Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][C:9]([C:11]2[CH:24]=[CH:23][C:22]3[S:21][C:20]4[C:15](=[CH:16][C:17]([C:25](=[O:40])[CH2:26][CH2:27][CH2:28][N:29]5C(=O)C6=CC=CC=C6C5=O)=[CH:18][CH:19]=4)[CH2:14][C:13]=3[CH:12]=2)=[O:10])C(=O)C2=CC=CC=C12.C1(=O)N(CCCC([Cl:57])=O)C(=O)C2=CC=CC=C12.C1C2CC3C(=CC=CC=3)SC=2C=CC=1.[ClH:78]>C(O)(=O)C>[ClH:57].[ClH:78].[NH2:29][CH2:28][CH2:27][CH2:26][C:25]([C:17]1[CH:18]=[CH:19][C:20]2[S:21][C:22]3[C:13](=[CH:12][C:11]([C:9](=[O:10])[CH2:8][CH2:7][CH2:6][NH2:5])=[CH:24][CH:23]=3)[CH2:14][C:15]=2[CH:16]=1)=[O:40]
Reactant: O=C(Cl)CCCN1C(=O)c2ccccc2C1=O
Reactant: O=C(CCCN1C(=O)c2ccccc2C1=O)c1ccc2c(c1)Cc1cc(C(=O)CCCN3C(=O)c4ccccc4C3=O)ccc1S2
Agent: Cl
Agent: c1ccc2c(c1)Cc1ccccc1S2
Solvent: CC(=O)O
Product: NCCCC(=O)c1ccc2c(c1)Cc1cc(C(=O)CCCN)ccc1S2

Procedure:
2,7-Bis(4-phthalimidobutyryl)thioxanthene, prepared from 4-phthalimidobutyryl chloride and thioxanthene by the method of S.S. Cheng et al., J. Med. Chem. 9, 945 (1966), is treated with hot glacial acetic acid after which concentrated HCl is added gradually with stirring. The mixture is heated to reflux for 24 hours with a constant stream of HCl gas passing through the mixture. The reaction mixture is stirred and refluxed for an additional 24 hours, cooled, and the product worked up in the usual manner.
Reaction SMILES: [SH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(ON=O)CC(C)C.[Cl:16][C:17]1[CH:23]=[CH:22][C:20](N)=[C:19]([S:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])=[CH:27][C:26]=2[Cl:36])[CH:18]=1>C(#N)C.O>[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([S:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:19]([S:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH2:34][CH3:35])(=[O:32])=[O:33])=[CH:27][C:26]=2[Cl:36])[CH:18]=1
Reactant: CCS(=O)(=O)c1ccc(Sc2cc(Cl)ccc2N)c(Cl)c1
Reactant: CCOC(=O)CS
Agent: CC(C)CCON=O
Solvent: O
Solvent: CC#N
Product: CCOC(=O)CSc1ccc(Cl)cc1Sc1ccc(S(=O)(=O)CC)cc1Cl
Temperature: 60 °C

