Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([F:17])=[C:9]([O:15][CH3:16])[C:10]=2[Cl:14])[C:5]1=[O:18])[CH:2]=[CH2:3].C1(=O)C=CC(=[O:29])C=C1.O.Cl(O)(=O)(=O)=O>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:19]([C:4]1([CH2:1][C:2](=[O:29])[CH3:3])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([F:17])=[C:9]([O:15][CH3:16])[C:10]=2[Cl:14])[C:5]1=[O:18])[CH2:20][CH2:21][CH3:22]
Reactant: C=CCC1(CCCC)CCc2c(cc(F)c(OC)c2Cl)C1=O
Reactant: O=C1C=CC(=O)C=C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC#N
Solvent: O
Product: CCCCC1(CC(C)=O)CCc2c(cc(F)c(OC)c2Cl)C1=O
Reaction time: 16.5 h

Procedure:
2-allyl-2-butyl-5-chloro-7-fluoro-6-methoxy-3,4-dihydro-2H-naphthalen-1-one (40 mg, 0.12 mmol) was dissolved in acetonitrile (0.36 mL) and treated with benzoquinone (20 mg, 0.18 mmol), Pd(OAc)2 (5 mg. 0.02 mmol), water (0.018 mL) and perchloric acid (70%, 0.005 mL) to give an orange solution. This solution was stirred under an air atmosphere for 16.5 hours, then purified by preparative layer chromatography on a 0.1×20×20 cm silica gel GF plate (Analtech, Newark, Del.), developing with 4:1 hexane-EtOAc. The band at Rf 0.53-0.59 was eluted with 5% MeOH in CH2Cl2 to give 2-butyl-5-chloro-7-fluoro-6-methoxy-2-(2-oxopropyl)-3,4-dihydro-2H-naphthalen-1-one as a slightly yellow oil.
Reaction SMILES: [Cl:1][CH2:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.CO.C1C(=O)N(Br)C(=[O:16])C1>O>[Cl:1][CH2:2][S:3]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[O:16]
Reactant: Cc1ccc(SCCl)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)CCl)cc1
Yield: 89.5 %

