Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][S:9][CH2:8]1.CN(P(N(C)C)(N(C)C)=O)C.[CH3:23][N:24]1[N:28]=[N:27][C:26]([C:29]2[CH:39]=[C:38]([CH3:40])[C:32]([O:33][CH2:34][CH2:35][CH2:36]Br)=[C:31]([CH3:41])[CH:30]=2)=[N:25]1.[Cl-].[NH4+]>C1COCC1>[CH3:6][N:7]1[CH:11]=[C:10]([CH2:36][CH2:35][CH2:34][O:33][C:32]2[C:31]([CH3:41])=[CH:30][C:29]([C:26]3[N:27]=[N:28][N:24]([CH3:23])[N:25]=3)=[CH:39][C:38]=2[CH3:40])[S:9][CH2:8]1
Reactant: CN1C=CSC1
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCC1=CN(C)CS1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 27.7 %

Procedure:
n-BuLi (2.5M, 1.33 ml, 3.33 mmol) was added slowly at -78° C. to a solution of 3-methyl-thiazole (300 mg, 3.03 mmol) in 8 ml of THF under nitrogen. After stirring at -78° C. for 15 min, HMPA (1.08 g, 6.06 mmol) was added and the resulting mixture was stirred for 10 min. To the above mixture was added at -78° C. 3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propylbromide (985 mg, 3.03 mmol) in 5 ml of THF. The mixture was allowed to warm to 20° C. and stirred for 3 h. Saturated ammonium chloride solution was added and the aqueous layer was extracted with ether (3×), and the organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (15 cm column, ethyl acetate/hexane, 1/8-3/1) to afford 290 mg (28%) of 3-methyl-5-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propyl]thiazole.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:12][O:11][C:10](=[O:13])[CH2:9]1.[CH3:14][CH2:15][Mg+].[Br-]>C1COCC1>[OH:11][CH2:12][CH:8]([O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH2:9][C:10]1([OH:13])[CH2:15][CH2:14]1
Reactant: O=C1CC(OC2CCCCO2)CO1
Reactant: CC[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: OCC(CC1(O)CC1)OC1CCCCO1
Reaction time: 2 h
Yield: 74 %

Procedure:
To a solution of 4-(tetrahydro-2H-pyran-2-yloxy)-dihydrofuran-2(3H)-one (2.23 g, 12 mmol) and Ti(Oi-Pr)4 (0.68 g, 2.4 mmol, Aldrich) in 40 mL of dry THF at 15° C. under N2 was added EtMgBr (30 mmol, 10 mL, 3M ether solution, Aldrich) dropwise via a syringe pump over 2 hrs. The temperature of the reaction was always kept below 20° C. After stirring for 2 hrs, the reaction mixture was quenched with 30 mL of saturated NH4Cl aqueous solution, and was extracted with ethyl acetate (50 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (1:1 (v/v) EtOAc/n-hexane) to afford 1-(3-hydroxy-2-(tetrahydro-2H-pyran-2-yloxy)propyl)cyclopropanol as yellow oil (1.92 g, 73%).2
Reaction SMILES: CN[C@@H]1C2C=CC=CC=2[C@H](C2C=CC(Cl)=C([Cl:19])C=2)CC1.[CH3:21][NH:22][CH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=2)[CH2:25][CH2:24]1>O1CCCC1>[ClH:19].[CH3:21][NH:22][C@H:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:26]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=2)[CH2:25][CH2:24]1
Reactant: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: CNC1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Solvent: C1CCOC1
Product: CN[C@@H]1CC[C@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Product: Cl

Procedure:
As previously indicated, the 2:1 (by weight) cis/trans-mixture of racemic N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro- 1-naphthaleneamine isomers afforded as a final product of the process of this invention is valuable as an intermediate product that leads to the antidepressant agent known as sertraline or cis-(1S)(4S)-N-methyl-1,2,3,4-tetrahydro-1-naphthaleneamine. More specifically, when the aforesaid 2:1 (by weight) resultant cis/trans-mixture of racemic N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine bases is first converted to the corresponding hydrochloride salts in an ethereal solvent system such as pure tetrahydrofuran, the pure crystalline racemic cis-amine salt exclusively separates from solution as a crystalline precipitate to afford pure racemic cis-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine hydrochloride, which is then recovered and converted back to the pure racemic cis-amine free base compound and subsequently resolved in a classical manner using the methods described by W. M. Welch, Jr. et al. in the aforesaid prior art to ultimately yield the desired pure cis-(1S)(4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine (sertraline) as the hydrochloride salt. The corresponding 2:1 (by weight) cis/trans-mixture of chiral N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine isomeric bases afforded as a final product of the process of this invention is similarly processed as an intermediate that leads to sertraline, except that the resolution step is not required since the desired pure chiral cis-(1S)(4S)-amine compound (sertraline) is obtained directly after isolation of the crystalline hydrochloride salt.