Procedure:
Ethyl mercaptoacetate (0.11 ml) followed by isoamylnitrite (0.16 ml) were added to a solution of the product from step (iii) (0.35 g) in dry acetonitrile (20 ml) and heated at 60° C. for 10 h. The mixture was diluted with water, extracted with diethylether, the organics dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/diethylether 1:1, yield 0.10 g.
Reaction SMILES: F[B-](F)(F)F.C(N([S+](F)[F:12])CC)C.[CH:14]1([N:17]2[C:25]3[CH:24]=[CH:23][N:22]=[CH:21][C:20]=3[N:19]([CH2:26][C:27]3[N:28]=[C:29]4[CH:34]=[N:33][CH:32]=[CH:31][N:30]4[C:35]=3[CH2:36][CH2:37][CH2:38][CH2:39]O)[C:18]2=[O:41])[CH2:16][CH2:15]1.F.F.F.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:14]1([N:17]2[C:25]3[CH:24]=[CH:23][N:22]=[CH:21][C:20]=3[N:19]([CH2:26][C:27]3[N:28]=[C:29]4[CH:34]=[N:33][CH:32]=[CH:31][N:30]4[C:35]=3[CH2:36][CH2:37][CH2:38][CH2:39][F:12])[C:18]2=[O:41])[CH2:16][CH2:15]1
Reactant: O=c1n(Cc2nc3cnccn3c2CCCCO)c2cnccc2n1C1CC1
Reactant: CCN(CC)[S+](F)F
Agent: F
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1n(Cc2nc3cnccn3c2CCCCF)c2cnccc2n1C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
A suspension of diethylaminodifluorosulfonium tetrafluoroborate (453 mg, 1.982 mmole), 1-cyclopropyl-3-((3-(4-hydroxybutyl)imidazo[1,2-a]pyrazin-2-yl)methyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one P17 (500 mg, 1.321 mmole), and triethylamine trihydrofluoride (319 mg, 1.5 eq) in DCM (20 mL) was stirred at RT under N2 atmosphere for 60 minutes. 100 mL sat NaHCO3 was then added and the mixture was stirred until gas evolution stopped (10 minutes), then was extracted with 150 mL DCM (2×). Combined organic layers were dried on Na2SO4, filtrated and evaporated to dryness. Purification by Prep HPLC on (RP Vydac Denali C18-10 μm, 250 g, 5 cm) with (0.25% NH4HCO3 solution in water, MeOH) as mobile phase, afforded the target compound P18 in 20% yield. m/z=381 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82-0.92 (m, 2H), 1.00-1.10 (m, 2H), 1.46-1.80 (m, 4H), 2.95 (tdd, J=6.96, 6.96, 3.64, 3.51 Hz, 1H), 3.12 (t, J=7.53 Hz, 2H), 4.43 (dt, J=47.43, 6.00 Hz, 2H), 5.23 (s, 2H), 7.24 (dd, J=5.27, 0.75 Hz, 1H), 7.89 (d, J=4.52 Hz, 1H), 8.22 (d, J=5.27 Hz, 1H), 8.41 (s, 1H), 8.47 (dd, J=4.77, 1.51 Hz, 1H), 8.98 (d, J=1.51 Hz, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=3[CH2:15][O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OCCCl)=O>ClCCl>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]2[CH2:15][O:14][C:11]3([CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:17]=2[CH:18]=1
Reactant: Clc1ccc2c(c1)C1(CCN(Cc3ccccc3)CC1)OC2
Agent: O=C(Cl)OCCCl
Solvent: ClCCl
Product: Clc1ccc2c(c1)C1(CCNCC1)OC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
To a solution of 1′-benzyl-6-chloro-3H-spiro[2-benzofuran-1,4′-piperidine] (850 mg, 2.7 mmol) in dichloromethane (CH2Cl2) (8 mL) was added chloroethyl chloroformate (Yang, B. V; o'Rourke, D; Li, J., Synlett, 1993, 195-196) (772 mg, 5.4 mmol) slowly at 0° C. After addition was complete the reaction mixture was stirred at 0° C. for 30 min. The volatiles were removed in vacuo, residue was dissolved in methanol (10 mL) and kept at reflux for 40 min. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (0-6% methanol in dichloromethane, 0.2% ammonium hydroxide (NH4OH)) to give the titled compound (170 mg) and 1′-benzyl-6-chloro-3H-spiro[2-benzofuran-1,4′-piperidine] was recovered (200 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=3)[C:10]=2[O:21][C:22]2[CH:37]=[CH:36][C:25]([O:26][CH2:27][CH2:28][N:29]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:24][CH:23]=2)[CH:5]=[CH:6][C:7]=1[F:8].[ClH:38].C(OCC)C.B(Br)(Br)Br>ClCCl.C([O-])(O)=O.[Na+].CO>[ClH:38].[N:29]1([CH2:28][CH2:27][O:26][C:25]2[CH:24]=[CH:23][C:22]([O:21][C:10]3[C:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)=[CH:18][CH:17]=[C:16]4[C:11]=3[CH:12]=[CH:13][C:14]([OH:19])=[CH:15]4)=[CH:37][CH:36]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCCC4)cc3)c(-c3ccc(F)c(F)c3)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: Oc1ccc2c(Oc3ccc(OCCN4CCCCCC4)cc3)c(-c3ccc(F)c(F)c3)ccc2c1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Dissolve 1-(2-{4-[2-(3,4-difluoro-phenyl)-6-methoxy-naphthalen-1-yloxy]-phenoxy}-ethyl)-azepane (630 mg, 1.25 mmol) in dichloromethane (20 ml). Add 2M HCl in diethyl ether (1 mL, 2.0 mmol). Stir for 5 minutes. Concentrate the slurry and dry in vacuo. Dilute the residue in dichloromethane (20 ml) and blanket with nitrogen. Cool the solution to 0° C. with external ice bath. Add BBr3 (0.4 mL, 4.3 mmol). Stir the reaction at room temperature for 30 minutes and add the reaction mixture in saturated aqueous NaHCO3 (20 ml), ice (5 g) and methanol (5 mL). Dilute with dichloromethane (20 mL), separate the layers, wash the organic layer with brine (10 ml), dry with MgSO4, filter, and concentrate in vacuo. Chromatograph the residue on a SiO2 column eluting the material with a step gradient of methanol/dichloromethane (0 to 5%) to get the free base of the title compound. Dissolve the free base in diethyl ether (5.0 ml), ethyl acetate (6.0 ml) and methanol (1.0 ml) and add 2M HCl (1 mL, 2.0 mmol) in diethyl ether. Collect the precipitate on filter paper, rinse with diethyl ether and dry in vacuo (<2 mm of Hg) to give 310 mg (47%) of the title compound: mass spectrum (ion spray) m/z=490.3 (M−Cl).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:27])[CH2:18][CH:19]2[CH2:24][C:23](=[O:25])[NH:22][C:21](=[O:26])[CH2:20]2)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:27])[CH2:18][CH:19]2[CH2:24][C:23](=[O:25])[N:22]([CH2:29][C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[C:21](=[O:26])[CH2:20]2)[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)CC2CC(=O)NC(=O)C2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)CC2CC(=O)N(CC(=O)OCc3ccccc3)C(=O)C2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 112.6 %

