Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=O)[CH:19]=2)[CH:14]=[N:13]1.N1CCCCC1>CO>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](/[CH:21]=[C:7]3/[C:8](=[O:11])[NH:9][C:10]4[C:6]/3=[CH:5][CH:4]=[CH:3][C:2]=4[NH2:1])[CH:19]=2)[CH:14]=[N:13]1
Reactant: Nc1cccc2c1NC(=O)C2
Reactant: O=Cc1ccc2cn[nH]c2c1
Solvent: CO
Solvent: C1CCNCC1
Product: Nc1cccc2c1NC(=O)/C2=C/c1ccc2cn[nH]c2c1
Temperature: 60 °C
Yield: 28 %

Procedure:
A 13 mg (0.0877 mmol) solution of 7-aminooxindole (T. Nakashima & I. Suzuki, Chem. Pharm. Bull. (1969) 11, 2293) and 1H-indazole-6-carbaldehyde (14 mg, 0.0965 mmol) in MeOH (1.0 mL) was treated with piperidine (˜1 uL, 0.00877 mmol) and the reaction was heated to 60° C. for 4 hours. The MeOH was then removed in vacuo and the residue treated with 95:5 CH2Cl2/MeOH. The resulting precipitate was filtered and washed with 95:5 CH2Cl2/MeOH to obtain the title compound as a orange powder (6.7 mg, 28%). NMR (400 MHz, CD3OD) δ 8.14 (s, 1H), 7.94-7.87 (m, 3H), 7.46 (d, J=8.19 Hz, 1H), 7.31 (d, J=7.63 Hz, 1H), 6.90 (d, J=7.89 Hz, 1H), 6.81 (t, J=7.79 Hz, 1H); MS ESI 277.0 [M+H]+, calcd for [C16H12N4O+H]+ 277.11.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17](I)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]>[Cl:14][C:15]1[CH:16]=[C:17]([N:1]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:14])[CH:20]=2)[C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Clc1cccc(I)c1
Reactant: Nc1ccc(-c2ccccc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Clc1cccc(N(c2ccc(-c3ccccc3)cc2)c2cccc(Cl)c2)c1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
A mixture of 5.3 grams of 4-aminobiphenyl, 25.0 grams of m-chloroiodobenzene and 16.5 grams of potassium carbonate in 150 milliliters of dimethyl sulfoxide was mechanically stirred and heated to 110° C. in a round-bottomed flask fitted with a reflux condenser under a nitrogen atmosphere. Subsequently, 9.5 grams of copper bronze powder was added, and the temperature of the reaction mixture was raised to 170° C. After 48 hours, the reaction mixture was filtered while still hot, and the filtrate was evaporated under reduced pressure to provide a viscous oil. Purification by column chromatography on neutral alumina using a mixture of methylene chloride and hexane (1:10) as the eluent afforded 7.9 grams of analytically pure bis(m-chlorophenyl)-4-biphenylylamine.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([CH:9]=[N:10]O)=[CH:7][CH:6]=[C:5]([Cl:12])[N:4]=1.O1CCOCC1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][CH:6]=[C:5]([Cl:12])[N:4]=1
Reactant: Nc1nc(Cl)ccc1C=NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: N#Cc1ccc(Cl)nc1N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
11.15 g (53.6 mmol) of 2-amino-6-chloropyridine-3-carbaldehyde oxime hydrochloride (Example 108A) are introduced into dioxane, 13 ml (161 mmol) of pyridine are added, and the mixture is cooled to 0° C. 8.3 ml (58.95 mmol) of trifluoroacetic anhydride are added, and the reaction is allowed to warm to RT and then stirred at 60° C. for 2 h. The reaction mixture is taken up in a mixture of ethyl acetate and sodium bicarbonate solution. The organic phase is washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated in a rotary evaporator. The residue is suspended in 3:1 dichloromethane:diethyl ether, and the solid is filtered off with suction and dried. 5.56 g (66% of theory) of the product are obtained as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].[CH2:24]([O:26][C:27]1[C:28]([C:41](Cl)=[O:42])=[N:29][N:30]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=2[CH3:40])[CH:31]=1)[CH3:25]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41]([C:28]2[C:27]([O:26][CH2:24][CH3:25])=[CH:31][N:30]([C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][C:33]=3[CH3:40])[N:29]=2)=[O:42])=[CH:18][C:17]=1[F:23]
Reactant: CCOc1cn(-c2ccc(OC)cc2C)nc1C(=O)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Product: CCOc1cn(-c2ccc(OC)cc2C)nc1C(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(F)c1

