Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:21]([N+:22]([O-])=O)=[C:20]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:19]=[C:18]([CH3:32])[C:17]=1[CH3:33]>O.C(O)C>[Cl:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]([CH3:33])=[C:18]([CH3:32])[N:19]=[C:20]([O:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:21]=1[NH2:22]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCCCl)c1C
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1nc(Oc2ccccc2)c(N)c(NCCCCCCl)c1C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
A solution of sodium dithionite (90.5 g, 520 mmol), available as approximately 85% pure sodium hydrosulfite, in water (200 mL) was added to a solution of (5-chloropentyl)-(2,3-dimethyl-5-nitro-6-phenoxy-pyridin-4-yl)amine (37.8 g, 104 mmol) in ethanol (575 mL), and the mixture was stirred rapidly for five hours. The mixture did not become homogeneous, and additional ethanol (200 mL) was added. The mixture remained heterogeneous and was separated into two batches. A solution of sodium dithionite (40 g, 230 mmol) in water (150 mL) was partitioned evenly between the two batches, and the reactions were stirred for an additional hour. An analysis by TLC indicated that the reactions were complete. A white solid was removed from the reaction mixtures by filtration and was washed with methanol. The solvents were removed under reduced pressure, and the residue was partitioned between dichloromethane (400 mL) and water (100 mL). Saturated aqueous sodium bicarbonate was added to the aqueous layer until it was basic, and the resulting solution was extracted with dichloromethane (2×100 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 34.7 g of N4-(5-chloropentyl)-5,6-dimethyl-2-phenoxypyridine-3,4-diamine as an orange-red liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH:23]=[CH2:24].CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C(N(CC)CC)C>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[CH:16]1([CH2:15][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2](/[CH:24]=[CH:23]/[CH2:22][NH:25][C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH:3]=2)[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(N(CC1CCCCC1)c1cccc(Br)c1)C(F)(F)F
Reactant: C=CCNC(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC/C=C/c1cccc(N(CC2CCCCC2)C(=O)C(F)(F)F)c1)C(F)(F)F
Temperature: 90 °C
Reaction time: 2 h

Procedure:
N-(3-Bromophenyl)-N-(cyclohexylmethyl)-2,2,2-trifluoroacetamide (1.0 g, 2.74 mmol), N-allyl-2,2,2-trifluoroacetamide (0.5 g, 3.29 mmol), tri-O-tolylphosphine (0.08 g, 0.27 mmol) and triethylamine (2 mL, 13.7 mmol) was added to DMF and the mixture was flushed with argon for 15 min. Pd(OAc)2 (0.06 g, 0.27 mmol) was charged to the reaction mixture which was stirred at 90° C. for 2 h. The reaction mixture was cooled and partitioned between ethyl acetate and water. Organic layer was washed thoroughly with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (100-200 silica mesh, 5% to 10% EtOAc in hexane) gave (E)-N-(cyclohexylmethyl)-2,2,2-trifluoro-N-(3-(3-(2,2,2-trifluoroacetamido)prop-1-enyl)phenyl)acetamide 5 as a colorless semi solid. Yield (0.4 g, 33%); 1H NMR (400 MHz, CDCl3) δ 7.43-7.41 (m, 2H), 7.18 (s, 1H), 7.13 (d, J=6.8 Hz, 1H), 6.61 (d, J=16.0 Hz, 1H), 6.48 (bs, 1H), 6.24-6.16 (m, 1H), 4.17 (t, J=6.0 Hz, 2H), 3.62 (bs, 2H), 1.73-1.65 (m, 5H), 1.56-1.48 (m, 1H), 1.21-1.14 (m, 3H), 1.07-0.99 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]([CH3:19])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)(Cl)Cl>[CH2:24]([O:23][C:21]([NH:9][CH:10]([CH3:19])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12])=[O:22])[CH3:25]
Reactant: CC(N)C(=O)c1ccccc1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)NC(C)C(=O)c1ccccc1
Reaction time: 4 h
Yield: 73.3 %