Procedure:
A suspension of 4-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}piperidine-2,6-dione (Example 14, 0.300 g, 0.81 mmol), benzyl bromoacetate (0.236 g, 0.97 mmol), and potassium carbonate (0.335 g, 2.42 mmol) in DMF (5 mL) was stirred at 60° C. for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution and brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give a pale yellow powder, which was re-crystallized from hexane and ethyl acetate to provide benzyl (4-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}-2,6-dioxopiperidin-1-yl)acetate (0.474 g, 79%) as an off-white powder.
Reaction SMILES: O.[CH2:2]([O:9][C:10]1[CH:39]=[CH:38][CH:37]=[CH:36][C:11]=1[O:12][C:13]1[CH:18]=[C:17]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])[C:16]([F:32])=[CH:15][C:14]=1[N+:33]([O-])=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(=O)C.[Fe]>[CH2:2]([O:9][C:10]1[CH:39]=[CH:38][CH:37]=[CH:36][C:11]=1[O:12][C:13]1[CH:18]=[C:17]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[N:21]([CH3:30])[C:20]2=[O:31])[C:16]([F:32])=[CH:15][C:14]=1[NH2:33])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCc3ccccc3)c([N+](=O)[O-])cc2F)c1=O
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCc3ccccc3)c(N)cc2F)c1=O
Reaction time: 2 h
Yield: 79.6 %