Procedure:
Following the general procedure reported in Preparative Example 16 Step 5×4 was prepared from A2 and 4-ethoxy-1-(4-methoxy-2-methylphenyl)-1H-pyrazole-3-carbonyl chloride, which was prepared similar to Preparative Example 16 step 1-4. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.36 (t, J=7.0 Hz, 3H), 2.20 (s, 3H), 3.80 (s, 3H), 3.94 (s, 6H), 4.05 (q, J=7.0 Hz, 2H), 6.46 (d, J=5.2 Hz, 1H), 6.90 (dd, J=2.9 Hz, J=8.8 Hz, 1H), 6.98 (d, J=2.7 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.40 (s, 1H), 7.43 (d, J=9.0 Hz, 1H), 7.53 (s, 1H), 7.71 (d, J=9.0 Hz, 1H), 7.95 (s, 1H), 8.03 (dd, J=2.4 Hz, J=13.3 Hz, 1H), 8.47 (d, J=5.2 Hz, 1H), 10.10 (s, 1H). MS (ES) C31H29FN4O6 requires: 572. Found: 573 (M+H)+.
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][C:12]([C:16]([O:18]CC)=[O:17])=[C:13]([CH3:15])[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].C(O)(=O)C>O1CCCC1.O>[C:1]([NH:9][C:10]1[S:11][C:12]([C:16]([OH:18])=[O:17])=[C:13]([CH3:15])[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(NC(=O)c2ccccc2)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc(NC(=O)c2ccccc2)sc1C(=O)O
Temperature: 50 °C
Reaction time: 20 h
Yield: 75 %

