Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([CH:13]([C:16]#[N:17])[C:14]#[N:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:18]([O-])(O)=O.[Na+].S(OC)(OC)(=O)=O>O.O1CCOCC1.CCOC(C)=O.[Cl-].[Na+].O>[CH3:18][O:12][C:11](=[C:13]([C:16]#[N:17])[C:14]#[N:15])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: N#CC(C#N)C(=O)Cc1cccc([N+](=O)[O-])c1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(Cc1cccc([N+](=O)[O-])c1)=C(C#N)C#N
Temperature: 80 °C
Reaction time: 12 h

Procedure:
The crude material containing 2-(2-(3-nitrophenyl)acetyl)malononitrile was dissolved in H2O (7 mL) and 1,4-dioxane (42 mL), to which NaHCO3 (11.5 g, 138 mmol) and dimethyl sulfate (10.5 mL, 110 mmol) were added. The reaction mixture was heated to 80° C. and left stirring for 12 hours. The reaction mixture was diluted with EtOAc (100 mL) and brine (100 mL). The aqueous portion was extracted with EtOAc (3×100 mL). The combined organic fractions were dried over MgSO4, filtered, and concentrated in vacuo. The recovered solid was purified by silica gel chromatography (100% chloroform). Fractions containing the desired enol ether were pooled, concentrated, and dissolved in hot MeOH. The solution was cooled and fine white crystals formed overnight, which were recovered by filtration and washed with ice cold MeOH to afford 2-(1-methoxy-2-(3-nitrophenyl)ethylidene)malononitrile. 1H NMR (400 MHz, DMSO): δ 7.78 (1H, d), 7.72 (t, 1H), 8.22 (d, 1H), 8.25 (s, 1H), 4.36 (s, 2H), 4.04 (s, 3H).
Reaction SMILES: [Cl:1]Cl.[N:3]([CH2:6][C:7]([CH3:35])([CH3:34])[C:8](=[O:33])[CH:9]([N:23]1[CH:26](SC(C)(C)C)[CH2:25][C:24]1=[O:32])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11])=[N+:4]=[N-:5]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[N:3]([CH2:6][C:7]([CH3:35])([CH3:34])[C:8](=[O:33])[CH:9]([N:23]1[CH:26]([Cl:1])[CH2:25][C:24]1=[O:32])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)=[O:11])=[N+:4]=[N-:5]
Reactant: ClCl
Reactant: CC(C)(C)SC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)C(C)(C)CN=[N+]=[N-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(CN=[N+]=[N-])C(=O)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1Cl