Procedure:
To a mixture of 8.6 g of iron powder, 27 ml of acetic acid and 2.7 ml of water was added dropwise a solution of 8.6 g of 2-(2-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene in 23 ml of acetic acid while keeping the temperature of the reaction solution at or below 35° C. After the addition was finished, the stirring was continued for 2 hours and then the reaction solution was filtered through celite and diluted with ethyl acetate. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and the organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica-gel column chromatography to give 6.46 g of 2-(2-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]aniline.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]2[C:3]=1[C:4]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][C:5]=1[NH:6]2.[H-].[Na+].CC1C=CC(S(O[CH2:30][CH2:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=O)=O)=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]2[C:3]=1[C:4]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][C:5]=1[N:6]2[CH2:30][CH2:31][C:32]1[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Reactant: CN1CCc2c([nH]c3c(Cl)ccc(Cl)c23)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CCn2c3c(c4c(Cl)ccc(Cl)c42)CCN(C)C3)cn1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5,8-dichloro-2,3,4,9-tetrahydro-2-methyl-1H-pyrido[3,4-b]indole (200 mg, 0.78 mmol) in DMF (2 mL), sodium hydride (94 mg, 2.36 mmol) was added. After stirring at 60° C. for 30 min., 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (572 mg, 1.96 mmol) was added to the reaction mixture and stirred at the same temperature for 40 min. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to get the residue that was purified by reverse phase HPLC to obtain the 5,8-dichloro-2,3,4,9-tetrahydro-2-methyl-9-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[3,4-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.43 (s, 1H), 8.18 (d, 1H), 7.74 (d, 1H), 7.09 (d, 1H), 7.04 (d, 1H), 4.79 (t, 2H), 4.65 b(s, 1H), 3.62 b(s, 1H), 3.5 (m, 2H), 3.35 (m, 2H), 3.25 (t, 2H), 3.16 (s, 3H), 2.75 (s, 3H).
Reaction SMILES: [NH2:1][C:2](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:32][CH2:31][S:30][S:29]3)=[O:22])[CH2:17][CH2:16]2)=[C:11](C)[CH:10]=1)[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.ClC1C=CC([N+]([O-])=O)=[C:39]([O:41]C)C=1>>[NH2:1][C:2](=[N:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]3[CH2:32][CH2:31][S:30][S:29]3)=[O:22])[CH2:19][CH2:20]2)=[CH:13][C:14]=1[O:41][CH3:39])[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(N=C(N)c2cccs2)ccc1N1CCN(C(=O)NCCCCC2CCSS2)CC1
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Product: COc1cc(N2CCN(C(=O)NCCCCC3CCSS3)CC2)ccc1N=C(N)c1cccs1
Yield: 4 %

Procedure:
The experimental protocol used is the same as that described for the compound of Example 6, 5-chloro-2-nitroanisole replacing 2-fluoro-5-nitrotoluene. A pale yellow foam is obtained (yield 4%).
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:28])[CH2:4][C@H:5]([NH:20]C(=O)OC(C)(C)C)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7]>C(OCC)(=O)C>[NH2:20][C@H:5]([C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])[CH2:4][CH:3]([CH3:2])[CH3:28]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ccccn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](N)C(=O)N1CCN(c2ccccn2)CC1
Reaction time: 0.5 h
Yield: 78 %

Procedure:
Under cooling with ice, hydrogen chloride gas was fed and saturated into ethyl acetate (200 ml), and tert-butyl (s)-3-methyl-1-[4-(2-pyridyl)piperazine-1-yl carbonyl]butylcarbamate (16.0 g) obtained above was added gradually. The mixture was stirred for 30 minutes. The solvent and hydrogen chloride were removed by distillation under reduced pressure, and 200 ml of water was added to the white powder thus obtained to dissolve the powder therein. After washing with ethyl acetate, an aqueous sodium bicarbonate solution was added to bring the pH to 8. Followed by the addition of sodium chloride, extraction with 100 ml of ethyl acetate was repeated three times. After drying over sodium sulfate, the solvent was removed by distillation under reduced pressure to yield 9.16 g of 1-L-leucyl-4-(2-pyridyl)piperazine (yield: 78.0%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[CH:11]=1)[C:5]([O:7]C)=[O:6].C1COCC1.CO.[OH-].[Na+]>CO.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH3:16])[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: CCCCC(=O)c1cc(C)cc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCC(=O)c1cc(C)cc(C(=O)O)c1

Procedure:
A mixture of methyl 3-methyl-5-pentanoylbenzoate (LXXVI, step 2. 133 mg, 0.605 mmol) in methanol (1 mL) is stirred with tetrahydrofuran/methanol/sodium hydroxide (2 N) (3/1/1, 3 mL) for 3 days. The reaction mixture is diluted with ethyl acetate and washed with water. The aqueous phase is separated and acidified with hydrochloric acid (1 N) and extracted with methylene chloride. The organic phase is dried (sodium sulfate), filtered, and concentrated under reduced pressure to give 3-methyl-5-pentanoylbenzoic acid (IX–LXXVII), NMR (300 MHz, CD3OD): δ 8.44, 8.03, 3.10, 2.33, 1.78, 1.64 and 1.34.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].C(Cl)(Cl)(Cl)Cl.[OH2:14]>CC#N>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:14])=[O:8]
Reactant: O
Reactant: OCC1CCCCO1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: O=C(O)C1CCCCO1
Reaction time: 0.33 h