Procedure:
(Choromethyl)(p-tolyl)sulfane (10 g, 57.91 mmol) was added to a mixture of methanol (50 mL) and water (10 mL). The resulting mixture was cooled to a temperature between 0° C. and 5° C. NBS (12.37 g, 1.2 eq) was added in small portions, maintaining the same temperature range. The reaction mixture was stirred within the same temperature range until the reaction was complete. Thereafter, the reaction mixture was quenched by the addition of Na2SO3 (10%, 30 mL). The pH of the reaction mixture was adjusted to a value between 7 and 8, with saturated NaHCO3 solution. The mixture was concentrated under vacuum at a temperature between 20° C. and 25° C. and then extracted with dichloromethane (40 mL, 30 mL). The combined organic layer was washed with water (2×60 ml) and concentrated to ⅓ of the volume. Heptane (10 mL) was added and then removed by distillation. The crude product was purified by flash chromatography (Ethyl Acetate/Hexane 30:70) to give 9.78 g (89.51%) of the desired product as a white solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:22][CH2:23][CH3:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=O)=[CH:7][CH:6]=1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH3:1][CH:2]([CH2:22][CH2:23][CH3:24])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:12][N:29]2[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]2)=[CH:7][CH:6]=1
Reactant: CCCC(C)COc1ccc([C@H](C=O)NC(=O)OC(C)(C)C)cc1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCC(C)COc1ccc([C@H](CN2CCN(C)CC2)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of t-butyl (1R)-1-(4-(2-methylpentyloxy)phenyl)-2-oxoethylcarbamate (80 mg, 0.238 mmol) in dichloroethane (1 mL) was added 1-methylpiperazine (0.032 mL, 0.286 mmol) followed by sodium triacetoxyborohydride (70.8 mg, 0.334 mmol). The mixture was stirred at room temperature for 3 h. Additional 1-methylpiperazine (0.064 mL, 0.572 mmol) and sodium triacetoxyborohydride (71 mg, 0.334 mmol) were added and the mixture was stirred at room temperature for 1 h. The reaction mixture was transferred to a separatory funnel containing saturated aqueous NaHCO3 solution (5 mL). The aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (5 mL), dried over MgSO4, filtered and concentrated. The product, t-butyl 1-(4-(2-methylpentyloxy)phenyl)-2-(4-methylpiperazin-1-yl)ethylcarbamate, was used directly in the next step: LRMS (ESI) m/e 420.3 [(M+H)+, calcd for C24H42N3O3 420.3].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([CH3:20])[C:9](N2[C@H](C(C)C)COC2=O)=[O:10])=[CH:4][CH:3]=1.[OH:21]O.[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([CH3:20])[C:9]([OH:10])=[O:21])=[CH:6][CH:7]=1
Reactant: OO
Reactant: CC(C)[C@@H]1COC(=O)N1C(=O)[C@H](C)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](C(=O)O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
To a solution of (4R)-3-[(2R)-2-(4-chlorophenyl) propanoyl]-4-isopropyl-1,3-oxazolidin-2-one (1.58 g, 5.35 mmol) in 45 mL THF/H2O (3:1) at 0° C., was added 30% H2O2 (4.9 mL, 42.8 mmol) followed by LiOH (449 mg, 10.7 mmol). The resulting mixture was stirred at 0° C. for 2 h and the excess peroxide was quenched at 0° C. with 1.5 N aqueous Na2SO3 (31 mL). After buffering to pH 9–10 with aqueous NaHCO3 and evaporation of the THF, the oxazolidone chiral auxiliary was recovered by EtOAc extraction (50 mL×3). The aqueous layer was acidified with 3N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 0.97 g (5.27 mmol, 98%) of (2R)-2-(4-chlorophenyl)propanoic acid; [α]D=−64.8° (C=1.05, MeOH): 1H NMR (400 MHz, CDCl3) δ 12.2–10.8 (br, 1 H), 7.32–7.23 (m, 4 H), 3.72 (q, 1 H, J=7.3 Hz), 1.50 (d, 3 H, J=7.3 Hz); ESMS m/e: 183.2 (M−H)+.
Reaction SMILES: [C:1]([C:5]1[C:6]([C:18](Cl)=[O:19])=[N:7][C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([Cl:16])[CH:11]=[C:10]([Cl:17])[CH:9]=2)([O:3]C)=O.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[NH:29][NH2:30]>O1CCCC1>[Cl:17][C:10]1[CH:11]=[C:12]([Cl:16])[C:13]2[C:14](=[O:15])[C:5]3[C:1](=[O:3])[N:29]([C:23]4[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=4[CH3:21])[N:30]=[C:18]([OH:19])[C:6]=3[NH:7][C:8]=2[CH:9]=1
Reactant: COC(=O)c1c(C(=O)Cl)nc2cc(Cl)cc(Cl)c2c1O
Reactant: Cc1ccc(NN)c(C)c1
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(O)c3[nH]c4cc(Cl)cc(Cl)c4c(=O)c3c2=O)c(C)c1

Procedure:
3-Carbomethoxy-5,7-dichloro-4-hydroxyquinoline-2-carbonyl chloride (3.65 g, 11.0 mM) was dissolved in tetrahydrofuran (274 mL) and added dropwise to a cooled (0° C.) solution of 2,4-dimethylphenylhydrazine (3.13 g, 23.0 mM) in tetrahydrofuran (172 mL) with stirring. A brown/red suspension slowly formed and the resulting mixture was stirred at 0° C. for 30 min. The reaction was quenched by adding cold water (223 mL) followed by 1N HCl (669 mL). The resulting mixture was stirred for 1 hr and then filtered to separate the precipitated solids. The collected solids were washed with water and then ether to provide, after air drying, the title compound (3.60 g, 76%) as a white powder; MS(CI): 434 (M+H). 1H NMR (DMSO-d6): 12.55 (br s, 1H, exchangeable), 10.67 (br s, 1H, exchangeable), 7.76 (d, J=1.6 Hz, 1H), 7.54 (d, J=1.6 Hz, 1H), 7.19 (br s, exchangeable, 1H), 6.91-6.76 (m, 3H), 3.69 (s, 3H), 2.19 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[C:24]4[N:23]=[CH:22][N:21]=[CH:20][C:19]=4[NH:18][N:17]=3)=[O:15])=[CH:11][N:10]([CH:25]([CH3:29])[C:26](O)=[O:27])[N:9]=2)[CH:7]=1.Cl.[O:33]1[CH2:36][CH:35]([NH2:37])[CH2:34]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:30][CH3:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[C:24]4[N:23]=[CH:22][N:21]=[CH:20][C:19]=4[NH:18][N:17]=3)=[O:15])=[CH:11][N:10]([CH:25]([CH3:29])[C:26]([NH:37][CH:35]3[CH2:36][O:33][CH2:34]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1nn(C(C)C(=O)O)cc1NC(=O)c1n[nH]c2cncnc12
Reactant: NC1COC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cl)cc1-c1nn(C(C)C(=O)NC2COC2)cc1NC(=O)c1n[nH]c2cncnc12
Reaction time: 6 h
Yield: 52.3 %

