Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)[CH2:4][CH3:5])[CH3:2].II.[Cl:15][C:16]1[C:17]([NH:26][NH2:27])=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1.O.OO>O.C(O)(=O)C.CN(C)C=O>[Cl:15][C:16]1[C:17]([N:26]=[N:27][C:9]2[CH:10]=[CH:11][C:6]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][C:8]=2[OH:12])=[N:18][CH:19]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:21]=1
Reactant: NNc1ncc(C(F)(F)F)cc1Cl
Reactant: CCN(CC)c1cccc(O)c1
Agent: II
Agent: OO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: CCN(CC)c1ccc(N=Nc2ncc(C(F)(F)F)cc2Cl)c(O)c1

Procedure:
Next, a reaction flask was loaded with 3-(N,N-diethlyamino)phenol (1.3 g), dimethylformamide (9 ml), acetic acid (3 ml) and iodine (0.14 g), and they were mixed, followed by addition of 3-chloro-2-hydrazino-5-trifluoromethylpyridine (1.0 g) to the flask with stirring. Then, to this mixture, a 30 % hydrogen peroxide water (1.4 g) was dropwise added in one hour and the mixture was stirred overnight. Water was added to this reaction mixture, followed by extraction with ether. The organic layer was condensed to precipitate crystals. The crystals were filtrated for collection and dried to give intended crystals (0.5 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:18]=[CH:17][CH:16]=[N:15][C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:19]1([C:2]2[N:3]=[C:4]3[CH:18]=[CH:17][CH:16]=[N:15][C:5]3=[N:6][C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(-c2nc3ncccc3nc2Cl)cc1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(-c2nc3ncccc3nc2-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-3-p-tolyl-pyrido[2,3-b]pyrazine (800 mg, 3.13 mmol), phenylboronic acid (572 mg, 4.69 mmol) and K2CO3 (1297 mg, 9.39 mmol) in dioxane (10 ml) was degassed by bubbling nitrogen through (×3). PdCl2(dppf) (229 mg, 0.313 mmol) was added and the reaction mixture was degassed by bubbling nitrogen through (×3). The resulting mixture was heated using microwave radiation at 150° C. for 2 hours. PdCl2(dppf) (229 mg, 0.313 mmol) was added and the mixture was heated using microwave radiation at 150° C. for 2 hours. After cooling to RT, the mixture was diluted with water and EtOAc, and filtered through Celite® (filter material). The phases were separated and the aqueous extracted with EtOAc The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by chromatography on silica eluting with 2-5% THF/DCM to give a contaminated gum. The material was re-purified by chromatography on silica eluting with 0-60% EtOAc/iso-hexane to afford the title compound;
Reaction SMILES: [F:1][C@@H:2]1[C:25]2[C@:20](C)([CH:21]=[CH:22][C:23](=[O:26])[CH:24]=2)[C:19]2[C@H:4]([C@H:5]3[C@:16]([CH3:28])([CH2:17]C=2)[C@@:8]([O:29][C:30](=[O:32])[CH3:31])([C:9](=[O:15])[CH2:10][O:11][C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:33])[CH2:6]3)[CH2:3]1.Br[C:35]1([Br:42])NC(=O)N[C:36]1=[O:41].C(OCC)(=O)C>O1CCOCC1.O>[F:1][C@@H:2]1[C:25]2[C@:20]([CH3:19])([CH:21]=[CH:22][C:23](=[O:26])[CH:24]=2)[C@:35]2([Br:42])[C@H:4]([C@H:5]3[C@:16]([CH3:17])([CH2:28][C@@H:36]2[OH:41])[C@@:8]([O:29][C:30](=[O:32])[CH3:31])([C:9](=[O:15])[CH2:10][O:11][C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:33])[CH2:6]3)[CH2:3]1
Reactant: O=C1NC(=O)C(Br)(Br)N1
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)[C@@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)C3=CC[C@@]21C
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)OCC(=O)[C@@]1(OC(C)=O)[C@@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(Br)[C@@H](O)C[C@@]21C
Reaction time: 0.17 h