Procedure:
A solution of triethylamine (15 g) in chloroform (15 ml) was added dropwise to a stirred mixture of 2-aminopropiophenone hydrochloride (12 g) and chloroform (65 ml) at ice bath temperature in 10 minutes. To the stirred mixture was added dropwise a solution of ethyl chloroformate (8 g) in chloroform (20 ml) under the same conditions and then stirring was continued for 4 hours at ice bath temperature. The solution was evaporated under reduced pressure and the residue was dissolved in a mixture of ethyl acetate and water. The organic layer was separated, washed successively with a saturated aqueous solution of sodium bicarbonate, water, 5% hydrochloric acid, and water, dried over magnesium sulfate, and evaporated under reduced pressure to give an oil containing the object compound. The above obtained product was purified by column chromatography on silica gel (200 g) using a mixture of diisopropyl ether and chloroform (1:4) as an eluent to give an oil of 2-ethoxycarbonylaminopropiophenone (10.48 g).
Reaction SMILES: CC([O-])=O.[K+].[C:6]([CH2:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])#[N:7].[Cl:15][C:16]([Cl:20])([Cl:19])[C:17]#[N:18].O>C(O)(C)C>[NH2:18][C:17]([C:16]([Cl:20])([Cl:19])[Cl:15])=[C:8]([C:6]#[N:7])[C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10]
Reactant: C=CCOC(=O)CC#N
Reactant: N#CC(Cl)(Cl)Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: C=CCOC(=O)C(C#N)=C(N)C(Cl)(Cl)Cl
Temperature: 5 °C
Reaction time: 3 h

Procedure:
To a solution of KOAc (589.4 g, 6.006 mol) in isopropanol (3 L) was added allyl cyanoacetate (429.4 g, 403.2 mL, 3.432 mol) and the reaction mixture was cooled to 5° C. Trichloroacetonitrile (495.5 g, 3.432 mol) was added in 50 mL portions, maintaining temperature below 15° C. The reaction mixture was then allowed to warm to 20° C. and stirred for 3 h. Water (˜4 L) was added to dissolve the inorganic materials and precipitate out the desired product. The mixture was stirred for 20 minutes and the solid was isolated by filtration under vacuum. This solid was filtered, washed with water (2×0.5 L) and dried in a vacuum oven overnight at 40° C. to afford allyl 3-amino-4,4,4-trichloro-2-cyanobut-2-enoate 2 as an off-white powder (787 g, 85%). 1H NMR (500 MHz, CDCl3) δ 10.17 (br s, 1H), 6.97 (m, 1H), 5.99 (m, 1H), 5.44 (m, 1H), 5.31 (m, 1H), 4.76 (m, 2H).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13]Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(=O)([O-])O.[Na+].[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>O>[C:1]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][S:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(N[C@@H](CCl)C(=O)O)OCc1ccccc1
Reactant: Sc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(N[C@@H](CSc1ccccc1)C(=O)O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
N-Carbobenzyloxy-β-chloro-L-alanine (0.091 g, 0.35 mmol) was dissolved in 0.45 ml of water and, then, 0.065 g (0.77 mmol) of sodium hydrogen carbonate was added. Thereafter, 0.046 g (0.42 mmol) of thiophenol was added dropwise at room temperature in a nitrogen gas atmosphere. After 2 hours of stirring at 60° C., the reaction mixture was cooled with ice and acidified with 1 N hydrochloric acid, and then extracted with ethyl acetate. The solvent was distilled off and the residue was purified by column chromatography to give 0.097 g (0.29mmol, 84%) of N-carbobenzyloxy-S-phenyl-L-cysteine. The product obtained had an optical purity of not less than 98% e.e. as determined by HPLC analysis following the same procedure as in Example 13.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[C:14]([CH2:24][CH:25]4[CH2:27][CH2:26]4)([CH3:23])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH:25]1([CH2:24][C:14]2([CH3:23])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]([OH:22])=[C:12]([C:7]3[NH:6][C:5]4[CH:29]=[CH:30][C:2]([NH:1][S:38]([CH3:37])(=[O:40])=[O:39])=[CH:3][C:4]=4[S:9](=[O:11])(=[O:10])[N:8]=3)[C:13]2=[O:28])[CH2:26][CH2:27]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(CC2CC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(CC2CC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reaction time: 12 h
Yield: 83.3 %