Procedure:
A solution of 2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)propanoic acid (66.0 mg, 0.150 mmol, 1 equiv), oxetan-3-amine hydrochloride (41.0 mg, 0.374 mmol, 2.50 equiv), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)uranium hexafluorophosphate (114 mg, 0.299 mmol, 2.00 equiv), and N,N-diisopropylethylamine (522 μL, 2.99 mmol, 20.0 equiv) in N,N-dimethylformamide (1.0 mL) was heated at 50° C. After 6 h, the reaction mixture was concentrated, and the resulting residue was partitioned between saturated aqueous sodium bicarbonate (10 mL) and ethyl acetate (10 mL). The aqueous was extracted with ethyl acetate (2×5 mL). The combined organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by preparative HPLC afforded product (39 mg, 51% yield). 1H NMR (400 MHz, DMSO-d6), δ: 9.70 (s, 1H), 9.33 (m, 1H), 9.02 (d, J=6.5 Hz, 1H), 8.77 (dd, J=4.2, 1.5 Hz, 1H), 8.65 (s, 1H), 8.36 (s, 1H), 7.50 (dd, J=8.9, 2.7 Hz, 1H), 7.38 (d, J=2.6 Hz, 1H), 7.27-7.31 (m, 2H), 5.06 (q, J=7.1 Hz, 1H), 4.80 (m, 1H), 4.73 (m, 2H), 4.44 (m, 2H), 3.84 (s, 3H), 1.66 (d, J=7.1 Hz, 3H). LCMS (ESI): M+H=496.1.
Reaction SMILES: [CH:1]1([NH:7][S:8](=[O:11])(=O)[OH:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:13]>C1C=CC=CC=1>[CH:1]1([NH:7][S:8]([Cl:13])(=[O:11])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(O)NC1CCCCC1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: O=S(=O)(Cl)NC1CCCCC1
Yield: 90.7 %

Procedure:
To a solution of cyclohexylsulfamic acid (5 g, 27.9 mmol) in benzene (30 mL) was added dropwise phosphorus pentachloride (6.4 g, 30.7 mmol), and the mixture heated at reflux for 4 h. After the solvent was removed, the residue was distilled under reduced pressure to give the title compound (5 g, 91%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[C:11]1[CH:18]3[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:20][CH:12]1[CH2:13]4)[CH2:17]3)[CH2:8]2.[Cl:21]Cl>ClC(Cl)(Cl)Cl>[Cl:21][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[C:2]1=[C:11]1[CH:12]3[CH2:20][CH:16]4[CH2:15][CH:14]([CH2:19][CH:18]1[CH2:17]4)[CH2:13]3)[CH2:10]2
Reactant: ClCl
Reactant: C1C2CC3CC1CC(C2)C3=C1C2CC3CC(C2)CC1C3
Solvent: ClC(Cl)(Cl)Cl
Product: ClC12CC3CC(CC(C3)C1=C1C3CC4CC(C3)CC1C4)C2