Procedure:
286 μl of a solution of chlorine in carbon tetrachloride containing 1.14 g/10 ml is added at -60° C. to a solution of 110 mg of p-nitrobenzyl 5-azido-2-(4-tert-butylthio-2-oxo-1-azetidinyl)-4,4-dimethyl-3-oxopentanoate in 9 ml of methylene chloride. The reaction solution is evaporated in a rotary evaporator, 119 mg of yellow oil being obtained. IR spectrum in CH2Cl2 : 2930, 2860, 2105, 1780, 1755, 1720, 1610, 1530, 1350, 1190 cm-1.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[C:32]([CH3:38])[N:31]=3)[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1C=C(Cl)C=C(C(OO)=[O:50])C=1>C(Cl)Cl>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[C:32]([CH3:38])[N+:31]=3[O-:50])[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COc1ccc(C)nc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(C)[n+]([O-])c1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(3-methoxy-6-methylpyridin-2-yl)-5-(trifluoromethyl) benzyl]-4-methyl-1,3-oxazolidin-2-one (Example 174) (7.6 mg, 0.0128 mmol) in CH2Cl2 (1.3 mL) was added m-CPBA (5.8 mg, 77% purity, 0.0256 mmol). The reaction was stirred at room temperature for 1 hour and then diluted with CH2Cl2 (10 mL), washed with aq. NaHSO3, saturated K2CO3, and brine (5 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by PTLC (50% Et2O/CH2Cl2) afforded the title compound. Rf=0.23 (50% Et2O/CH2Cl2). LCMS=609.2 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.85 (s, 1H), 7.78 (d, J=7.7 Hz, 1H), 7.70 (s, 2H), 7.62 (s, 1H), 7.53 (d, J=7.8 Hz, 1H), 7.32 (d, J=8.9 Hz, 1H), 7.04 (d, J=9.2 Hz, 1H), 5.74 (d, J=8.3 Hz, 1H), 4.88 (d, J=14.8 Hz, 1H), 4.11-3.96 (m, 1H), 3.88 (d, J=14.9 Hz, 1H), 3.86 (s, 3H), 2.49 (s, 3H), 0.65 (d, J=6.6 Hz, 3H).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:11][C:12]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]SC1SCC(=O)N=1.[OH-].[Na+]>CN(C=O)C>[Cl:11][C:12]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][S:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: COc1ccc(OCCCCCCSC2=NC(=O)CS2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc(OCCCCCCSc2nc3ccccc3[nH]2)c(Cl)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Stir at room temperature for four days 2.5 gms. 2-mercapto-benzimidazole, 2 gms. of the iodide prepared in Examples 2 or 3, 25 ml. DMF and 0.71 gm. sodium hydroxide in a reaction flask. Remove the solvent and partition with water/methylene chloride. Elute on a silica column with 100% methylene chloride then 50/50 ethylacetate/methylene chloride to obtain the title compound. MS: m/z 391 (M+) H1 -NMR-200 mHz-δH (CDCl3), 1.5-1.6 (4H,m), 1.7-1.9 (4H,m), 3.35 (2H,t,J 7Hz), 3.75 (3H,s) 3.95 (2H,t,J 6Hz), 6.7-7.0 (3H,m), 7.2-7.4 (4H,m), 7.65-7.75 (1H,m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[C:3]=1[C:10]1[C:18]2[O:17][CH:16]([CH2:19][OH:20])[CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:20][CH2:19][CH:16]2[CH2:15][C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:9])[C:18]=3[O:17]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: OCC1Cc2cccc(-c3c(Cl)cc(Cl)cc3Cl)c2O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4c(Cl)cccc4Cl)c3O2)cc1
Yield: 74.2 %

Procedure:
Treatment of 2,4,6-trichlorobromobenzene (14.5 g, 55.69 mmol) with 2-methoxybenzeneboronic acid (12.69 g, 83.54 mol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.656 g, 0.835 mmol), and potassium carbonate (19.21 g, 139.22 mmol) generally according to the procedure described for Intermediate 37 provided 9.8 g (61%) of 2′ 4′,6′-trichloro-1,1′-biphenyl-2-yl methyl ether. To a solution of 2′4′,6′-trichloro-1,1′-biphenyl-2-yl methyl ether (9.8 g, 34.08 mmol) in dichloromethane (100 mL) cooled to −78° C. was added boron tribromide (9.38 g, 1.0 M in dichloromethane) generally according to the procedure described for Intermediate 163 provided provided 9.2 g of a yellow solid. Treatment of 2′,4′,6′-trichloro-1,1′-biphenyl-2-ol (9.17 g, 33.52 mmol) with potassium carbonate (18.53 g, 134.1 mmol) and allyl bromide (4.46 g, 36.87 mol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-2′,4′,6′-trichloro-1,1′-biphenyl-2-ol. Treatment of 3-allyl-2′,4′,6′-trichloro-1,1′-biphenyl-2-ol. (10.35 g, 33.00 mmol) with 3-chloroperoxybenzoic acid (17.08 g, 99.00 mmol, 77%) followed by potassium carbonate (11.40 g, 82.51 mmol) generally according to the procedure described for Intermediate 9 afforded 10.4 g (95%) of (±)-[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol. Treatment of (±)-[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanol (10.38 g, 31.49 mmol) with p-toluenesulfonyl chloride (7.20 g, 37.79 mol) generally according to the procedure described for Intermediate 10 gave 10.5 g (68%) of (±)-[7-(2,6-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. mp 178-180° C.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[CH3:31][CH:32]1[CH2:37][NH:36][CH2:35][CH:34]([CH3:38])[NH:33]1>>[CH3:38][C@H:34]1[NH:33][C@@H:32]([CH3:31])[CH2:37][N:36]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:30])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:16])([CH3:17])[C:10]=3[CH:18]=2)[CH2:35]1
Reactant: CC1CNCC(C)N1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: C[C@@H]1CN(c2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)C[C@H](C)N1