Procedure:
To a stirring solution of Example 165 (0.080 g, 0.189 mmol) and pyridine (0.122 mL, 1.512 mmol) in dichloromethane was added methanesulfonyl chloride (0.017 mL, 0.227 mmol) dropwise over 5 minutes and the resulting reaction mixture stirred for 12 hours. The solution was concentrated in. vacuo and purified by flash chromatography on SiO2 eluting with a 0-100% ethyl acetate/hexane gradient yielding the title compound (0.079 g, 84% yield) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm −0.39 (m, 1 H)-0.13 (m, 1 H) 0.03 (m, 2 H) 0.21 (m, 1 H) 1.24 (m, 1 H) 1.43 (s, 3 H) 1.78 (m, 1 H) 1.99 (m, 1 H) 3.01 (s, 3H) 7.38 (m, 3 H) 7.50 (m, 3 H) 8.07 (d, J=7.35 Hz, 1 H) 9.92 (s, 1 H) 15.36 (s, 1 H).). MS (ESI+) m/z=502 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:25][CH3:26])[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28].[CH3:31][CH2:32]N(C(C)C)C(C)C.C(I)C>ClCCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[N:19]([CH2:31][CH3:32])[CH:20]=[C:21]([CH2:25][CH3:26])[C:22](=[O:24])[N:23]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:27]([F:28])([F:30])[F:29]
Reactant: CCc1c[nH]c(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: CCI
Solvent: ClCCCl
Product: CCc1cn(CC)c(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Temperature: 40 °C
Yield: 39.4 %

Procedure:
To a solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-5-ethyl-4(1H)-pyrimidinone (60 mg, 0.137 mmol), DIPEA (0.036 mL, 0.205 mmol) in DCE (2 mL) was added EtI (0.013 mL, 0.164 mmol). The mixture was heated at 40° C. for 1 h. Purification via reverse phase flash chromatography then afforded the title compound (25 mg, 0.054 mmol, 39.2% yield). LCMS: rt=3.80 min, [M+H+]=467
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18][CH3:19])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(CC)CC)C.Cl.[OH:28][CH2:29][C@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C@H:31]1[NH2:36].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18][CH3:19])[CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:36][C@@H:31]1[CH2:32][CH2:33][CH2:34][CH2:35][C@@H:30]1[CH2:29][OH:28])=[O:9]
Reactant: N[C@@H]1CCCC[C@@H]1CO
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@@H]2CCCC[C@@H]2CO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.6 %

Procedure:
5-Fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (200 mg, 0.716 mmol) was dissolved in dimethylformamide (3 ml) and triethylamine (300 μl, 2.14 mmol) was added followed by cis-2-hydroxymethyl-1-cyclohexylamine hydrochloride (125 mg, 0.755 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (151 mg, 0.788 mmol) and 1-hydroxybenzotriazole(106 mg, 0.785 mmol). The reaction was stirred at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between water (30 ml) and ethyl acetate (30 ml). The organic phase dried over Na2SO4, the solvent removed under reduced pressure, and the residue purified by column chromatography on silica gel using dichloromethane:methanol (95:5) as eluent to afford an oil which crystallized from n-pentane to give the title compound as a white solid (136 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([CH3:22])[CH3:21]>CN(C)C=O>[CH:20]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:25][CH2:24]1)([CH3:22])[CH3:21]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C

Procedure:
To a vial was added 4-fluoronitrobenzene (1.41 g, 1.06 mL, 0.01 mol), N,N-diisopropylethylamine (1.92 mL, 0.011 mmol), isopropylpiperazine (1.41 g, 0.011 mmol), and N,N-dimethylformamide (10 mL). Mixture was heated at 100° C. for 48 h in a sealed tube. The reaction mixture was cooled to room temperature and concentrated. The residue was purified via silica gel column chromatography (gradient elution with 0 to 10% methanol in dichloromethane) to afford 1-isopropyl-4-(4-nitrophenyl)piperazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:5]2=[N:6][CH:7]=1.Br[C:29]1[CH:30]=[C:31]([NH:35][C@H:36]([CH:45]([CH3:47])[CH3:46])[C:37]([NH:39][CH2:40][C:41]([F:44])([F:43])[F:42])=[O:38])[CH:32]=[N:33][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:29]3[CH:30]=[C:31]([NH:35][CH:36]([CH:45]([CH3:47])[CH3:46])[C:37]([NH:39][CH2:40][C:41]([F:44])([F:43])[F:42])=[O:38])[CH:32]=[N:33][CH:34]=3)=[CH:9][N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)OB(c2cn(COCC[Si](C)(C)C)c3ncc(Cl)cc23)OC1(C)C
Reactant: CC(C)[C@@H](Nc1cncc(Br)c1)C(=O)NCC(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)C(Nc1cncc(-c2cn(COCC[Si](C)(C)C)c3ncc(Cl)cc23)c1)C(=O)NCC(F)(F)F
Temperature: 100 °C
Yield: 73.8 %