Procedure:
A mixture of ethyl 2-benzamido-4-methylthiazole-5-carboxylate (3.00 g, 10.00 mmol) and lithium hydroxide (2.50 g, 103.00 mmol) in a mixture of tetrahydrofuran (40 mL) and water (10 mL) was stirred at 50° C. for 20 h. The mixture was then cooled to 0° C. and neutralized with acetic acid to pH 7. The precipitate obtained was collected by filtration, washed with water and dried in vacuo to afford the title compound as a white solid in 75% yield (2.0 g); 1H NMR (DMSO-d6, 300 MHz) δ 12.92 (s, br, 1H), 8.06-8.04 (m, 2H), 7.63-7.48 (m, 3H), 2.53 (s, 3H).
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[C:25]12([N:35]=[C:36]=[O:37])[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2>>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:36]([NH:35][C:25]23[CH2:34][CH:29]4[CH2:28][CH:27]([CH2:33][CH:31]([CH2:30]4)[CH2:32]2)[CH2:26]3)=[O:37])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Product: Cc1ccc(C(OC2CN(C(=O)NC34CC5CC(CC(C5)C3)C4)C2)c2ccccc2C(F)(F)F)cc1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-4′-methylbenzhydryloxy]azetidine hydrochloride (151) (0.56 mmol) and 1-adamantyl isocyanate (0.56 mmol) using the procedure described for compound (10). The desired product was obtained as a white foam (264 mg, 94%).
Reaction SMILES: N1CCCCC1.[NH:7](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:18]([NH:20][C@H:21]([C:23]([NH:25][C@H:26]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:24])[CH3:22])=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15])=[O:11]>CN(C=O)C>[NH2:7][CH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:18]([NH:20][C@H:21]([C:23]([NH:25][C@H:26]([C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[CH2:27][CH:28]([CH3:29])[CH3:30])=[O:24])[CH3:22])=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15])=[O:11]
Reactant: CC[C@H](C)[C@H](NC(=O)CCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)CCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
In a round bottom flask (25 mL), Fmoc-β-Ala-Ile-Ala-Leu-OBn SEQ ID NO: 119 (0.7 g, 1.0 mmol) is dissolved in 5 mL of anhydrous DMF. Piperidine (1.2 mL, 12.1 mmol) is added to the solution and the mixture is stirred at room temperature for 25 minutes. The reaction is quenched with water (6 mL) and extracted with ethyl acetate (2×10 mL). The combined organic layer is further washed by water (2×5 mL), brine (5 mL) and dried over sodium sulfate. A white solid (0.8 g) is obtained after removal of solvent.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[C:16]([F:17])=[CH:15][C:14]([NH:18][C:19](=[O:24])[CH2:20][C:21]([OH:23])=O)=[C:13]([F:25])[CH:12]=2)[CH:7]=[CH:6][N:5]=1)(=[O:3])[NH2:2].[C:26]1([CH:32]([NH2:34])[CH3:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:17][C:16]1[CH:15]=[C:14]([NH:18][C:19](=[O:24])[CH2:20][C:21](=[O:23])[NH:34][CH:32]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:33])[C:13]([F:25])=[CH:12][C:11]=1[O:10][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([C:1]([NH2:2])=[O:3])[CH:9]=1
Reactant: CC(N)c1ccccc1
Reactant: NC(=O)c1cc(Oc2cc(F)c(NC(=O)CC(=O)O)cc2F)ccn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)CC(=O)Nc1cc(F)c(Oc2ccnc(C(N)=O)c2)cc1F)c1ccccc1
Reaction time: 15 h
Yield: 37 %

Procedure:
To a homogeneous mixture of 3-(4-(2-carbamoylpyridin-4-yloxy)-2,5-difluorophenylamino)-3-oxopropanoic acid (89 mg, 0.25 mmol) and (±)-1-phenyl-ethanamine (Aldrich, 0.05 mL, 0.38 mmol) in DMF (3 mL) was added DIPEA (0.07 mL, 0.38 mmol) and O-benzotriazol-1-yl-N,N,N′,N′-bis(tetramethylene)uranium hexafluorophosphate (TBTU) (121 mg, 0.38 mmol). The resulting solution was stirred for 15 hours before being quenched with 10% LiCl (aq). The mixture was partitioned between EtOAc and 10% LiCl (aq), the layers separated, and the aqueous layer extracted with EtOAc. The combined organic layers were washed twice with 10% LiCl (aq), then concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 1:3 hexane/EtOAc) and the appropriate fractions were concentrated in vacuo to afford the title compound (42 mg, 37%). HRMS(ESI+), 455.1532 (M+H)+ calcd., 455.1528 (M+H)+ found.
Reaction SMILES: OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:6].[CH3:16][N:17]([CH3:33])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:32])[C:24]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:25]=2[N:26]=1.FC(F)(F)C(O)=O>C(Cl)Cl.C(Cl)(Cl)Cl.N>[CH3:33][N:17]([CH3:16])[CH2:18][CH2:19][NH:20][C:21]1[N:22]=[N+:23]([O-:32])[C:24]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:25]=2[N+:26]=1[O-:6]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1ccc2c(c1)nc(NCCN(C)C)n[n+]2[O-]
Agent: N
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)[n+]([O-])c(NCCN(C)C)n[n+]2[O-]
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 34.2 %