Procedure:
Ten (10) g of 6α-fluoro-16β-methyl-17α,21-diacetoxypregna-1,4,9(11)-triene-3,20-dione in 110 ml of dioxane (A.R.) plus 2.2 mls of a solution of 4.4 ml 70% HClO4 in 200 mls of water, is treated with 4 g of dibromohydantoin in the dark at R.T. for a period of one hour or when TLC using 50% ethyl acetate/50% hexane shows the reaction to be complete. The reaction mixture is precipitated in 2 l of water, stirred for 10 minutes and the crystalline precipitate collected by filtration, washed with water, and air dried to give 11.4 g of 6α-fluoro-9α-bromo-11β-hydroxy-16β-methyl-17α,21-diacetoxypregna-1,4-diene-3,20-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[F:73][C:74]1[CH:81]=[C:80]([F:82])[CH:79]=[CH:78][C:75]=1[CH2:76][NH2:77].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:77][CH2:76][C:75]1[CH:78]=[CH:79][C:80]([F:82])=[CH:81][C:74]=1[F:73]
Reactant: NCc1ccc(F)cc1F
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(F)cc3F)c2CC1)C(F)(F)F
Temperature: 100 °C
Yield: 76.1 %

Procedure:
Use a method similar to the General Procedure 5-1 to react 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (3 g, 7.06 mmol), palladium(II) acetate (0.16 g, 0.71 mmol), BINAP (0.88 g, 1.41 mmol), 2,4-difluorobenzylamine (3.03 g, 21.18 mmol) and cesium carbonate (3.22 g, 9.88 mmol) in degassed toluene (120 mL). Degas the mixture with vacuum/nitrogen purge and heat to 100° C. for 16 h. Cool the mixture to room temperature, dilute with EtOAc, filter through Celite® and concentrate in vacuo to give a brown oil. Purify the crude mixture by chromatography on silica gel eluting with hexane and then hexane/THF (95:5) to obtain 7-chloro-6-(2,4-difluorobenzylamino)-3-(2,2,2,trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as oil (2.25 g, 76%). MS (ES+) m/z: 419 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[C:10]([C:19]([OH:21])=O)=[CH:9]2)=[CH:4][CH:3]=1.O=S(Cl)[Cl:24]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[C:10]([C:19]([Cl:24])=[O:21])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2ccccc2c1=O
Product: O=C(Cl)c1cn(-c2ccc(F)cc2)c2ccccc2c1=O
Yield: 95.1 %

Procedure:
A mixture of intermediate k 2 g (0.007 moL) and sulfoxide chloride (20 mL) was heated to reflux for 6 h, the excess sulfoxide chloride was evaporated in vacuo to obtain white solid 2 g. Yield: 95.1%.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:4]([CH:7]=[C:8]([S:10][CH3:11])[CH:9]=1)[CH:5]=O.Cl.[NH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]1[NH:32][C:31]2[CH:33]=[CH:34][S:35][C:30]=2[C:29](=[O:36])[CH:28]=1>>[Br:1][C:2]1[C:3]([O:12][CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:4]([CH:7]=[C:8]([S:10][CH3:11])[CH:9]=1)[CH2:5][NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]1[NH:32][C:31]2[CH:33]=[CH:34][S:35][C:30]=2[C:29](=[O:36])[CH:28]=1
Reactant: CSc1cc(Br)c(OCCc2cccnc2)c(C=O)c1
Reactant: NCCCNc1cc(=O)c2sccc2[nH]1
Agent: Cl
Product: CSc1cc(Br)c(OCCc2cccnc2)c(CNCCCNc2cc(=O)c3sccc3[nH]2)c1

Procedure:
5-{3-[3-Bromo-5-methylsulfanyl-2-(2-pyridin-3-yl-ethoxy)-benzylamino]-propylamino}-4H-thieno[3,2-b]pyridin-7-one was prepared by reductive amination of the aldehyde prepared in Example 2 with amine XVIII following method C, Scheme 1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[N+:11]([O-])([O-:13])=[O:12].[K+]>[N+]([O-])([O-])=O.[K+].OS(O)(=O)=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 94.7 %