Procedure:
To a nitrogen gas purged mixture of 5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridine (231 mg, 0.565 mmol), (R)-2-(5-bromopyridin-3-ylamino)-3-methyl-N-(2,2,2-trifluoroethyl)butanamide (200 mg, 0.565 mmol), and Na2CO3 (847 μl, 1.694 mmol) in DME (3765 μl) was added Tetrakis (131 mg, 0.113 mmol). The reaction mixture was heated at 100° C. in a sealed microwave vessel for 1 h. Water (10 mL) was added and the mixture was extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried with sodium sulfate, and concentrated under reduced pressure. Purification of the residue on silica (0-5% methanol/ethyl acetate, 25 gm silica) to give 232 mg foam, (2-1a).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[C:9]([S-:11])#[N:10].[K+].BrBr.O>C(O)(=O)C>[F:1][C:2]1[N:7]=[C:6]2[S:11][C:9]([NH2:10])=[N:8][C:5]2=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)nc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc2ccc(F)nc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
6-Fluoropyridin-3-amine (4 g, 35.7 mmol) was added to a mechanically stirred suspension of potassium rhodanate (27.7 g, 285 mmol) in acetic acid (89 mL) at 0° C. The flask 3-neck flask was then fitted with an addition funnel charged with bromine (5.70 mL, 111 mmol) in acetic acid (29.7 mL). The bromine solution was added over 30 min and the solution turned into a viscous and yellow mixture. After bromine addition was complete, the reaction mixture was allowed to warm to ambient temperature and stirred at that temperature for 16 h. Water (30 mL) was added to the reaction mixture and it was heated to 85° C. for 20 min before the solids were filtered and washed with water and methanol to give 5-fluorothiazolo[5,4-b]pyridin-2-amine (4.18 g, 24.71 mmol, 69.2% yield) as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:29]([C:32](=O)[CH2:33]Br)=[CH:28][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([NH2:39])(=[S:38])[CH3:37].C(=O)([O-])O.[Na+].C(O)C>O>[CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:29]([C:32]2[N:39]=[C:36]([CH3:37])[S:38][CH:33]=2)=[CH:28][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:17]=[C:16]([C:24]([F:27])([F:25])[F:26])[CH:15]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(N)=S
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1nc(-c2ccc(OCc3ccccc3)c(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2)cs1
Yield: 67.5 %

Procedure:
A mixture of 2-benzyloxy-5-(2-bromoacetyl)-N-[3,5-bis(trifluoromethyl)phenyl]benzamide (280 mg, 0.5 mmol), thioacetamide (41 mg, 0.55 mmol), sodium hydrogen carbonate (50 mg, 0.6 mmol) and ethanol (15 mL) was refluxed for 1 hour. The reaction mixture was poured into water, neutralized by sodium hydrogen carbonate, and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (hexane:ethyl acetate=4:1) to give the title compound (181 mg, 67.5%) as a white solid.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].N=C1C(C)CCCN1.[NH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1>>[C:1]([OH:4])(=[O:3])[CH3:2].[NH:13]=[C:14]1[CH2:19][CH:18]([CH3:20])[CH2:17][CH:16]([CH3:21])[NH:15]1
Reactant: Cc1cc(C)nc(N)c1
Agent: CC1CCCNC1=N
Solvent: CC(=O)O
Product: CC1CC(=N)NC(C)C1