Procedure:
Hydrogen peroxide (70%, 1.1 mL, ca. 22.9 mmol) was added dropwise to a stirred solution of trifluoroacetic anhydride (3.2 mL, 22.9 mmol) in DCM (20 mL) at 5° C. The mixture was stirred at 5° C. for 5 min, warmed to 20° C., stirred for 10 min, and cooled to 5° C. The mixture was added to a stirred solution of 1-oxide 2 (566 mg, 2.3 mmol) and trifluoroacetic acid (353 μL, 4.6 mmol) in CHCl3 (20 mL) at 5° C. and the mixture stirred at 20° C. for 16 h. The solution was carefully diluted with dilute aqueous NH3 solution (20 mL) and the mixture extracted with CHCl3 (5×50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 3 (207 mg, 34%) as a red solid, mp (MeOH/EtOAc) 187-189° C.; 1H NMR δ 8.19 (d, J=9.0 Hz, 1 H, H-8), 8.05 (d, J=1.7 Hz, 1 H, H-5), 7.44. (br s, 1 H, NH), 7.29 (dd, J=9.0, 1.7 Hz, 1 H, H-7), 3.58-3.64 (m, 2 H, CH2N), 2.57-2.61 (m, 2 H, CH2N), 2.56 (s, 3 H, CH3), 2.28 [s, 6 H, (CH3)2]; 13C NMR δ 149.9, 148.0, 138.2, 129.3, 128.8, 121.4, 116.0, 57.4, 45.2 (2), 38.8, 22.3. Anal. Calcd for C12H17N5O2: C, 54.7; H, 6.5; N, 26.6. Found: C, 54.3: H, 6.7; N, 26.8%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:11](C(OCC2C=CC=CC=2)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][C:2]=1[CH3:1]
Reactant: [H][H]
Reactant: CCOC(=O)C(C(=O)OCc1ccccc1)c1ccc([N+](=O)[O-])c(C)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(N)c(C)c1
Reaction time: 2 h

Procedure:
Batch 2: ethyl phenylmethyl (3-methyl-4-nitrophenyl)propanedioate (35 g, 98 mmol) was taken up in Ethanol (500 ml) and subjected to a hydrogenation at atmospheric pressure using 10% palladium on carbon (3.13 g, 2.94 mmol). After 2 hours a sample was taken for analysis. The reservoir was refilled with hydrogen and the reaction continued overnight. The catalyst was removed by filtration through celite and fresh catalyst palladium on carbon (3.13 g, 2.94 mmol) was added to the reaction mixture. The reaction was put on again for 3 hours. After leaving the reaction mixture under these conditions for the weekend, it was combined with BATCH 1 reaction mixture (equivalent reaction mixture) and filtered through celite to give a colourless filtrate. This solution was concentrated to an oily solid (wt=31.9 g). To this mixture was added toluene (200 ml) and the mixture was filtered from an insoluble white gum (wt=0.65 g). The filtrate was passed down a silica gel Biotage 75 L chromatography column eluting with the following ethyl acetate/iso-hexane gradient mixture and collecting 400 ml fractions:
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]([CH3:28])[CH3:27])[C:20]=2[S:29][CH2:30]C)[CH:11]=1>CO>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]([CH3:27])[CH3:28])[C:20]=2[S:29][CH3:30])[CH:11]=1
Reactant: CCSc1c(CN(C)C)cccc1Oc1cc(Cl)ccc1C#N
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Product: CSc1c(CN(C)C)cccc1Oc1cc(Cl)ccc1C#N
Reaction time: 17 h

