Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH2:12][CH:13]([OH:15])[CH3:14])[CH:3]=1.N1C=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([O:15][CH:13]([CH3:14])[CH2:12][CH2:11][C:4]1[CH:3]=[C:2]([OH:1])[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=1)(=[O:24])[CH3:23]
Reactant: CC(O)CCc1cc(O)n2nccc2n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC(C)CCc1cc(O)n2nccc2n1

Procedure:
The crystals obtained in step (3) (4.16 g) were dissolved in 40 ml of acetic anhydride and 40 ml of pyridine and stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was recrystallized from methanol-diethyl ether to provide 4.2 g of 5-(3-acetoxybutyl)-7-hydroxypyrazolo[1,5-a]pyrimidine as colorless crystals.
Reaction SMILES: Br[C:2]1[Se:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([F:19])[C:11]=1[F:20])[CH3:8].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:7]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[Se:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([F:19])[C:11]=1[F:20])[CH3:8]
Reactant: Brc1ccc[se]1
Reactant: CCOc1ccc(B(O)O)c(F)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2ccc[se]2)c(F)c1F

Procedure:
A mixture of 45.0 g (0.21 mol) of 2-bromoselenophene, 52.0 g (0.26 mol) of 4-ethoxy-2,3-difluorophenylboronic acid, 20.0 g (17.3 mmol) of tetrakis(triphenylphosphine)palladium(0) and 600 ml of 2 N sodium carbonate soln. in 1100 ml of toluene/ethanol (1:1) is heated under reflux for 20 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted with toluene. The combined organic phases are washed with sat. sodium hydrogencarbonate soln., 1 N hydrochloric acid and sat. sodium chloride soln. The solution is dried using sodium sulfate and concentrated to dryness. The residue is purified by column chromatography (SiO2, n-heptane:toluene=3:2). Further purification is carried out by recrystallisation from ethanol; 2-(4-ethoxy-2,3-difluorophenyl)selenophene is obtained as a beige solid.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[S:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[C:35](Cl)=[O:36]>C(Cl)Cl>[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[CH2:21][N:20]([C:35]([C:31]2[S:30][CH:34]=[CH:33][CH:32]=2)=[O:36])[CH2:19][CH2:18]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: c1cc2c(c(OCCCN3CCCCC3)c1)CNCC2
Reactant: O=C(Cl)c1cccs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccs1)N1CCc2cccc(OCCCN3CCCCC3)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
To a mixture of 8-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride salt (300 mg, 0.86 mmol) and NEt3 (0.36 mL, 2.6 mmol) in CH2Cl2 (10 mL) is added 2-thiophene carbonyl chloride (0.10 mL, 0.95 mmol). After stirring at room temperature overnight, the mixture is partitioned between EtOAc and water. The organic phase is washed with brine, dried (MgSO4), and concentrated. The residue is purified by flash chromatography [Biotage 40S SiO2, elute 20% (90/10/1 CH2Cl2/MeOH/NH4OH)/80% CH2Cl2 to 100% (90/10/1 CH2Cl2/MeOH/NH4OH)] to yield the title compound as a yellow oil (0.181 g, 55%). MS (ES+) 385.3.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:15][CH3:16])[C:10]=2[Br:14])[CH:5]=1)(=[O:3])[CH3:2].C[O-].[Na+].Cl.[C:21](OCC)(=[O:23])[CH3:22]>>[Br:14][C:10]1[C:9]([O:15][CH3:16])=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:12]=[CH:13][C:4]([C:1]([OH:3])=[CH:2][C:21](=[O:23])[CH3:22])=[CH:5]2
Reactant: CCOC(C)=O
Reactant: COc1ccc2cc(C(C)=O)ccc2c1Br
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: COc1ccc2cc(C(O)=CC(C)=O)ccc2c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
139.4 Grams (0.499 moles) of 2-acetyl-5-bromo-6-methoxynaphthalene and 1450 ml of ethyl acetate are placed in a flask equipped with refrigerator and stirrer and, under stirring and at the temperature of 45° C., 30 g (0.556 moles) of sodium methoxide are added. The temperature of the reaction mixture goes up to 55° C. and is kept at 65° C. for one hour, then other 10 g (0.185 moles) of sodium methoxide are added and, after half an hour, still other 10 g (0.185 moles) of sodium methoxide, always under stirring and keeping the temperature at 65° C. for another hour and half. The reaction mixture is then cooled to room temperature and brought to pH 4 by adding a concentrated aqueous solution of hydrochloric acid. The reaction mixture is then heated to reflux for 15 minutes, cooled to 5° C. in one hour and kept at this temperature for 2 hours. The precipitated solid is filtered, abundantly washed with water on the filter, then washed with ethyl acetate and dried in oven under vacuum obtaining 145.7 g of product with a yield equal to 90.8%.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[N:38]=[N:39][N:40](COCC4C=CC=CC=4)[N:41]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.Cl>CO>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:37]4[NH:38][N:39]=[N:40][N:41]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4nnn(COCc5ccccc5)n4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: CO
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4nnn[nH]4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 115.4 %