Procedure:
In Tetrahedron Letters 1970, 4579-82, J. H. Wieringa, J. Strating and H. Wynberg describe a process in which adamantylidene adamantane is reacted with chlorine is tetrachloromethane at a temperature of -20° to +10° C. to form 4-eq.-chloroadamantylidene adamantane in addition to polychlorinated products. The chloro-substituted adamantane compound is the starting point for further reaction in the presence of AgNO3 and THF/H2O to form a mixture of the corresponding 4-hydroxy-adamantylidene adamantane compounds, which with the appropriate oxidant (Jones reagent: CrO3, H2SO4, acetone) are finally converted into the corresponding ketone compound, in which the carbonyl group is in the 4-position.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].Cl.N1C=CC=CC=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]2[NH:28][N:29]=[N:30][C:26]=2[CH:25]=1>C(OCCO)C>[N:28]1[C:27]2[CH:31]=[CH:32][C:24]([NH:23][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:14]#[N:15])=[CH:25][C:26]=2[NH:30][N:29]=1
Reactant: Nc1ccc2[nH]nnc2c1
Reactant: COc1ccc2ncc(C#N)c(Cl)c2c1
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: COc1ccc2ncc(C#N)c(Nc3ccc4nn[nH]c4c3)c2c1
Yield: 95.8 %

Procedure:
Using an analogous procedure to that described in Example 141, 218.6 mg (1 mmol) of 4-chloro-6-methoxy-3-quinolinecarbonitrile in 10 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 161.0 mg (1.2 mmol) of 5-aminobenzotriazole to give 302.9 mg (95.8%) of the product as a yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 316.9. HRCIMS calcd: 316.107 for C17H12N6O(M+), obsd 316.1081
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C[O-].[Na+]>CO>[O:20]([C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccc([N+](=O)[O-])cc1Oc1ccccc1
Temperature: 180 °C
Yield: 120.4 %

Procedure:
To a stirred solution of 2-chloro-4-nitrobenzoic acid (3 g, 14.9 mmole) and phenol (3 g, 31.9 mmole) in MeOH (20 mL) was added a solution of NaOMe in MeOH (25 wt %, 9 mL, 39.4 mmole). After 15 minutes the solution was concentrated to dryness and the residue was taken up in dimethylacetamide (50 mL). Copper powder (100 mg) was added and the mixture was heated at reflux with stirring (180° C. oil bath). After 1 hr the reaction was cooled to RT, acidified with 1.0 N HCl (40 mL), and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), and concentrated under vacuum. The remaining residue was triturated with 1:1 Et2O/petroleum ether and dried under vacuum to afford the title compound (4.65 g). This was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(Cl)(=O)C(Cl)=O.O[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
Prepared using General Procedure 2: To a stirring solution of 4-(heptyloxy)benzoic acid (1.0 g, 4.23 mmol) in DCM (10 mL) were added DMF (1 drop) and oxalyl chloride (0.47 mL, 5.5 mmol). The reaction mixture was stirred at room temperature for 1 h. Solvent was evaporated under high vacuum. DCM (10 mL) was added and the reaction mixture evaporated again to dryness. The residue was dissolved in DCM (10 mL) then added to a stirring mixture of 4-hydroxy benzaldehyde (0.56 g, 4.6 mmol) and TEA (0.706 mL, 5.07 mmol) in DCM (5 mL) at 0° C. The reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was quenched with NaHCO3 (10 mL). The aqueous phase was extracted with DCM and the combined organic phases were dried over MgSO4 and concentrated to give 977 mg (62%) of 4-formylphenyl 4-(heptyloxy)benzoate INT-12 which was used in the next step without purification. LCMS-ESI (m/z) calculated for C21H24O4: 340; found 341 [M+H]+, tR=11.91 min (Method 2). 1H NMR (400 MHz, DMSO) δ 10.03 (s, 1H), 8.19-7.91 (m, 4H), 7.63-7.41 (m, 2H), 7.24-7.01 (m, 2H), 4.09 (t, J=6.5 Hz, 2H), 1.86-1.62 (m, 2H), 1.50-1.07 (m, 8H), 0.87 (t, J=6.9 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([Cl:19])=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>CC(N(C)C)=O>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[N:14][C:13]=2[N:31]([C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:23])([F:35])[F:34])[CH:26]=2)[C:32]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1c2cc(F)c(Cl)nc2n(-c2cccc(C(F)(F)F)c2)c(=O)n1OCc1ccccc1
Yield: 69.1 %