Procedure:
To a vigorously stirred solution of tetrahydropyran-2-methanol (2.32 g, 40 mmol) in a mixture of CH3CN (20 ml), CCl4 (20 ml) and water (10 ml) at 0° C. was added NaIO4 (9.42 g, 44 mmol) and then RuCl3H2O(414 mg, 2 mmol). After 20 min, the cooling bath was removed. After 40 min at room temperature, TLC showed reaction was complete. The reaction mixture was partitioned into ethyl acetate and ice-cold Na2S2O5 solution. More Na2S2O5 was added until all the brown material dissolved and a greenish mixture was obtained. The aqueous portion was extracted with more ethyl acetate and combined layer was washed with 10% Na2S2O5, H2O, brine, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography using methylene chloride/methanol/acetic acid=95:5:0.5 to afford the product as an oil (1.5 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.C(O)(=O)C>O1CCCC1.[Zn]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:9]([F:12])([F:10])[F:11])=[CH:6][N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: FC(F)(F)c1cnc(Cl)nc1
Temperature: 25 °C

Procedure:
2,4-Dichloro-5-trifluoromethyl-pyrimidine (300 mg, 1.4 mmol), zinc dust (90 mg, 1.4 mmol) and tetrahydrofuran (3 ml) heated to reflux. Acetic acid (0.16 ml, 2.8 mmol) in tetrahydrofuran (3 ml) added dropwise to the mixture over 30 minutes. The resultant mixture was heated for a further 3 hours and then allowed to cool to room temperature and filtered through GF-A paper. The liquors were concentrated and wet with dichloromethane. The mixture was washed with dilute bicarbonate solution and then concentrated in vacuo furnishing a crude material from which the desired target molecule was produced.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][C:11]([S:15]([NH:18][C:19]3[N:24]=[C:23]([NH:25]C(=O)OC(C)(C)C)[CH:22]=[C:21]([CH3:33])[CH:20]=3)(=[O:17])=[O:16])=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1)#[N:2].FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[NH2:25][C:23]1[N:24]=[C:19]([NH:18][S:15]([C:11]2[S:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)=[N:13][C:12]=2[CH3:14])(=[O:17])=[O:16])[CH:20]=[C:21]([CH3:33])[CH:22]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(NS(=O)(=O)c2sc(-c3ccc(C#N)cc3)nc2C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N)nc(NS(=O)(=O)c2sc(-c3ccc(C#N)cc3)nc2C)c1
Temperature: 24 °C
Reaction time: 48 h
Yield: 83.9 %

Procedure:
To a solution of tert-butyl [6-({[2-(4-cyanophenyl)4-methyl-1,3-thiazol-5-yl]sulfonyl}amino)-4-methylpyridin-2-yl]carbamate (0.334 g, 0.68 mmol, 1 equiv) in dichloromethane (3 mL) was added trifluoroacetic acid (0.21 mL, 4 equiv). The reaction mixture was stirred at 24° C. for 48 h. The solution was neutralized with saturated aqueous sodium bicarbonate, and the resulting solution was extracted with dichloromethane (3×20 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by high performance flash chromatography (0→1% methanol in dichloromethane) provided the titled product N-(6-Amino-4-methylpyridin-2-yl)-2-(4-cyanophenyl)-4-methyl-1,3-thiazole-5-sulfonamide (0.22 g, 81%). 1H NMR (400 MHz, DMSO-d6), δ: 12.08 (br s, 1H), 8.09 (d, J=8.3 Hz, 2H), 7.95 (d, J=8.3 Hz, 2H), 6.62 (br s, 2H), 6.12 (s, 1H), 5.79 (s, 1H), 2.59 (s, 3H), 2.08 (s, 3H); HRMS (ESI): Calculated for C17H16N5O2S2 m/z 386.0740. Found: 386.0745;. Anal. Calcd for C17H15N5O2S2: C, 52.97; H, 3.92; N, 18.17; Found: C, 52.75; H, 3.76; N, 18.03.
Reaction SMILES: OC[CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[C:18]([O:27][CH3:28])(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O-:25])=[O:24].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:18]([O:27][CH3:28])(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][N:9]([CH3:17])[C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:24]
Reactant: COC(=O)CCCCC(=O)[O-]
Reactant: CN(OCCOCCCO)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCCCC(=O)OCCOCCON(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 2-(3-hydroxypropoxy)ethoxy(methyl)carbamate (152 mg, 0.646 mmol) and monomethyl adipate (104 mg, 0.646 mmol) in CH2Cl2 (4 mL) were added DCC (146 mg, 0.711 mmol) and DMAP (16 mg, 0.129 mmol). The reaction mixture was stirred at room temperature for 16 h and filtered. The solvent was removed under reduced pressure. The crude product was purified by silica gel flash column chromatography using 27% EtOAc/hexanes as eluent. The desired product was obtained as colorless oil (152 mg, 0.403 mmol, 62%). 1H NMR (CDCl3, 400 MHz): 6 (ppm) 1.41 (s, 9H), 1.56-1.60 (m, 4H), 2.25-2.27 (m, 4H), 3.03 (s, 3H), 3.58 (s, 3H), 3.59-3.63 (m, 4H), 3.91-3.94 (m, 2H), 4.14-4.16 (m, 2H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].[CH3:9][C:10]1[C:15]([OH:16])=[C:14]([CH:17]=O)[C:13]([CH2:19][OH:20])=[CH:12][N:11]=1.Cl.C(=O)([O-])O.[Na+].O>C(O)C>[OH:16][C:15]1[C:10]([CH3:9])=[N:11][CH:12]=[C:13]([CH2:19][OH:20])[C:14]=1[CH:17]1[NH:2][CH:3]([C:6]([OH:8])=[O:7])[CH2:4][S:5]1
Reactant: Cc1ncc(CO)c(C=O)c1O
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ncc(CO)c(C2NC(C(=O)O)CS2)c1O
Reaction time: 48 h
Yield: 91.8 %

