into water, followed by the extraction with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated acueous solution of common salt, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. The obtained residue was purified by silica gel chromatography (developer: 5% ethyl acetate/hexane) to give 16.0 g of the title compound as a colorless oil.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11](O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][CH2:23][CH2:24]Cl>CCC(C)=O.CO>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:22][CH2:23][CH3:24])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: ClCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CO
Product: CCCc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.6 %

Procedure:
The compound of 4-phenoxyphenol (81.03 g, 435.5 mmol) was dissolved in 810 ml MEK at ambient temperature under Nitrogen. Powdered potassium carbonate (577.16 g, 4,176.27 mmol) was added followed by 1,3-dichloropropane (300.00 g, 2,655.1 mmol), and the resulting solution was heated to reflux for 15.5 hours. The solution was cooled to room temperature, filtered and washed with 750 ml MEK. The filtrate was concentrated under vacuum to give a crude orange liquid. The crude liquid was dissolved in 260 ml absolute MeOH at ambient temperature and stirred 5 minutes, which was then cooled in an ice/acetone/water bath for 1.5 hours. White precipitate was filtered off and washed with 480 ml cold absolute MeOH. The white solid was collected and dried under vacuum at 30° C. for 16 hours to afford about 81.87 g of compound (a).
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>C1COCC1>[Br:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][CH:5]=[O:7])=[CH:14][CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Br)cc1
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CNc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
A 5-Liter round bottom flask was charged with acetic anhydride (488 mL, 5.2 mol) and cooled to 0° C. Formic acid (240 mL, 6.4 mol) was then added at a rate that did not elevate the temperature of the reaction mixture above 10° C. After the formic acid was added, the temperature of the reaction was raised to 50-60° C. and stirred for 3 hours. The reaction was then cooled to 0° C. and 400 mL of THF was added. A solution of 4-bromoaniline (344 g, 2.0 mol) in 800 mL of THF was added dropwise. After the addition was complete, the reaction was allowed to stir at this temperature for 4 hours. The reaction was checked by thin-layer chromatography and found to be complete. The reaction mixture was transferred to a round bottom flask and the solvent was removed in vacuo. When the solvent had been removed, the residue crystallized. The solid was triturated with heptane and filtered. Obtained 396.8 grams of desired N-(4-bromo-phenyl)-formamide. Yield 99.2% The spectral properties of the solid were consistent with the desired material. Step (2): (4-bromo-phenyl)-methyl-amine
Reaction SMILES: [N:1]1[C:11]2[O:10][C:9]3[CH:12]=[CH:13][C:14]([CH2:16][C:17]([OH:19])=[O:18])=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(=O)([O-])O.[Na+].[CH2:26](O)[CH3:27]>>[CH2:26]([O:18][C:17](=[O:19])[CH2:16][C:14]1[CH:13]=[CH:12][C:9]2[O:10][C:11]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7][C:8]=2[CH:15]=1)[CH3:27]
Reactant: CCO
Reactant: O=C(O)Cc1ccc2c(c1)CCc1cccnc1O2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)Cc1ccc2c(c1)CCc1cccnc1O2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.8 %

Procedure:
To a mixture of 20 mg of (5,6-dihydro benzo[b]pyrido-[3,2-f]oxepin-8-yl)-acetic acid and 0.5 ml of ethanol was added 2.5 ml of a saturated hydrogen chloride gas-ethanol solution, and the resulting mixture was stirred at room temperature for 1.5 hours. After the completion of the reaction, this was basified with a saturated sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain an oil, which was chromatographed over 1 g of silica gel and eluted with benzene/chloroform (9/1-8/1), thereby yielding 18 mg (yield: 81.8%) of ethyl(5,6-dihydro benzo[b]pyrido[3,2-f]-oxepin-8-yl)-acetate as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[CH:11]([C:13]2[N:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH3:12])=[N:6][CH:7]=1.P(Cl)(Cl)(Cl)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH:11]([C:13]3[N:14]=[N:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[CH3:12])=[N:9][N:8]=2)[CH:7]=1
Reactant: CC(C(=O)NNc1ccc(Br)cn1)c1ccc(Cl)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(c1ccc(Cl)nn1)c1nnc2ccc(Br)cn12
Yield: 46.4 %