Procedure:
Using the General Method 5, the reaction of N-benzyloxy-2,6-dichloro-5-fluoro-3-pyridinecarboxamide (Example M-2, 2.00 g, 6.34 mmol) and 60% NaH in oil (300 mg, 7.52 mmol) with 3-trifluoromethylphenyl isocyanate (1.31 mL, 9.51 mmol) in DMA afforded 2.04 g of the title compound as a solid, mp 207-208° C.
Reaction SMILES: [CH2:1]([S:8][C@H:9]1[N:12]([CH2:13][C:14]([O:16]CC2C=CC(OC)=CC=2)=[O:15])[C:11](=[O:26])[C@@H:10]1[Br:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO>[CH2:1]([S:8][C@H:9]1[N:12]([CH2:13][C:14]([OH:16])=[O:15])[C:11](=[O:26])[C@@H:10]1[Br:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(COC(=O)CN2C(=O)[C@H](Br)[C@H]2SCc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN1C(=O)[C@H](Br)[C@H]1SCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of p-methoxybenzyl [(3S, 4R)-4-benzylthio-3-bromo-2-oxoazetidin-1-yl]acetate (3.03 g, 0.0067 mol) in methanol (50 ml) at -5 to -10° C. a 1M solution of potassium hydroxide (7.4 ml) was added dropwise with stirring. After 2 h, the methanol was evaporated off and the residue diluted with water, extracted twice with ether, and the aq. layer acidified with ice cooling to pH 3 (2M HCl). The oil which precipitated soon crystallised and was filtered, washed and dried to give the title compound, yield 0.9 g (41%), m.p. 138-40° C.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[F:30].C(N(CC)CC)C.[CH:38]1([C:44](Cl)=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>ClCCl>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:44]([CH:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:45])=[C:3]([F:30])[CH:4]=3)[CH2:9][CH2:10]2)[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)c1
Reactant: O=C(Cl)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)C4CCCCC4)c(F)c3)CC2)c1
Reaction time: 16 h
Yield: 44.3 %

Procedure:
To a stirred solution of 3-((4-(4-amino-3-fluorobenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (0.121 mmol, 50 mg) and triethylamine (0.485 mmol, 0.068 mL, 49.1 mg) in dichloromethane (1.5 mL) was added cyclohexanecarbonyl chloride (0.133 mmol, 19.55 mg). After 16 hours stirring, the reaction was concentrated under vacuum and purified by acidic reverse phase HPLC to yield the title compound (28 mg).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N+:14]([O-])([OH:16])=[O:15].OS(O)(=O)=O>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([N+:14]([O-:16])=[O:15])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(C(C)C)cc1
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1ccc(C(C)C)cc1[N+](=O)[O-]

Procedure:
N-(4-Isopropylphenyl)acetamide obtained in step I above was nitrated using nitric acid (1.2 eq)+H2SO4 (1.0 eq) at 0 to 5° C. for 2 hrs. After the completion of the reaction, reaction mixture was added to ice and pH was adjusted to 8, extracted with dichloromethane, which was evaporated to dryness to obtain N-(4-isopropyl-2-nitrophenyl)acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:26]=[C:11]3[N:12]=[C:13]([CH3:25])[C:14]([C@H:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21])=[C:15]([CH:16]([CH3:18])[CH3:17])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(O[C:31]([CH3:34])([CH3:33])[CH3:32])(=O)C.Cl(O)(=O)(=O)=O>C(Cl)Cl.CCOCC>[C:31]([O:24][C@@H:19]([C:14]1[C:13]([CH3:25])=[N:12][C:11]2[N:10]([N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:26]=2)[C:15]=1[CH:16]([CH3:18])[CH3:17])[C:20]([O:22][CH3:23])=[O:21])([CH3:34])([CH3:33])[CH3:32]
Reactant: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1C(C)C
Reactant: CC(=O)OC(C)(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1C(C)C
Reaction time: 3 h
Yield: 131.9 %