Procedure:
L-Cysteine hydrochloride (8.00 g, 45.6 mmol), pyridoxal hydrochloride (8.80 g, 43.25 mmol), and sodium hydrogen carbonate (7.60 g, 90.5 mmol) were added to a mixed solvent of water (60 ml) and ethanol (120 ml), and the mixture was at stored −20° C. for 2 days. The precipitated solid was collected by filtration, and dried under reduced pressure to give 2-[3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl]thiazolidine-4-carboxylic acid as a pale-yellow solid (10.73 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[N:22][C:23]=3[CH3:27])[N:18]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[C:28]1([CH2:34][CH2:35]C=O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:27][C:23]1[N:22]=[CH:21][CH:20]=[C:19]2[C:24]=1[CH:25]=[CH:26][C:17]([NH:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][N:8]([CH2:1][CH2:35][CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:9][CH2:10]1)=[N:18]2
Reactant: O=CCCc1ccccc1
Reactant: Cc1nccc2nc(NCCN3CCN(Cc4ccccc4)CC3)ccc12
Product: Cc1nccc2nc(NCCN3CCN(CCCc4ccccc4)CC3)ccc12

Procedure:
Compound 11 was prepared as described for compound 9, using 3-phenylpropionaldehyde in place of benzaldehyde. 1H NMR (CD3OD, 400 MHz) δ 8.20 (d, 1H, J=5.5 Hz), 8.10 (d, 1H, J=7.5 Hz), 7.10-7.35 (m, 6H), 6.82 (d, 1H, J=7.5 Hz), 3.60-3.70 (m, 2H), 2.50-2.90 (m, 15H), 2.30-2.45 (m, 2H), 1.75-1.90 (m, 2H). LCMS (EI) m/z 390 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]2[S:15][C:14]([CH3:24])=[N:13][C:12]=2[C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@H:8]([CH3:9])[C@@H:3]2[CH2:2][NH:1][C:29]2[N:28]=[C:27]([O:26][CH3:25])[CH:32]=[CH:31][N:30]=2)=[O:11])=[CH:22][CH:21]=1
Reactant: COc1ccnc(Cl)n1
Reactant: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CN)c(-c2ccc(F)cc2)s1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccnc(NC[C@H]2[C@@H](C)CCCN2C(=O)c2nc(C)sc2-c2ccc(F)cc2)n1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
A mixture of rac-cis-(2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone, 4-methoxy-2-chloropyrimidine, and DIPEA in isopropanol was stirred at 110° C. for 18 h. The reaction was cooled and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 456.02 (M+H).