Procedure:
Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and 2,6-dimethylpiperazine.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[BH4-].[Na+]>CO.O>[O:3]1[C:4]2([CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]2)[O:11][CH2:1][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.1 %

Procedure:
1,4-Cyclohexanedione mono-ethylene ketal (5.0 g, 32 mmol) in 20 mL of MeOH/water (1:1) was added NaBH4 (1.21 g, 32 mmol). The mixture was stirred at room temperature overnight. The MeOH was removed via rotary evaporation. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), and concentrated to give an oil which was stored on a high vacuum line overnight to afford 5.12 g of 1,4-dioxaspiro[4.5]decan-8-ol as an oil. MS (EI) calcd: (M+H)+=159.1. Found: 159.2.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:8][CH2:7][CH:6]([C:9](OC)=O)[C:5]1=[O:13].[Cl:14][C:15]1[CH:22]=[CH:21][C:18](CCl)=[CH:17][CH:16]=1>C1C=CC=CC=1>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:9][CH:6]2[CH2:7][CH2:8][CH:4]([CH3:3])[C:5]2=[O:13])=[CH:17][CH:16]=1
Reactant: COC(=O)C1CCC(C)C1=O
Reactant: ClCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC1CCC(Cc2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into 126 ml of anhydrous benzene, 3.04 g of sodium hydride (prepared by washing 60 % oily sodium hydride with anhydrous benzene) were added, and then 18 g of methyl 3-methyl-2-oxocyclopentanecarboxylate were added to the thus formed mixture. After stirring the whole mixture for one hour at room temperature, 21.5 g of 4-chlorobenzyl chloride were added to the mixture and the thus obtained mixture was refluxed for 6 hours in an oil bath at 90° C.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][S:16][C:15]2[CH:19]=[C:20]([NH:23][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[NH:25])[CH:21]=[CH:22][C:14]1=2)C(=O)OC(C)(C)C>Cl>[CH3:1][NH:2][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][S:16][C:15]2[CH:19]=[C:20]([NH:23][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[NH:25])[CH:21]=[CH:22][C:14]1=2
Reactant: CN(CCCN1CCSc2cc(NC(=N)c3cccs3)ccc21)C(=O)OC(C)(C)C
Agent: Cl
Product: CNCCCN1CCSc2cc(NC(=N)c3cccs3)ccc21
Yield: 93.8 %