Procedure:
A solution of N′-(5-bromopyridin-2-yl)-2-(6-chloropyridazin-3-yl)propanehydrazide (5.0 g, 14.02 mmol) and phosphoryl trichloride (100 mL, 1073 mmol) was stirred at 90° C. for 5 hrs. The reaction was cooled, stripped to dryness, and the resulting material was reconstituted in a mixture of EtOAc and saturated NaHCO3 (400 mL, 1:1)). The organic phase was isolated, washed with saturated NaHCO3 (1×100 mL), and dried over MgSO4. The organic phase was removed via rotary evaporation to provide the title compound, 6-bromo-3-(1-(6-chloropyridazin-3-yl)ethyl)-[1,2,4]triazolo[4,3-a]pyridine 48D (2.2 g, 6.50 mmol, 46.3% yield). This material was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.86 (d, J=7.07 Hz, 3 H) 5.27 (d, J=7.33 Hz, 1 H) 7.49 (dd, J=9.60, 1.77 Hz, 1 H) 7.78 (dd, J=9.85, 1.01 Hz, 1 H) 7.94 (s, 2 H) 8.79 (s, 1 H). ESI-MS:m/z 339.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH2:12][CH3:13])[C:9](=O)[CH3:10])=[CH:4][CH:3]=1.[O:15]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[O:15]([C:22]1[CH:23]=[C:24]([CH2:25][CH2:10][CH2:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([CH3:14])[CH2:12][CH3:13])[CH:27]=[CH:28][CH:29]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCC(C)(C(C)=O)c1ccc(Cl)cc1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Product: CCC(C)(CCCc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1

Procedure:
In the same manner as described in Synthesis Example 2, 3-(4-chlorophenyl)-3-methyl-2-pentanone and 3-phenoxybenzaldehyde were treated to give 1-(3-phenoxyphenyl)-4-(4-chlorophenyl)-4-methyl-hexane.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23](O)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH:49]([CH:52]1[CH2:56][CH2:55][CH2:54][NH:53]1)([CH3:51])[CH3:50].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:53]3[CH2:54][CH2:55][CH2:56][CH:52]3[CH:49]([CH3:51])[CH3:50])=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: CC(C)C1CCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C1CCCN1C(=O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 2-isopropylpyrrolidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C@H:26]([C:42]([N:44]3[CH2:49][CH2:48][N:47]([C:50]([O:52][CH2:53][C:54]4[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][CH:55]=4)=[O:51])[CH2:46][CH:45]3[CH3:63])=[O:43])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[SH:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[C@H:26]([C:42]([N:44]2[CH2:49][CH2:48][N:47]([C:50]([O:52][CH2:53][C:54]3[CH:55]=[CH:56][C:57]([N+:60]([O-:62])=[O:61])=[CH:58][CH:59]=3)=[O:51])[CH2:46][CH:45]2[CH3:63])=[O:43])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)CC3C)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(C(=O)OCc2ccc([N+](=O)[O-])cc2)CCN1C(=O)[C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 100.2 %

Procedure:
23 ml of trifluoroacetic acid, followed by 0.57 ml of trifluoromethanesulfonic acid, were added dropwise to a solution of 2.26 g of (2S,4S)-4-(4-methoxybenzylthio)-2-[2-methyl-4-(4-nitrobenzyloxycarbonyl)piperazin-1-yl-carbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (iii) above] in 3.48 ml of anisole, and the resulting mixture was worked up and purified by the same procedure as described in Preparation 4(ii), to give 1.88 g of the title compound, as an amorphous solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]([CH2:17][C:18]([O:20]C)=O)[NH2:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][N:23]=[C:24]=[O:25].C[O-].[Na+]>>[CH3:22][N:23]1[C:18](=[O:20])[CH2:17][N:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][CH:13]=2)[NH:16][C:24]1=[O:25]
Reactant: COC(=O)CN(N)c1ccc(OCc2ccccc2)cc1
Reactant: CN=C=O
Agent: C[O-]
Agent: [Na+]
Product: CN1C(=O)CN(c2ccc(OCc3ccccc3)cc2)NC1=O

Procedure:
Methyl [1-[4-(phenylmethoxy)phenyl]hydrazino]acetate (0.73 g) was treated with methyl isocyanate (0.5 ml) and then with sodium methoxide solution (3.5 ml). The product was recrystallised from tetrahydrofuran-hexane to give the title compound (0.56 g), m.p. 224°-227°, t.l.c. (ethyl acetate) Rf 0.55.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[C@H:24]2[CH2:29][C@@H:28]([NH:30]C(=O)OC(C)(C)C)[C@@H:27]([OH:38])[C@@H:26]([CH3:39])[CH2:25]2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:40].[CH3:41][S:42](Cl)(=[O:44])=[O:43]>N1C=CC=CC=1>[CH3:41][S:42]([O:38][C@H:27]1[C@@H:26]([CH3:39])[CH2:25][C@@H:24]([C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[NH:17][C:15](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([F:40])=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[N:14]=2)[CH2:29][C@H:28]1[NH2:30])(=[O:44])=[O:43]
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](N)[C@H]1OS(C)(=O)=O
Reaction time: 0.08 h
Yield: 45 %