Procedure:
To a stirred solution of (S)-methyl 2-(2-(3-chlorophenyl)-7-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (0.069 g, 0.185 mmol) and tert-butyl acetate (1.247 ml, 9.23 mmol) in CH2Cl2 (5 mL) was added 70% perchloric acid (0.048 ml, 0.554 mmol) at rt. After 3 h, the reaction mixture was diluted with Et2O (35 mL), washed with sat Na2CO3 (2×5 mL), brine (5 mL), dried (Na2SO4), filtered and concentrated to give colorless paste which was purified by prep-HPLC to afford (S)-methyl 2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-isopropyl-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (0.0496 g, 0.244 mmol, 62.5% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ: 7.98 (t, J=1.7 Hz, 1H), 7.87 (dt, J=7.6, 1.4 Hz, 1H), 7.41-7.32 (m, 2H), 6.77 (s, 1H), 5.42 (s, 1H), 4.07 (dt, J=13.6, 6.9 Hz, 1H), 3.71 (s, 3H), 2.73 (s, 3H), 1.68 (d, J=7.0 Hz, 3H), 1.56 (d, J=7.0 Hz, 3H), 1.26 (s, 9H). LCMS (M+H) calcd for C23H29ClN3O3: 430.19. found: 430.3.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5]1[NH:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=1.[Br:16]N1C(=O)CCC1=O>CO>[Br:16][C:6]1[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][NH:9][C:5]=1[CH2:4][CH2:3][S:2][CH3:1]
Reactant: CSCCc1cc(-c2ccccc2)n[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Product: CSCCc1[nH]nc(-c2ccccc2)c1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 62.4 %

Procedure:
To a solution of 5-(2-(methylthio)ethyl)-3-phenyl-1H-pyrazole (4.0 g, 18.32 mmol) in methanol (20 mL) was added N-bromosuccinimide (3.26 g, 18.32 mmol) slowly at 0° C. The reaction was stirred at 0° C. for 2 h. The mixture was concentrated and purified by silica gel column chromatography to give the title compound (3.4 g). LCMS m/z=297.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.11 (s, 3H), 2.79 (t, J=7.83 Hz, 2H), 2.83-2.97 (m, 2H), 7.32-736 (m, 3H), 7.67-7.88 (m, 2H), 13.20 (bs, 1H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C(N(CC)CC)C.[CH:11]1([C:14]2[N:19]=[C:18]([C:20]3[NH:37][C:23]4=[N:24][C:25]([N:28]5[CH2:33][CH2:32][CH2:31][C@@H:30]([C:34](O)=[O:35])[CH2:29]5)=[CH:26][CH:27]=[C:22]4[N:21]=3)[CH:17]=[CH:16][N:15]=2)[CH2:13][CH2:12]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH:11]1([C:14]2[N:19]=[C:18]([C:20]3[NH:37][C:23]4=[N:24][C:25]([N:28]5[CH2:33][CH2:32][CH2:31][C@@H:30]([C:34]([N:2]([CH3:3])[CH3:1])=[O:35])[CH2:29]5)=[CH:26][CH:27]=[C:22]4[N:21]=3)[CH:17]=[CH:16][N:15]=2)[CH2:13][CH2:12]1
Reactant: CNC
Reactant: O=C(O)[C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)[C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of dimethylamine (175 μmol) in N,N-dimethylformamide (200 μL) was added triethylamine (35 μL, 250 μmol) and (R)-1-(2-(2-cyclopropylpyrimidin-4-yl)-3H-imidazo[4,5-b]pyridin-5-yl)piperidine-3-carboxylic acid (200 μL, 50 μmol, 0.25M in N,N-dimethylformamide) followed by 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (250 μL, 100 μmol, 0.4M in N,N-dimethylformamide). The reaction mixture was stirred at 50° C. for 16 h. The solvent was removed by Speedvac and the residue was purified via HPLC to afford the title compound. MS API-ES+ (M+H) 392; HPLC retention time 2.43 min (Method C).