Procedure:
To mechanically stirred conc. H2SO4 (700 mL) at 3° C. was added p-hydroxyacetophenone (66.0 g, 480 mmol) followed by KNO3 (48.3 g, 477 mmol) in two approximately equal portions about four minutes apart. An additional 3.76 g of KNO3 was added after 1.67 hours to insure reaction completion. The reaction was slowly poured into 8 L crushed ice/water and extracted with 4 L ethyl acetate (EtOAc). The extract was concentrated in vacuo to a volume of ~1.25 L, 500 mL heptane were added and concentration was continued. Once a thick yellow suspension formed at 50° C., it was cooled to ~10° C. and filtered. The collected solids were washed with ~150 mL heptane and dried in vacuo at ~40° C. to give 81.8 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[NH:16])=[O:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=1)[C:25](O)=[O:26]>>[Br:19][C:20]1[CH:28]=[C:24]([C:25]([N:16]=[S:14]([C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:6](=[O:18])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:9][CH:10]=2)([CH3:17])=[O:15])=[O:26])[CH:23]=[N:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(S(C)(=N)=O)cc1
Reactant: O=C(O)c1cncc(Br)c1
Product: CC(C)(C)OC(=O)Nc1ccc(S(C)(=O)=NC(=O)c2cncc(Br)c2)cc1
Yield: 74.6 %

Procedure:
In a manner similar to that described in Example 480 (step 6), tert-Butyl[4-(S-methylsulfonimidoyl)phenyl]carbamate (0.141 g, 0.522 mmol) and 5-bromonicotinic acid (0.104 g, 0.522 mmol), were converted to the title compound (0.177 g, 75%).
Reaction SMILES: CC([N:5]=[C:6]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[CH2:15][CH2:14][CH2:13]2)[CH2:7][CH2:8][CH3:9])(C)C.[CH:21]([C:30]([O:32][CH3:33])=[O:31])([C:26](OC)=[O:27])[C:22](OC)=[O:23]>COCCOCCOC>[CH2:8]([C:7]1[C:22]([OH:23])=[C:21]([C:30]([O:32][CH3:33])=[O:31])[C:26](=[O:27])[NH:5][C:6]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[CH2:15][CH2:14][CH2:13]2)[CH3:9]
Reactant: COC(=O)C(C(=O)OC)C(=O)OC
Reactant: CCCC(=NC(C)(C)C)c1ccc2c(c1)CCCN2C
Solvent: COCCOCCOC
Product: CCc1c(-c2ccc3c(c2)CCCN3C)[nH]c(=O)c(C(=O)OC)c1O
Temperature: 160 °C
Reaction time: 4 h
Yield: 6.1 %

Procedure:
To a suspension of 2-methyl-N-(1-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)butylidene)propan-2-amine (1.96 g, ca. 7.2 mmol), prepared according to procedure described in Example 1 Step 6, in diglyme (7 mL) was added trimethyl methanetricarboxylate (2.33 g, 12.2 mmol, 1.7 eq). The reaction was stirred at 160° C. for 4 h then cooled to room temperature. The precipitate was collected by filtration then washed with Et2O to afford the title compound as a yellow solid (150 mg, 0.44 mmol, 6.5% over two steps).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4][C:3]1=[O:12].[Cl-].[Al+3].[Cl-].[Cl-].[C:17]([CH2:21][CH:22]([CH3:26])[C:23](Cl)=[O:24])([O:19][CH3:20])=[O:18]>C(=S)=S>[C:17]([CH2:21][CH:22]([CH3:26])[C:23]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[N:2]([CH3:1])[C:3](=[O:12])[NH:4][CH2:5]2)=[O:24])([O:19][CH3:20])=[O:18]
Reactant: CN1C(=O)NCc2ccccc21
Reactant: COC(=O)CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)CC(C)C(=O)c1ccc2c(c1)CNC(=O)N2C
Temperature: 25 °C