Procedure:
A mixture of 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(2-benzyloxymethyl-2H-tetrazol-5-yl)-2-thienylmethyl)-4-chlorobenzene (247 mg), 6M aqueous hydrochloric acid solution (2 ml) and methanol (20 ml) was refluxed overnight. The solvent was evaporated under reduced pressure and the residue was triturated with diethyl ether to give the desired 1-(β-D-glucopyranosyl)-4-chloro-3-(5-(1H-tetrazol-5-yl)-2-thienylmethyl)benzene (172 mg) as colorless powder. ESI-Mass m/Z 437/439 (M−H).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)O[C:4](=[O:18])[CH2:3]1.C(N(CC)CC)C.[NH:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[NH2:27]>ClCCl>[CH2:31]([O:30][C:28]([NH:26][N:27]1[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)=[CH:7][CH:2]([CH3:1])[CH2:3][C:4]1=[O:18])=[O:29])[CH3:32]
Reactant: CCOC(=O)NN
Reactant: CC1C=C(c2cccc(C(F)(F)F)c2)OC(=O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NN1C(=O)CC(C)C=C1c1cccc(C(F)(F)F)c1

Procedure:
A solution of 4 g (16 mmol) of 3,4-dihydro-4-methyl-6-(3'-trifluoromethylphenyl)-2-(1H)-pyrone in 100 ml dichloromethane is treated with 5.6 ml of triethylamine and 7.31 g (70 mmol) of ethyl hydrazinoformate, and the mixture is refluxed for 8 hours. After cooling, the reaction solution is washed alternately with distilled H2O, dilute HCl and distilled H2O, dried over Na2SO4 and concentrated on a rotary evaporator. The oil which remains is taken up in 150 ml of toluene, the solution is treated with a spatula-tip full of PTSA and the mixture is refluxed on a water separator until the reaction is complete. For working-up, the reaction solution is washed first with dilute K2CO3 solution and then with distilled H2O and subsequently dried over Na2SO4. The oil obtained after the solvent has been evaporated in vacuo is purified by column chromatography on silica gel (eluent: toluene:acetone=95:5).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][CH:25]([F:49])[CH2:26][C@@H:27]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:28]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-])=O)=[CH:37][CH:36]=1)(=[O:34])=[O:33])[CH:29]([CH3:31])[CH3:30])=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][CH:25]([F:49])[CH2:26][C@@H:27]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:28]([S:32]([C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])[CH:29]([CH3:31])[CH3:30])=[O:21])[CH:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:4]
Reactant: CCOC(=O)[C@H](CC(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)N(C(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CC(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)N(C(C)C)S(=O)(=O)c1ccc(N)cc1
Reaction time: 8 h
Yield: 77.9 %