Procedure:
4-Chloro-2-fluorobenzonitrile (0.974 g, 6.26 mmol), 3-dimethylaminomethyl-2-methylsulfanyl-phenol hydrobromide (1.74 g, 6.26 mmol) and cesium carbonate (4.08 g, 12.5 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 17 h. The reaction was complete by LC/MS analysis. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water (1×), 10% sodium carbonate solution (2×), water (2×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(3-dimethylaminomethyl-2-methylsulfanyl-phenoxy)-benzonitrile (1.2 g, 58%) as a yellow oil. Fumaric acid (92 mg, 0.3 mmol) in methanol (5 mL) was added to 4-chloro-2-(3-dimethylaminomethyl-2-ethylsulfanyl-phenoxy)-benzonitrile (91 mg, 0.26 mmol). The solvent was removed in vacuo and diethyl ether (20 mL) was added with stirring. After 17 h, 4-chloro-2-(3-dimethylaminomethyl-2-methysulfanyl-phenoxy)-benzonitrile fumarate (63.2 mg, 47%) was filtered off as a white solid.
Reaction SMILES: CC([O-])(C)C.[K+].[CH2:7]1[O:15][C:14]2[CH:13]=[CH:12][C:11]([OH:16])=[CH:10][C:9]=2[O:8]1.[K].C(S([C:23]1[CH:28]=[CH:27][C:26](S(CC)(=O)=O)=[CH:25][N:24]=1)(=O)=O)C>CS(C)=O.C1COCC1>[CH2:7]1[O:15][C:14]2[CH:13]=[CH:12][C:11]([O:16][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:10][C:9]=2[O:8]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CCS(=O)(=O)c1ccc(S(=O)(=O)CC)nc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [K]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: c1ccc(Oc2ccc3c(c2)OCO3)nc1
Temperature: 0 °C

Procedure:
Into a reaction flask was weighed 5.6 g of t-BuOK and then 50 ml of THF was added. In 50 ml of DMSO was dissolved 6.2 g of 3,4-methylenedioxyphenol which was then slowly added to the t-BuOK solution with stirring. To the resulting potassium phenate solution was added 10.5 g of 2,5-bis(ethylsulfonyl)pyridine and this mixture heated at 50°-55° C. for 3 hrs. After cooling, the reaction mixture was poured into 400 g of ice, stirred and then filtered. The solid which was recovered was dissolved in CH2Cl2, treated with charcoal, dried over MgSO4 and then filtered. The CH2Cl2 solution was concentrated to 50 ml, diluted with an equal volume of hexane and then chilled and a crystalline material recovered, which provided 9.9 g, (80% yield), of 5-ethylsulfonyl)-2-(3,4-methylenedioxyphenoxy)pyridine, m.p. 97°-99° C.
Reaction SMILES: [O-:1]O.[OH:3][CH2:4]/[CH:5]=[C:6](/[CH3:13])\[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11]>>[OH:3][CH2:4][CH:5]1[O:1][C:6]1([CH3:13])[CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11]
Reactant: CC(C)=CCC/C(C)=C\CO
Reactant: [O-]O
Product: CC(C)=CCCC1(C)OC1CO

Procedure:
The hydroperoxide resulting from nerol can be reduced to the corresponding hydroxyl compound and this can then be cyclized with acid catalysis to give nerol oxide.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:12]3[CH:20]=[CH:19][C:15]4[O:16][CH2:17][O:18][C:14]=4[CH:13]=3)O)=[CH:9][C:4]=2[O:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:32][CH2:33][O:34][C:35]([CH2:37][N+:38]([O-:40])=[O:39])=[O:36]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:12]3[CH:20]=[CH:19][C:15]4[O:16][CH2:17][O:18][C:14]=4[CH:13]=3)[CH:37]([N+:38]([O-:40])=[O:39])[C:35]([O:34][CH2:33][CH3:32])=[O:36])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: OC(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)C(C(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2)[N+](=O)[O-]
Temperature: 120 °C
Yield: 79 %

Procedure:
The alcohol of Example 17 is dissolved in 5 mL of nitro ethyl acetate. A catalytic amount of p-toluene-sulfonic acid is added and the reaction mixture is heated to 120° C. for 3 hours. Excess nitro ethyl acetate is removed by distillation and the residue is purified by silica gel chromatography eluting with 15% ethyl acetate-hexane to give 2.25 g (79%) of product as a yellow oil;
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][C:6]([OH:24])([CH3:23])[CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11](Cl)[C:10]=1[N+:20]([O-:22])=[O:21].CN(C)C=O.CC(C)=O>O>[CH3:23][C:6]([OH:24])([CH3:5])[CH2:7][NH:8][C:9]1[C:18]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:1]2[N:2]=[N:3][N:12]=[C:11]2[C:10]=1[N+:20]([O-:22])=[O:21]
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(O)CNc1c([N+](=O)[O-])c2nnnn2c2ccccc12