Procedure:
3,4-Dihydro-1-methyl-2(1H)-quinazolinone (2.5 g) is added to a stirred suspension of anhydrous aluminum chloride (10.5 g) in carbon disulfide (120 ml) under nitrogen. 3-Carbomethoxy-2-methyl-propionyl chloride (2.5 g) is added dropwise to the stirred suspension, which is refluxed for about 18 hours and cooled to RT. The liquid phase is decanted and the residue treated with ice/H2O and 6N HCl (25 ml). The aqueous mixture is extracted with methylene chloride, the organic extract dried, filtered and concentrated in vacuo, affording the desired product as an oil which is used in the next step without further purification.
Reaction SMILES: C(O[C:4](=[O:19])[C:5]([F:18])([F:17])[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[OH:7])C.[CH:20]([NH2:23])([CH3:22])[CH3:21]>CCO>[CH3:21][CH:20]([NH:23][C:4](=[O:19])[C:5]([F:17])([F:18])[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[OH:7])[CH3:22]
Reactant: CC(C)N
Reactant: CCOC(=O)C(F)(F)C(O)c1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: CC(C)NC(=O)C(F)(F)C(O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a solution of the ester from Step 1 (1.50 g, 5.45 mmol) in EtOH (20 mL) was added isopropylamine (1.86 mL, 21.8 mmol). The solution was heated to reflux for 20 h and cooled to ambient temperature. Concentration under a nitrogen atmosphere afforded the amide quantitatively: Anal. Calc'd. for C12H14F2N2O4 plus 0.15 mol H2O: C, 49.54; H, 4.95; N, 9.63. Found: C, 49.52; H, 5.52; N, 9.46.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:13]([NH:20][C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: NCc1ccccc1
Solvent: CCO
Product: OC[C@H]1O[C@@H](NCc2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 48 h

Procedure:
50 g of D-glucose were dissolved in 1,000 ml of hot ethanol and, after addition of 89 g of benzylamine, were left at room temperature for 48 hours. The mixture was then cooled with ice and the product was precipitated with petroleum ether. It was filtered off with suction, washed with ether and dried in vacuo.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=2[O:8][CH2:9][C:10]([O:12]CC)=O)=[N:2]1.[NH2:19][CH2:20][CH:21]([OH:33])[CH2:22][N:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1>CCO.C(OCC)(=O)C>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=2[O:8][CH2:9][C:10]([NH:19][CH2:20][CH:21]([OH:33])[CH2:22][N:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)=[O:12])=[N:2]1
Reactant: CCOC(=O)COc1ccccc1-c1cc[nH]n1
Reactant: NCC(O)CN1CCc2ccccc2C1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(COc1ccccc1-c1cc[nH]n1)NCC(O)CN1CCc2ccccc2C1
Temperature: 120 °C
Yield: 51 %

Procedure:
To a solution of ethyl 2-(2-(1H-pyrazol-3-yl)phenoxy)acetate (100 mg, 0.41 mmol) in EtOH (10 mL) was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (84 mg, 0.41 mmol). The mixture was stirred at 120° C. under microwave heating for 2 h. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with water (10 mL), dried over Na2SO4 and concentrated to give the crude product. The residue was purified by prep-HPLC to afford the desired title compound (85 mg, 44%). 1H NMR (400 MHz, MeOD): δ 7.71-7.69 (m, 2H), 7.34-7.33 (m, 1H), 7.10-7.01 (m, 6H), 6.74 (d, J=2 Hz, 1H), 4.67 (s, 1H), 4.04-4.02 (m, 1H), 3.67 (s, 2H), 3.50-3.49 (m, 1H), 3.37-3.33 (m, 1H), 2.89-2.87 (m, 2H), 2.81-2.78 (m, 2H), 2.58-2.57 (m, 2H) ppm; ESI-MS (m/z): 469.3 [M+1]+.
Reaction SMILES: [OH-].[K+].[OH-].[Na+].C([O:7][C:8]([C:10]1([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)=[O:9])C>O.C(O)C>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][C:10]([CH2:23][CH:24]([CH3:26])[CH3:25])([C:8]([OH:9])=[O:7])[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)C1(CC(C)C)CCN(C(=O)OC(C)(C)C)CC1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)CC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
A solution of potassium hydroxide (85% assay, 2.69 g, 0.041 mol) and sodium hydroxide (1.94 g, 0.048 mol) in demineralized water (8 mL) is added to a solution of 4-isobutylpiperidine-1,4-dicarboxylic acid-1-tertbutyl ester-4-ethyl ester (0.95 g, 0.003 mol) in ethanol (15 mL). The reaction mixture is refluxed for 48 hrs. It is cooled to room temperature, concentrated under reduced pressure, and then treated with demineralized water (10 mL). The pH is adjusted to ˜3-4 using 2N HCl (10 mL) and the aqueous layer is extracted with ethyl acetate (2×15 mL). The combined extract is dried over sodium sulfate. Removal of solvent gives a crude residue which is purified by column chromatography (230-400 mesh, ethyl acetate:n-hexane 1:3) to furnish 4-isobutylpiperidine-1,4-dicarboxylic acid monotertbutyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.CO[CH:17]1[CH2:21][CH2:20][CH:19](OC)O1.C>C1(C)C=CC=CC=1.C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)[CH:17]=[CH:21][CH:20]=[CH:19]1
Reactant: COC1CCC(OC)O1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Agent: C
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C=Cc1ccc(-n2cccc2)cc1