Procedure:
A suspension of tert-butyl methyl(3-(7-(thiophene-2-carboximidamido)-2H-benzo[b][1,4]thiazin-4(3H)-yl)propyl)carbamate (0.55 g, 1.231 mmol) in 3M hydrochloric acid (25 mL) was refluxed for 1 hour. The reaction was brought to room temperature, filtered, and washed with water (2×10 mL). The combined aqueous layers were evaporated. The crude material was basified with 3 M NaOH solution (50 mL), and the product was extracted into CH2Cl2 (3×20 mL). The combined CH2Cl2 layers were washed with brine (15 mL) and dried (Na2SO4). The organic solvent was evaporated, and the crude material was purified by column chromatography (5:95 to 1:9 (2M NH3 in MeOH):CH2Cl2) on silica gel to obtain compound 23 (0.4 g, 94%) as a solid. 1H NMR (DMSO-d6) δ 7.68 (dd, 1H, J=1.2, 3.7 Hz), 7.56 (dd, 1H, J=0.9, 5.1 Hz), 7.06 (dd, 1H, J=3.6, 4.9 Hz), 6.70 (d, 1H, J=8.7 Hz), 6.51-6.44 (m, 2H), 6.31 (s, 2H), 3.50-3.47 (m, 2H), 3.32-3.25 (m, 4H), 3.04-3.01 (m, 2H), 2.27 (s, 3H), 1.70-1.61 (m, 2H); ESI-MS (m/z, %): 347 (MH+, 80), 276 (100); HPLC purity: 96.05% by area.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:15]([CH:20]=[O:21])=[N:16][O:17][C:18]=2[CH3:19])=[O:7])=[CH:4][CH:3]=1.[CH2:24]1COCC1.C[Mg]Cl.[Cl-].[NH4+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:15]([CH:20]([OH:21])[CH3:24])=[N:16][O:17][C:18]=2[CH3:19])=[O:7])=[CH:22][CH:23]=1
Reactant: C1CCOC1
Reactant: Cc1onc(C=O)c1-c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Cc1onc(C(C)O)c1-c1ccccc1C(=O)c1ccc(Cl)cc1

Procedure:
To a resealable vial was added 4-(2-(4-chlorobenzoyl)phenyl)-5-methylisoxazole-3-carbaldehyde from Example 15 (0.100 g, 0.307 mmol) and THF (2.0 mL). The vial was sealed and cooled to −78° C. before addition of methylmagnesium chloride (0.107 mL, 0.322 mmol). The reaction was stirred at −78° C. for 30 min before addition of ammonium chloride solution and water. The aqueous was extracted with EtOAc and the combined layers washed with brine, dried over Na2SO4, filtered, and concentrated to afford crude (4-chlorophenyl)(2-(3-(1-hydroxyethyl)-5-methylisoxazol-4-yl)phenyl)methanone (0.092 g, 0.269 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:24][C:25]2[CH:30]=[C:29]([CH3:31])[C:28](=[O:32])[N:27]([CH3:33])[CH:26]=2)[C:9]2[C:10]([C:21]([OH:23])=O)=[N:11][N:12]([CH:18]3[CH2:20][CH2:19]3)[C:13]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([CH:18]4[CH2:20][CH2:19]4)[C:13]=3[C:14]([F:16])([F:17])[F:15])[C:21](=[O:23])[N:24]2[C:25]2[CH:30]=[C:29]([CH3:31])[C:28](=[O:32])[N:27]([CH3:33])[CH:26]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(NC(c2ccc(Cl)cc2)c2c(C(=O)O)nn(C3CC3)c2C(F)(F)F)cn(C)c1=O
Solvent: ClCCl
Product: Cc1cc(N2C(=O)c3nn(C4CC4)c(C(F)(F)F)c3C2c2ccc(Cl)cc2)cn(C)c1=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)((1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)amino)methyl)-1-cyclopropyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (Step 43.2) at RT for 30 min. tR: 1.10 min (LC-MS 2); ESI-MS: 463 [M+H]+ (LC-MS 2); Rf=0.43 (CH2Cl2/5% MeOH/1% ammonia); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.21 (m, 2H) 1.21-1.37 (m, 2H) 1.89 (s, 3H) 3.33 (s, 3H) 3.87-3.97 (m, 1H) 6.32 (s, 1H) 7.23 (d, J=8.6 Hz, 2H) 7.29-7.39 (m, 3H) 7.68 (d, J=2.7 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([NH:15][C:16](=[O:27])[C@H:17]([CH2:24]CC)[NH:18][CH2:19][C@@H:20]([NH2:23])[CH2:21][SH:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(C(O)=O)(F)(F)F>O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([NH:15][C:16](=[O:27])[C@H:17]([CH3:24])[NH:18][CH2:19][C@@H:20]([NH2:23])[CH2:21][SH:22])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCC[C@H](NC[C@@H](N)CS)C(=O)NCc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC[C@@H](N)CS)C(=O)NCc1ccccc1