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][C@H:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[CH3:46][O:47][C:48]([C:50]1[N:51]=[C:52]([NH2:55])[S:53][CH:54]=1)=[O:49]>C(Cl)Cl>[CH3:46][O:47][C:48]([C:50]1[N:51]=[C:52]([NH:55][C:35](=[O:37])[C@@H:34]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=2)[CH2:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)[S:53][CH:54]=1)=[O:49]
Reactant: COC(=O)c1csc(N)n1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1csc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution triphenylphosphine (164 mg, 0.63 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (112 mg, 0.63 mmol) in small portions. The resulting orange reaction mixture was stirred at 0° C. for 20 min and then treated with 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionic acid (prepared as in Example 54A, 150 mg, 0.52 mmol). The reaction mixture was stirred at 0° C. for an additional 15 min and then allowed to warm to 25° C. The reaction mixture was then treated with 2-aminothiazole-4-carboxylic acid methyl ester (181 mg, 1.15 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The crude reaction mixture was directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) to afford impure (2R)-2-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester. The impure product was diluted with ethyl acetate and then washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to provide pure (2R)-2-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionylamino]-thiazole-4-carboxylic acid methyl ester (92 mg, 41%) as a white solid: mp 143-144° C.; [α]23589=−10.2° (c=0.98, chloroform); EI-HRMS m/e calcd for C19H20Cl2N2O3S (M+) 426.0572, found 426.0562.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([OH:14])=[O:13].S(Cl)([Cl:18])(=O)=O>C(Cl)(Cl)Cl>[Cl:18][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:12]([OH:14])=[O:13])[CH:4]=1
Reactant: O=C(O)c1ccc2ccccc2c1O
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(O)c1cc(Cl)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 1-hydroxy-2-naphthoic acid (3.76 g; 0.02 m) in chloroform (50 ml) was added sulphuryl chloride (2.97 g; 0.022 m) dropwise and the solution stirred at room temperature for two hours. The solvent was removed in vacuo to give a white solid which was washed with water, collected and dried. The crude solid was recrystallised from ethanol to give 4-chloro-1-hydroxy-naphthalene-2-carboxylic acid as white needles.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24](O)=[O:25])[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[O:27]1[CH2:32][CH2:31][CH:30]([CH2:33][NH2:34])[CH2:29][CH2:28]1>>[C:1]([N:5]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][C:24]([NH:34][CH2:33][CH:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)=[O:25])[N:22]=2)[CH:7]=[N:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1Cc1ccc(F)cc1
Reactant: NCC1CCOCC1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1Cc1ccc(F)cc1

Procedure:
Using the compound obtained in step 4 and (tetrahydro-2H-pyran-4-yl)methanamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH2:9][CH2:8]1.[Cl:26]N1C(=O)CCC1=O>CN(C=O)C.[Cl-].[Na+].O>[Cl:26][C:5]1[N:4]=[CH:3][C:2]([N:7]2[CH2:12][CH2:11][CH:10]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[CH2:9][CH2:8]2)=[N:1][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cnccn3)CC2)CC1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cnc(Cl)cn3)CC2)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The tert-butyl 1′-pyrazin-2-yl-4,4′-bipiperidine-1-carboxylate (64 mg, 0.19 mmol, prepared as described for Example 8) and N-chlorosuccinimide (27 mg, 0.20 mmol) were dissolved in DMF (0.9 ml) and the solution stirred overnight at 50° C. The slurry was diluted with 15% brine:water (40 ml) and extracted with ethyl acetate (3×25 ml). The combined organic fraction was washed with brine, dried over magnesium sulfate, filtered, and the volatiles removed in vac. The crude material was purified by chromatography on silica gel with 10% acetone:hexanes to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[C:7]([OH:13])[CH:6]=[CH:5]2.