Procedure:
A solution of ethyl 4-aminocinnamate (1 g) and 2,5-dimethoxytetrahydrofuran (0.677 ml) in toluene (3 ml) and acetic acid (3 ml) was refluxed for 5 hours with removing methane. After cooling, the mixture was washed with water twice and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo. The residue was purified with column chromatography eluting with n-hexane-ethyl acetate to give ethyl 4-(1-pyrrolyl)cinnamate (740 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([C:3]([CH3:14])([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([OH:6])=O)[CH3:2]>O>[CH2:1]([C:3]1([CH3:14])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]1=[O:6])[CH3:2]
Reactant: CCC(C)(Cc1ccccc1)C(=O)O
Solvent: O
Product: CCC1(C)Cc2ccccc2C1=O

Procedure:
69 g of α-ethyl-α-methyl-dihydrocinnamic acid are added dropwise at 150°, within 5 minutes, to 700 g of polyphosphoric acid, while stirring. The reaction mixture is stirred at 160° for a further 10 minutes, is cooled to 100° and 100 cc of water are added dropwise. The reaction mixture is then poured on ice, extracted with ether, the ether extract is washed with water and dried over sodium sulphate. The 2-ethyl-2-methyl-1-indanone, obtained after evaporating the solvent, is purified by distillation. B.P. 137°-140° at 20 mm of Hg.
Reaction SMILES: [Na].Br[C:3]1[N:11]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]2[C:9](=[O:17])[N:8]([CH2:18][CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[C:7](=[O:29])[N:6]([CH3:30])[C:5]=2[N:4]=1.Cl.[CH:32]([OH:35])([CH3:34])[CH3:33]>O>[OH:21][CH2:20][CH2:19][CH2:18][N:8]1[C:9](=[O:17])[C:10]2[N:11]([CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[C:3]([O:35][CH:32]([CH3:34])[CH3:33])=[N:4][C:5]=2[N:6]([CH3:30])[C:7]1=[O:29]
Reactant: CC(C)O
Reactant: CC(C)CCn1c(Br)nc2c1c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C
Agent: Cl
Agent: [Na]
Solvent: O
Product: CC(C)CCn1c(OC(C)C)nc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Sodium (0.12 g, 5.15 mmol) was dissolved in isopropanol (8 mL) and 8-bromo-1-(3-((tert-butyldimethylsilyl)oxy)propyl-7-isopentyl-3-methyl-1H-purine-2,6(3H,7H)-dione (0.50 g, 1.03 mmol, intermediate 82) was added. The reaction was stirred at room temperature for 15 h. The reaction was treated with 6N HCl to achieve pH=1, and stirred at room temperature for 1 h. The reaction was diluted with water (100 mL) and extracted with DCM (3×75 mL). The combined extracts were dried with magnesium sulfate, filtered and evaporated under reduced pressure to leave a golden oil. The oil was purified using two 2000 micron preparative TLC plate eluted with 50% ethyl acetate/hexanes to give 1-(3-hydroxypropyl)-7-isopentyl-8-isopropoxy-3-methyl-1H-purine-2,6(3H,7H)-dione (0.27 g, 75 yield) as a white solid. LCMS retention time=3.325 min and 97% purity, LCMS MH+=353. 1H NMR (CDCl3) δ 5.20-5.30 (m, 1H), 4.17 (t, 2H, J=8 Hz), 4.07 (t, 2H, J=8 Hz), 3.73 (t, 1H, J=8 Hz), 3.45-3.54 (m, 5H), 1.85-1.93 (m, 2H), 1.58-1.66 (m, 2H), 1.48-1.57 (m, 1H), 1.42 (d, 6H, J=8 Hz), 0.94 (d, 6H, J=8 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][CH:18]=[CH2:19])=[CH:12][CH:11]=2)[CH:3]=1.[Zn](CC)[CH2:21]C.ICI>C(OCC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][CH:18]3[CH2:21][CH2:19]3)=[CH:12][CH:11]=2)[CH:3]=1
Reactant: CC[Zn]CC
Reactant: C=COCc1ccc(Cc2cc(Br)ccc2Cl)cc1
Solvent: ICI
Solvent: CCOCC
Product: Clc1ccc(Br)cc1Cc1ccc(COC2CC2)cc1
Reaction time: 8 h