Procedure:
N-(3-mercapto-2(R)-aminopropyl)-L-norvaline-benzyl amide trifluoroacetate salt, mp 60°-67° C. Anal. Calcd for C16H27N3OS. 2 CF3CO2H. 0.84 H2O: C, 42.37; H, 5.37; N, 7.80. Found: C, 42.42; H, 5.21; N, 7.45.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.S(Cl)(Cl)=O.[OH-].[NH4+:16]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:16])=[O:10])=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: NC(=O)c1ccc(Cl)cn1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 87.4 %

Procedure:
A 500-mL round-bottomed flask was charged with 5-chloro-2-pyridinecarboxylic acid (Ark Pharm, 10.00 g, 63.5 mmol) and thionyl chloride (Aldrich, 100 ml, 1371 mmol). A catalytic amount of DMF (0.2 ml) was added and the reaction mixture was heated to 80° C. under Argon atmosphere for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with DCM (100 ml) and added slowly to a stirred solution of ammonium hydroxide (131 ml, 3364 mmol) at 0° C. After completed addition, the reaction mixture was allowed to stir an additional 10 min. The reaction mixture was concentrated under reduced pressure and the precipitate was filtered off. The solid was washed with water and dried to give the title compound (8.686 g, 55.5 mmol, 87% yield) as an off-white solid. MS m/z=157 [M+H]+. Calculated for C6H5ClN2O: 156
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]2(O)[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:41]=[CH:40][CH:39]=3)(O)[C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.I.[PH2](O)=O>C(O)(=O)C>[C:38]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[C:24]2[C:25]3[C:30]([C:17]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[C:1]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[CH:4]=[CH:3][CH:2]=4)=[C:18]4[C:23]=2[CH:22]=[CH:21][CH:20]=[CH:19]4)=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: OC1(c2ccccc2-c2cccc3ccccc23)c2ccccc2C(O)(c2ccccc2-c2cccc3ccccc23)c2ccccc21
Agent: I
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: c1ccc(-c2c3ccccc3c(-c3ccccc3-c3cccc4ccccc34)c3ccccc23)c(-c2cccc3ccccc23)c1
Temperature: 100 °C
Reaction time: 7 h
Yield: 96.3 %

Procedure:
9,10-bis(2-(1-Naphthyl)phenyl)-9,10-dihydroxy-9,10-dihydroanthracene (3.5 g, 5.7 mmole) was suspended in acetic acid (80 ml). To the resultant suspension, a 57% hydroiodic acid (15 ml, 0.11 mole, 20 eq) was added and the obtained mixture was stirred at 100° C. for 7 hours. To the reaction mixture, a 50% aqueous solution of hypophosphorous acid (30 ml) was added. The formed solid was separated by filtration and washed with water, methanol and acetone and a white solid (3.2 g, 96%) was obtained.
Reaction SMILES: Br[C:2]([F:19])([F:18])[C:3]([F:17])([F:16])[S:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1Cl.Cl>CS(C)=O>[Cl:11][C:10]1[C:5]2[S:4][C:3]([F:17])([F:16])[C:2]([F:19])([F:18])[C:6]=2[CH:7]=[C:8]([N+:12]([O-:14])=[O:13])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(SC(F)(F)C(F)(F)Br)c(Cl)c1
Agent: Cl
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(Cl)c2c(c1)C(F)(F)C(F)(F)S2
Temperature: 150 °C
Yield: 55.5 %