Procedure:
The method of preparation of 2-Imino-3-methylpiperidine acetate, EXAMPLE 6, was used to convert 2-amino-4,6-dimethylpyridine to the title compound which was obtained as a white solid. The analysis of the product was found to be consistent with the proposed structure. m.p. 163-166° C. MH+=127; 1H NMR (D2O): δ3.48-3.40 (m, 1H); 2.52-2.40 (m, 1H); 2.07-1.95 (m, 1H); 1.85-1.75 (m, 2H); 1.75 (s, 3H); 1.12 (d, J=6.3 Hz, 3H); 1.02-0.92 (m, 1H); 0.86 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][CH2:33][CH:34]([NH2:37])[CH2:35][CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH2:33]([CH:34]([NH:37][CH2:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]2)=[CH:26][CH:25]=1)[CH2:35][CH3:36])[CH3:32]
Reactant: CCC(N)CC
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=O)cc4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCC(CC)NCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cc1
Reaction time: 2 h
Yield: 75.1 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7-carboxamide (40 mg, 0.09 mmol) in DMSO (900 μL) and acetic acid (2 drops) was added 3-pentanamine (108 μL, 1.08 mmol). After 2 h, sodium triacetoxyborohydride (172 mg, 0.81 mmol) was added. Reaction mixture was stirred overnight. Compound was purified by Gilson Preparatory HPLC to afford 34.5 mg of the title compound (74%).
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[O:17][C:16]3=[O:25])=[CH:11][CH:10]=2)[CH2:5][CH:4]1[F:26].CSC.C(Cl)(=O)C>>[O:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:19][C@H:18]([CH2:20][CH2:21][C:22]([NH2:24])=[O:23])[O:17][C:16]3=[O:25])=[CH:11][CH:10]=2)[CH2:5][CH:4]1[F:26]
Reactant: COC1(OC)CCN(c2ccc(N3C[C@H](CCC(N)=O)OC3=O)cc2)CC1F
Solvent: CSC
Solvent: CC(=O)Cl
Product: NC(=O)CC[C@H]1CN(c2ccc(N3CCC(=O)C(F)C3)cc2)C(=O)O1
Temperature: 40 °C
Reaction time: 96 h
Yield: 61 %

Procedure:
The mixture of (S)-{3-[4-(4,4-dimethoxy-3-fluoropiperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol), freshly fused zinc chloride (3.1 mmol), dimethyl sulphide (5.1 mmol), acetyl chloride (3.1 mmol) in tetrahydrofuaran (50 ml) was stirred at 40° C. for 4 days. The reaction mixture was extracted with ethyl acetate water mixture and the organic layer was dried over sodium sulfate. The removal of the solvent afforded a residue, which was chromatographed over silica gel to give title compound in 61% yield.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C:17]1[CH:26]=[CH:25][C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[N:18]=1)[CH2:14][CH2:15][CH3:16].C[Si]([N:31]=[C:32]=[S:33])(C)C>C1C=CC=CC=1>[CH2:13]([C:17]1[CH:26]=[CH:25][C:24]2[CH2:23][CH2:22][CH2:21][CH:20]([C:32](=[S:33])[NH2:31])[C:19]=2[N:18]=1)[CH2:14][CH2:15][CH3:16]
Reactant: C[Si](C)(C)N=C=S
Reactant: CCCCc1ccc2c(n1)CCCC2
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: c1ccccc1
Product: CCCCc1ccc2c(n1)C(C(N)=S)CCC2
Yield: 16.1 %

Procedure:
By the method described in Example 11 using di-isopropylamine (4.45 ml 0.03 mol) in benzene (50 ml), n-butyl lithium solution (9% w/v, 13.5 g, 0.03 mol), 2-butyl-5,6,7,8-tetrahydroquinoline (6 g, 0.03 mol) and trimethylsilyl isothiocyanate (4.45 ml 0.033 mol) was obtained 2-butyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide (1.2g, 15%) m.p. 54-6° C. (Found: C, 68.0; H, 8.4; N, 11.2. C14H20N2S requires C, 67.8; H, 8.1; N, 11.3%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH2:25])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11].N1C=CC=CC=1CCNC(C1C(C2C=CC=CC=2)=CC=CC=1CN[C:45]([O:47][CH:48]([CH3:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH:25][C:45]([O:47][C@@H:48]([CH3:55])[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:46])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: CC(OC(=O)NCc1cccc(-c2ccccc2)c1C(=O)NCCc1ccccn1)c1ccccc1
Reactant: NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccn1
Product: C[C@H](OC(=O)NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccn1)c1ccccc1

Procedure:
From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid 2-(2-pyridyl)-ethylamide (precursor 5d) and (S)-α-methylbenzyl N-succinimido-carbonate (precursor 4 h), according to the general working procedure 60 mg of (S)-2′-(α-methylbenzyloxycarbonylaminomethylbiphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide were obtained. MS (ES+): m/e=480 (M+l ).