Procedure:
To a stirred mixture of 4-bromo-1-chloro-2-(4-(vinyloxymethyl)benzyl)benzene (0.7 g, 2.07 mmol) and Et2Zn (5.18 mL, 5.18 mmol, 1.0 M in hexane) in dry ethyl ether (10 mL) was added diiodomethane (0.42 mL, 5.18 mmol) dropwise during 20 min at room temperature under argon. After stirring overnight, the reaction mixture was poured slowly into ice cold dilute hydrochloride solution with stirring. The mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (20 mL) and then with brine (20 mL), and then dried over sodium sulfate. The residue was concentrated and purified by column chromatography (eluent EA:PE=1:200) to obtain intermediate CV (0.6 g) as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ 7.33˜7.24 (m, 5H), 7.18 (d, 2H), 4.55 (s, 2H), 4.07 (s, 2H), 3.40˜3.37 (m, 1H), 0.69˜0.49 (m, 4H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12]O)=[N:10][C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:40]>ClCCl>[Br:40][CH2:12][C:11]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1nc(-c2ccccc2)nn1-c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1nc(-c2ccccc2)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 193.3 %

Procedure:
To a suspension of (1,3-diphenyl-1H-1,2,4-triazol-5-yl)methanol (350 mg, 1.39 mmol) and triphenylphosphine polymer bound (679 mg, 2.02 mmol) in dichloromethane (6 mL) was added at 0-5° C. carbon tetrabromide (670 mg, 2.02 mmol). The ice bath was removed and the mixture was stirred at RT for 18 h. The suspension was filtered, washed with dichloromethane and evaporated to give 844 mg of yellow oil. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as colorless solid (267 mg, 850 μmol, 61.0%).
Reaction SMILES: [C:1]1([S:7]([CH:10]([CH3:25])[CH:11]([CH3:24])[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([C:20]([F:23])([F:22])[F:21])[CH2:16][CH2:15]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26]I>>[C:1]1([S:7]([C:10]([CH3:26])([CH3:25])[CH:11]([CH3:24])[CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([C:20]([F:23])([F:22])[F:21])[CH2:18][CH2:19]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(CCN1CCC(C(F)(F)F)CC1)C(C)S(=O)(=O)c1ccccc1
Reactant: CI
Product: CC(CCN1CCC(C(F)(F)F)CC1)C(C)(C)S(=O)(=O)c1ccccc1

Procedure:
Prepared from 1-(4-benzenesulfonyl-3-methylpentyl)-4-trifluoromethylpiperidine (example 126) and methyl iodide by the method of Example 187.