Procedure:
To a solution of tert-butyl (1R,2S,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-2-hydroxy-3-methylcyclohexylcarbamate (1.0 equiv.) in pyridine (0.12 M) was added MsCl (7.0 equiv.). The capped solution was stirred for 5 minutes and then the homogeneous solution was left standing at rt for 16 hrs. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with H2O, 10% CuSO4, H2O, Na2CO3(sat.), NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO chromatography. The Boc protected product was treated with 25% TFA/CH2Cl2 for 20 minutes at which time the volatiles were removed in vacuo and the residue was dissolved in DMSO and purified by RP-HPLC. The product fractions were lyophilized directly to yield (1S,2R,4R,6S)-2-amino-4-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-6-methylcyclohexyl methanesulfonate in 45% yield. LC/MS (m/z)=535.2 (MH+), Rt=0.60 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](OCC)=[C:8]2[C:14]([CH3:15])=[N:13][O:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:23][CH2:19][CH2:20][CH2:21][CH3:22])=[C:8]2[C:14]([CH3:15])=[N:13][O:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCCCN
Reactant: CCOC(=O)c1cnc2onc(C)c2c1OCC
Solvent: c1ccccc1
Product: CCCCNc1c(C(=O)OCC)cnc2onc(C)c12

Procedure:
25 g. of 4-ethoxy-3-methylisoxazolo[5,4-b]pyridine-5-carboxylic acid ethyl ester (0.113 mol.) are dissolved in 100 ml. of benzene and after adding 8 g. of butylamine (0.23 mol.), the solution is refluxed for 12 hours. The solvent is distilled off and the residual 4-butylamino-3-methylisoxazolo[5,4-b]pyridine-5-carboxylic acid ethyl ester is recrystallized from ligroin, m.p. 60°, yield 23.5 g. (85%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:15]=[C:16]1[CH2:21][NH:20][CH2:19][CH2:18][NH:17]1.C(O)C.Cl.[H-]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:20]2[CH2:19][CH2:18][NH:17][C:16](=[O:15])[CH2:21]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CNCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N2CCNC(=O)C2)CC1
Reaction time: 0.75 h
Yield: 34.1 %

Procedure:
A mixture of 1-t-butoxycarbonyl-4-oxopiperidine (2.985 g) and 2-oxopiperazine (1.5 g) was dissolved in methanol (25 ml), and molecular sieves 3A (2.5 g) and 1N ethanol-hydrochloric acid (2.5 ml) were then added, followed by stirring for 45 minutes. Cyanoboronsodium hydride (945 ml) was divided into three portions and they were then separately added to the solution under ice-cooling, followed by stirring 5 hours at room temperature. After insolubles were removed with sellaite, the filtrate was then concentrated. To the resultant residue, a saturated sodium hydrogencarbonate solution was added, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated saline solution and then dried over magnesium sulfate. After the solvent was evaporated, the residue was purified by silica gel column chromatography (300 g, chloroform:methanol=30:1 to 10:1) to give 1.448 g of 4-(1-t-butoxycarbonylpiperidin-4-yl)-2-oxopiperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C([Li])CCC.Br[CH2:18][CH2:19][CH2:20][Cl:21].C(OCC)(=O)C>C1COCC1>[Cl:21][CH2:20][CH2:19][CH2:18][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:9]([OH:11])=[O:10]
Reactant: ClCCCBr
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)C(CCCCl)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 4-chlorophenylacetic acid (1 g) in THF (30 mL) was stirred at −78° C. for 20 minutes. n-Butyl lithium (2.66 M solution in hexane, 4.41 mL) was added to the solution, and the reaction solution was stirred at −78° C. for one hour. Thereafter, the reaction solution was stirred at 0° C. for one hour, 1-bromo-3-chloropropane (0.638 mL) was added to the reaction solution, and the reaction solution was stirred at room temperature for 18 hours. Thereafter, ethyl acetate and 1 N aqueous 2hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 1.55 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH2:8])=[N:6][CH:7]=1.N1C(C)=CC=CC=1C.[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:17](=[O:19])[CH3:18])=[N:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Nc1ncc(Br)cn1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(=O)Nc1ncc(Br)cn1
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 5-bromo2-aminopyrimidine (2.0 g, 11.5 mmole) in CH2Cl2 (75 mL) at RT was added 2,6-lutidine (2.7 mL, 23.0 mmole) followed by acetyl chloride (0.99 g, 12.6 mmole). After stirring for 8 hours, the reaction solution was concentrated under vacuum. The remaining residue was dissolved EtOAc (200 mL), washed with H2O (100 mL) and brine, and dried over Na2SO4. Flash chromatography on silica gel (95:5 CHCl3/MeOH) and drying under high vacuum gave the title compound (1.74 g, 70%) as a yellow solid: MS (ES) m/e 217 (M+H)+.