Procedure:
Under a dry argon atmosphere a stirred mixture of 18.8 g (0.047 mole) 4-(2-bromo-1,1,2,2-tetrafluoroethylthio)-3,5-dichloronitrobenzene, 14.8 g (0.23 mole) cooper powder, and 7.3 g (0.0478 mole) 2,2'-dipyridyl in 300 ml of dimethyl sulfoxide was heated at 150° C. for 15 minutes. The mixture was cooled and poured into a separatory funnel containing approximately 100 g of 2N hydrochloric acid. The aqueous mixture was extracted with three 150 ml portions of diethyl ether and the extracts were combined. The extract was washed in succession with two 100 ml portions of 2N hydrochloric acid, two 100 ml portions of a saturated aqueous sodium chloride solution, two 100 ml portions of 2N sodium hydroxide, and 100 ml of 2N hydrochloric acid. The washed organic solution was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to leave an oil. This oil was subjected to column chromatography on silica gel, elution with n-heptane:toluene (90:10), to provide a solid after evaporation of the appropriate fractions. This solid was recrystallized from n-heptane to yield 7.5 g 7-chloro-2,2,3,3-tetrafluoro-2,3-dihydro-5-nitrobenzothiophene (mp 61.5°-62° C.).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=1)#[N:2].[H-].[Na+].I[CH3:30]>CN(C=O)C.O>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH3:30])[S:23]([CH3:26])(=[O:24])=[O:25])=[CH:18][CH:17]=1)#[N:2]
Reactant: CI
Reactant: CCn1c(-c2ccc(NS(C)(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(-c2ccc(N(C)S(C)(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.7 %

Procedure:
A solution of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methanesulfonamide (130 mg, 0.35 mmol), prepared as in Example 1Y, in DMF (10 mL) was treated with NaH (21 mg, 0.53 mmol), and stirred at room temperature for 10 min. Iodomethane (0.03 mL, 0.53 mmol) was added, and the mixture was stirred at room temperature for 18 h. The reaction mixture was then diluted with H2O, and extracted with EtOAc (2×). The organic phases were washed with H2O and saturated NaCl and then dried and concentrated. Purification by flash chromatography over silica gel (EtOAc/CH2Cl2, 0-1%) gave 60 mg (45%) of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-N-methyl methanesulfonamide as a white solid.
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([C:22]2[N:23]=[N:24][N:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:26]=2)=[N:20][C:19]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH:42]([CH3:44])[CH3:43])(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[CH:18][N:17]=1)C(=O)OC(C)(C)C)=O)(C)(C)C.C(O)(C(F)(F)F)=O.CC#N>C(Cl)Cl>[CH:42]([S:39]([C:36]1[CH:35]=[CH:34][C:33]([C:19]2[N:20]=[C:21]([C:22]3[N:23]=[N:24][N:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:26]=3)[C:16]([NH2:8])=[N:17][CH:18]=2)=[CH:38][CH:37]=1)(=[O:41])=[O:40])([CH3:44])[CH3:43]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cn(-c4ccccc4)nn3)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3cn(-c4ccccc4)nn3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonyl-N-[5-(4-isopropylsulfonylphenyl)-3-(1-phenyltriazol-4-yl)pyrazin-2-yl]carbamate (193 mg, 0.3109 mmol) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was concentrated in vacuo, more DCM was added and concentrated in vacuo to leave a yellow solid. The solid was sonicated in a small amount of MeCN and solid collected by filtration and dried by suction to provide the sub-titled product 5-(4-(isopropylsulfonyl)phenyl)-3-(1-phenyl-1H-1,2,3-triazol-4-yl)pyrazin-2-amine Compound I-1 as a pale yellow solid (105 mg, 80%). 1H NMR (400.0 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.85 (s, 1H), 8.46 (d, 2H), 8.12 (d, 2H), 7.91 (d, 2H), 7.74 (br s, 2H), 7.67 (t, 2H), 7.58 (t, 1H), 3.47 (quintet, 1H) and 1.19 (d, 6H) ppm; LC/MS m/z 421.1 [M+H]+.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH2:20]([NH2:24])[CH:21]([CH3:23])[CH3:22].CCN(C(C)C)C(C)C>>[CH2:20]([NH:24][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[CH:21]([CH3:23])[CH3:22]
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: CC(C)CN
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CNC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, isobutylamine and DIEA to give 2-isobutylamino-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 415 (MH+).