[CH2:14]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.C(O)C>[CH2:14]([C:19]1[CH:20]=[CH:21][C:22]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([Cl:12])=[C:7]([OH:13])[CH:6]=[CH:5]3)=[CH:23][CH:24]=1)[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Oc1ccc2cc(Br)ccc2c1Cl
Reactant: CCCCCc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(-c2ccc3c(Cl)c(O)ccc3c2)cc1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
55 g of 6-bromo-1-chloro-2-naphthol (S1-2), 12.3 g of 4-pentylphenylboronic acid (S1-3), 1.0 g of tetrakistriphenylphosphine palladium, 13.6 g of sodium carbonate and 100 mL of a mixed solvent of toluene, ethanol and water (3/3/1) were added to a reactor under a nitrogen atmosphere and refluxed for 10 hours. The reaction mixture was cooled to room temperature, and toluene was added thereto. The reaction mixture was washed with 1N hydrochloric acid and water, and after drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography with toluene as a developing solvent to provide 15 g of 6-(4-pentylphenyl)-1-chloro-2-naphthol (S1-4).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:26]([CH2:27][CH3:28])=[N:25][N:24]([C:29]3[CH:34]=[C:33]([N+:35]([O-])=O)[CH:32]=[CH:31][C:30]=3[C:38]([F:41])([F:40])[F:39])[C:23]2=[O:42])=[C:17]([F:43])[CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCO.[H][H]>O=[Pt]=O.CCOC(C)=O>[NH2:35][C:33]1[CH:32]=[CH:31][C:30]([C:38]([F:39])([F:41])[F:40])=[C:29]([N:24]2[C:23](=[O:42])[N:22]([CH2:21][C:18]3[CH:19]=[CH:20][C:15]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[S:6](=[O:7])(=[O:8])[NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:16][C:17]=3[F:43])[C:26]([CH2:27][CH3:28])=[N:25]2)[CH:34]=1
Reactant: CCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F

Procedure:
A mixture of 388 mg (0.625 mmol) of 4-[[2'-(N-t -butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-2,4-dihydro-5-ethyl-2-[5-nitro-2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step A), 6 mL of EtOH, 8 mL of EtOAc, and 30 mg of 5% PtO2 was shaken with hydrogen for 3.5 hours on a Parr hydrogenation apparatus. Removal of the catalyst followed by evaporation of volatiles gave 383 mg (quantitative) of a cream-colored solid [top >105° C. (gradual)] of sufficient purity to be used in the next step without further purification; mass spectrum (FAB) m/e 599 (M+Li)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH:10]([CH3:12])[CH3:11])[C:3]=1[CH3:13].[Li]CCCC.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[C:23]([CH3:29])[CH:22]=1>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:25]([C:24]2[CH:27]=[CH:28][C:21]([O:20][CH3:19])=[CH:22][C:23]=2[CH3:29])[OH:26])=[C:3]([CH3:13])[C:4]=1[CH:10]([CH3:12])[CH3:11]
Reactant: COc1ccc(C=O)c(C)c1
Reactant: COc1ccc(Br)c(C)c1C(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccc(OC)c(C(C)C)c2C)c(C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 116.1 %

Procedure:
To a stirring solution of 1-bromo-3-iso-propyl-4-methoxy-2-methyl-benzene (compound 7-16, step c; 0.7 g, 2.88 mmol) in THF (20 mL) at −78° C. was added n-BuLi (1.6 mL, 2.5 M in hexanes). The mixture was stirred at −78° C. for 1 hr and 4-methoxy-2-methyl-benzaldehyde (0.37 mL, 2.74 mmol) was added. The reaction mixture was stirred at −78° C. for 1 hr, allowed to warm to room temperature and stirred for 1 hr. The reaction mixture was quenched with saturated NH4Cl and diluted with diethyl ether. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude (4′-methoxy-3′-iso-propyl-2′-methylphenyl)-(4-methoxy-2-methylphenyl)-methanol as a light yellow oil (1.0 g, 100%). This crude oil was dissolved into EtOAc (25 mL) and AcOH (5 mL) and Pd/C (0.1 g) was added. After stirring at rt for 6 hours, the reaction mixture was filtered through the Celite and concentrated under reduced pressure to afford crude 4-(4′-methoxy-2′-methyl-3′-iso-propylbenzyl)-3-methyl-anisole as a yellow oil (0.8 g, 93%): 1H NMR (300 MHz, DMSO-d6): δ 6.88-6.80 (m, 5 H), 3.77 (s, 2 H), 3.74 (s, 3 H), 3.71 (s, 3 H), 3.34 (m, 1 H), 2.22 (s, 3 H), 2.14 (s, 3 H), 1.28 (d, J=6.9 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=8% ethyl acetate in hexanes; Rf=0.56.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]>[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([S:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: Brc1cccc2ccccc12
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(Sc2cccc3ccccc23)cc1
Yield: 35.5 %

Procedure:
1-Bromonaphthalene (0.15 mole, 31.0 g), 4-nitrothiophenol(0.11 mole, 17.0 g), potassium carbonate (0.15 moles, 20.7 g), copper bronze (0.3 moles, 18.9 g) and cuprous chloride (0.06 moles, 6.0 g) were refluxed in 500 ml pyridine for 3 days. The reaction was filtered while hot, and then concentrated. Ethyl acetate was added and the solution washed with water and 5N HCl, dried over sodium sulfate and concentrated. The product was purified twice by HPLC over silica gel eluted with 20% ethyl acetate/hexane followed by 5% ethyl acetate/hexane to yield 1-(4-nitrophenylthio)naphthalene 11.0 g, 26%. Mass Spec (FD) 282. Calculated for C16H11NO2S: C, 68.31H, 3.94, N, 4.98. Found: C, 68.52; H, 4.00; N, 4.77.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:34]=[N:33][N:32]([CH:35]([CH3:37])[CH3:36])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:24][CH:25]=2)[CH:19]=1)=[O:13].CCN(CC)CC.[S:45](Cl)([CH3:48])(=[O:47])=[O:46]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:34]=[N:33][N:32]([CH:35]([CH3:37])[CH3:36])[C:16]=2[N:17]=[C:18]([C:20]2[CH2:21][CH2:22][N:23]([CH:26]3[CH2:27][CH2:28][N:29]([S:45]([CH3:48])(=[O:47])=[O:46])[CH2:30][CH2:31]3)[CH2:24][CH:25]=2)[CH:19]=1)=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C4CCNCC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CCN(C4CCN(S(C)(=O)=O)CC4)CC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-(1-(piperidin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.2 g, 0.397 mmol) in DCM (5 mL), Et3N (0.06 g, 0.596 mmol) and mesyl chloride (0.046 g, 0.403 mmol) were added at 0° C. and stirred it at room temperature for 2 h. After completion, reaction was quenched with ice-water. Extraction was carried out using DCM; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure to afford crude material which was purified by prep. HPLC to give the desired compound. LCMS: 582.30 (M+1)+; HPLC: 92.74% (@ 254 nm) (Rt;5.006); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 9.86 (bs, 1H), 8.87 (t, 1H, J=4.8 Hz), 8.34 (s, 1H), 7.90 (s, 1H), 6.93 (s, 1H), 5.90 (s, 1H), 5.23-5.20 (m, 1H), 4.39 (d, 2H, J=4.4 Hz), 4.08 (bs, 2H), 3.80 (bs, 2H), 3.72 (d, 2H, J=11.60 Hz), 3.30 (bs, 2H), 3.15 (d, 2H, J=15.60 Hz), 2.93 (s, 3H), 2.84-2.76 (m, 2H), 2.27 (m, 1H), 2.21 (s, 3H), 2.12 (s, 3H), 1.81-1.73 (m, 2H), 1.51 (d, 6H, J=6.8 Hz).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.Cl.C(N=C=N)C.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.[CH2:36]([NH2:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1>[CH2:36]([NH:43][C:8]([C:4]1[S:3][C:2]([Br:1])=[N:6][C:5]=1[CH3:7])=[O:10])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Cc1nc(Br)sc1C(=O)O
Reactant: NCc1ccccc1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a mixture of 2-bromo-4-methylthiazole-5-carboxylic acid (10.00 g, 45.03 mmol) and 1-(3-dimethyl)aminopropyl)-3-ethylcarbodiimide hydrochloride (12.09 g, 63.04 mmol) in tetrahydrofuran (170 mL) under nitrogen atmosphere was added N,N-diisopropylethylamine (17.46 g, 135.0 mmol). After the mixture was stirred at ambient temperature for 30 minutes, 1-hydroxybenzotriazole (8.52 g, 63.04 mmol) and benzylamine (6.76 g, 6.88 mL, 63.04 mmol) were added. The mixture was stirred at ambient temperature for 16 hours and concentrated in vacuo. The residue was dissolved in dichloromethane (500 mL), washed with water (2×100 mL) and brine (2×100 mL). The organic layer was dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography (ethyl acetate:petroleum ether, 2:1) to afford the title compound (11.91 g, 85%): 1H NMR (300 MHz, DMSO-d6) δ 9.92 (t, J=6.0 Hz, 1H), 7.34-7.25 (m, 5H), 4.46 (d, J=6.0 Hz, 2H), 2.53 (s, 3H); MS (ES+) m/z 298.1 (M+1), 300.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[C:5]([N:13]=O)[C:4]([CH3:15])=[N:3]1>[Pd].CCOC(C)=O>[CH3:10][C:9]([CH3:12])([CH3:11])[CH2:8][NH:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:15])[C:5]=1[NH2:13]