Procedure:
Sodium Azide (19.5 g, 0.3 moles), 2-methyl-[(2-chloro-3-nitroquinolin-4-yl)amino]-2-propanol (29.6 g, 0.10 mole, U.S. Pat. No. 4,988,815 Example 12) and N,N-dimethylformamide (100 mL) were added to a jacketed 1 liter round bottom flask with the outside portion containing acetone. The reaction mixture was stirred with a stirring bar and the acetone refluxed to provide a constant internal reaction temperature of 53° C. After 18 hours the reaction mixture was diluted with water (100 mL). The resulting yellow precipitate was isolated by filtration then washed with 50% N,N-dimethylformamide/water until the washes became light colored. The yellow/green solid was then washed with water, pressed dry and washed with ether. The solid was air dried to provide 27.2 g of crude product as a yellow/light green solid. This material was recrystallized from ethanol/dichloromethane to provide 2-methyl-[(4-nitro-5-tetrazolo[1,5-a]quinolinyl)amino]-2-propanol as a yellow crystalline solid, m.p. 204° C. (dec.). Analysis: Calculated for: C13H14N6O3: % C, 51.65; % H, 4.67; % N, 27.8; Found: % C, 51.30; % H, 4.69; % N, 27.43.
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:26](Cl)(=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>N1C=CC=CC=1>[C:26]([O:1][CH:2]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:3][C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5])(=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCCCCC(O)CC(=O)OC(C)(C)C
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 79.9 %

Procedure:
To tert-butyl 3-hydroxyoctadecanoate (120 g) in pyridine (500 ml) was added palmitoyl chloride (120 g) at 0° C. The mixture was stirred at 0° C. for 5 hours and then allowed to stand over-night at room temperature. Pyridine was removed under reduced pressure and the residue was poured into water. The resulting mixture was stirred at ambient temperature for 2 hours, acidified with 1N HCl, extracted with ethyl acetate, and washed with water. Evaporation of the solvent gave a residue which was purified by silica gel column chromatography (30% CH2Cl2 --CCl4) to afford tert-butyl 3-hexadecanoyloxyoctadecanoate (160 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:33][CH2:32][C:19]3([CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.Cl.CCOC(C)=O>ClCCl>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:33][CH2:32][C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CCC4(CC3)CCN(C(=O)OC(C)(C)C)CC4)n2)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cn1cc(Nc2ncc(Cl)c(NC3CCC4(CCNCC4)CC3)n2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79.8 %

Procedure:
To a solution of tert-butyl 9-((5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino) pyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (87.0 mg, 0.18 mmol) in dichloromethane (5 mL) was added a solution of HCl in EtOAc (2 mL, 8 mmol). The mixture was stirred at room temperature for 5 h and then concentrated in vacuo. The residue was dissolved in MeOH (2 mL) and adjusted to pH=10 with a saturated Na2CO3 aqueous solution, then extracted with DCM (20 mL×3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by preparative TLC (MeOH/DCM (v/v)=1/5) to give the product as a light yellow solid (54.0 mg, 78.6%).
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1.[CH:10]1(B(O)O)[CH2:12][CH2:11]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>O>[Cl:1][C:2]1[C:3]([CH:10]2[CH2:12][CH2:11]2)=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1cnc(I)c(Cl)n1
Reactant: OB(O)C1CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1cnc(C2CC2)c(Cl)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of 3,5-dichloro-2-iodopyrazine (2 g), cyclopropylboronic acid (750 mg), tetrakistriphenylphosphine palladium (0) (1.68 g), potassium phosphate (3.09 g), toluene (40 mL), and water (4 mL) was stirred at 110° C. overnight. After leaving to be cooled, the insoluble matter was removed by decantation, followed liquid separation by the addition of ethyl acetate and water. The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=98:2) to obtain 3,5-dichloro-2-cyclopropylpyrazine (784 mg) as a colorless oily material.