Reactant: Cc1nn(C)c(NCC(C)(C)C)c1N=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1nn(C)c(NCC(C)(C)C)c1N
Temperature: 23 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
(2,5-Dimethyl-4-nitroso-2H-pyrazol-3-yl)-(2,2-dimethyl-propyl)-amine (3.44 g, 16.36 mmol), 400 mg of 10% Pd/C and 60 mL EtOAc were placed under a balloon of H2 and stirred at 23° C. After 4 h, the reaction mixture was filtered through Celite and evaporated to an orange oil. Flash chromatography on silica gel, eluting with CHCl3/MeOH (20/1), gave a yellow solid. Recrystallization from hot hexanes/EtOAc gave 2.86 g (14.57 mmol, an 89% yield) of the title compound as an off-white crystalline solid. mp: 65-69° C.; 1H NMR (300 MHz, CDCl3): δ1.00 (s, 9H), 1.65 (brs, 2H), 2.13 (s, 3H), 2.77 (brs, 2H), 2.89 (brs, 1H), 3.62 (s, 3H); IR (KBr, cm−1): 3347-3204brs, 2952s, 2903w, 1599m, 1528m, 1495m, 1477m, 1378m, 1316m; MS (ES) m/z (relative intensity): 197 (M++H, 100). Anal. Calcd. for C10H20N4: C, 61.19; H, 10.27; N, 28.54. Found: C, 56.19; H, 10.56; N, 26.37
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=O)CCl)=[N:6][CH:7]=1.[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.[C:17](=[O:20])([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:17]([CH:8]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:20])[N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(CCl)c1ccc(Cl)cn1
Reactant: c1nc[nH]n1
Agent: [K+]
Solvent: CC#N
Product: O=C(C(c1ccc(Cl)cn1)n1cncn1)C(c1ccc(Cl)cn1)n1cncn1
Reaction time: 2 h

Procedure:
5-Chloro-2-chloroacetylpyridine (20 g.) was dissolved in acetonitrile (25 ml.) and added dropwise to a refluxing solution of 1,2,4-triazole (6.2 g.) and potassium carbonate (13.4 g.) in acetonitrile (25 ml.). When the addition was complete, the solution was allowed to cool and was stirred for 2 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed twice with water and twice with brine, dried over sodium sulphate and filtered. The filtrate was evaporated to dryness under reduced pressure, and the residue was chromatographed on a K60 silica column, eluting with ethyl acetate, to give 5-chloropyrid-2-yl-1,2,4-triazol-1-ylmethyl ketone which after crystallisation from ethyl acetate/petroleum ether (b.p. 60°-80°), had m.p. 146°-148°.
Reaction SMILES: [H-].[Na+].C(O[C:6](=O)[CH2:7][C@@H:8]([N:10]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:11][C:12]([O:14]CC)=O)C)C.[CH2:25](O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl>[CH2:17]([N:10]1[CH2:8][C@@H:7]([CH3:6])[CH2:25][C:12](=[O:14])[CH2:11]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCO
Reactant: CCOC(=O)C[C@H](C)N(CC(=O)OCC)Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@H]1CC(=O)CN(Cc2ccccc2)C1
Temperature: 120 °C
Yield: 43 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 6.4 g, 14 mmol) in toluene (90 ml) was added (S)-3-(benzyl-ethoxycarbonylmethyl-amino)-butyric acid ethyl ester (20.3 g, 0.06 mol) in toluene (10 ml), followed by ethanol (1 ml). A vigorous reaction ensued, after 15 minutes the reaction was diluted with ethyl acetate, washed with 10% aq. citric acid solution, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (ethyl acetate/heptane 1:9) affording a complex mixture of diastereomers (7.2 g, 42%). A portion of this material (3.5 g, 13 mmol) was dissolved in 25% aq. hydrochloric acid solution (20 ml) and heated in a loosely closed tube at 120° C. for 36 h. The solvent was evaporated, the residue redissolved in dichloromethane, washed with sat. aq. sodium hydrogencarbonate solution, dried (Na2SO4) and concentrated. Purification by flash column chromatography (ethyl acetate/heptane 1:4) afforded the titled product as a crystalline solid (1.1 g, 43%). MS (ISP)=204.3 (M+H)+.