Procedure:
To the material from Step 6 (31 mg, 0.044 mmol) and 10% palladium on carbon (5 mg, 0.004 mmol) was added ethyl acetate (0.5 mL). The reaction mixture was purged with nitrogen, and stirred under hydrogen (1 atm) overnight. Upon addition of DCM, the reaction mixture was filtered through celite, washed with dichloromethane, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel using ethyl acetate-hexanes (0:100 to 90:10) to afford 23 mg of the title compound as a colorless foam. LCMS (M+1)=671.
Reaction SMILES: [C:1]12[C:12]([NH:13][CH:14]3[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]3)=[N:11][CH:10]=[N:9][C:8]=1[S:7][C:6]1[CH2:5][CH2:4][CH2:3][C:2]2=1.C(S(O[CH2:29][C:30]([F:33])([F:32])[F:31])(=O)=O)(F)(F)F.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:1]12[C:12]([NH:13][CH:14]3[CH2:19][CH2:18][CH:17]([NH:20][CH2:29][C:30]([F:33])([F:32])[F:31])[CH2:16][CH2:15]3)=[N:11][CH:10]=[N:9][C:8]=1[S:7][C:6]1[CH2:5][CH2:4][CH2:3][C:2]2=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: NC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: FC(F)(F)CNC1CCC(Nc2ncnc3sc4c(c23)CCC4)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a 50 mL round-bottom flask containing a solution of 1-N-[7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]cyclohexane-1,4-diamine (288 mg, 1.00 mmol, 1.00 equiv) in DMF (10 mL) was added F3CSO3CH2CF3 (700 mg, 3.02 mmol, 3.00 equiv) and DBU (457 mg, 3.01 mmol, 3.00 equiv) in ice-water bath under nitrogen. The resulting solution was stirred overnight at 60° C. After completion of the reaction, the reaction solution was cooled down to room temperature and then quenched with water, diluted with DCM (30 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/methanol (30:1 to 20:1) to provide the desired 1-N-[7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]-4-N-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (300 mg, 81%) as a white solid. MS (electrospray) m/z 371 (M+H)+; 1H NMR (400 MHz, CD3OD): 8.22 (s, 1H), 4.06-4.14 (m, 1H), 3.24-3.32 (q, 2H), 3.01 (t, 2H), 3.07 (t, 2H), 2.51-2.78 (m, 3H), 2.04-2.15 (m, 4H), 1.43-1.55 (m, 2H), 1.28-1.35 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([C:37]([O:39]CC)=[O:38])([CH3:36])[CH3:35])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[F:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([C:37]([OH:39])=[O:38])([CH3:35])[CH3:36])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[F:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Br)cc1C1CC(=O)NC(c2cc(F)ccc2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(Oc1ccc(Br)cc1C1CC(=O)NC(c2cc(F)ccc2F)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Temperature: 70 °C
Yield: 67.9 %

Procedure:
To a mixture of racemic (2′R,3S,4′R)-4′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(2,5-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (120 mg, 0.19 mmol) in methanol (4 mL) was added a solution of NaOH (24 mg, 0.6 mmol) in water (2 mL). The mixture was heated at 70° C. for 3 h, evaporated to remove most of methanol, cooled to room temperature, and acidified to “pH” 1 with aqueous HCl solution. The precipitate was collected and dried to give product as a white solid (80 mg). m/z (M+H)+: 619
Reaction SMILES: Cl.[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:4])[CH3:3].[CH3:32][N:33]([CH3:38])[S:34](Cl)(=[O:36])=[O:35]>>[CH3:32][N:33]([CH3:38])[S:34]([N:29]1[CH2:28][CH2:27][N:26]([C:24]([C:6]2[N:5]([CH:2]([CH3:3])[CH3:4])[C:13]3[C:8]([CH:7]=2)=[CH:9][C:10]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)=[CH:11][CH:12]=3)=[O:25])[CH2:31][CH2:30]1)(=[O:36])=[O:35]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3C(C)C)CC1
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)N(C)C)CC2)n3C(C)C)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-isopropyl-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and dimethylsulfamoyl chloride. Light-yellow foam. MS (m/z): 520.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][CH:14]=[C:13]2[C:17]#[N:18])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH:24]([O:26]C)Cl>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([CH:24]=[O:26])[CH:14]=[C:13]2[C:17]#[N:18])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: COC(Cl)Cl
Reactant: CCOC(=O)c1ccc(-n2cccc2C#N)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)c1ccc(-n2cc(C=O)cc2C#N)cc1
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a mixture of 1-(4-ethoxycarbonylphenyl)pyrrole-2-carbonitrile (5.16 g) and aluminum chloride (5.72 g) in 1,2-dichloroethane (51 ml) was added a solution of dichloromethylmethyl ether (2.97 g) in 1,2-dichloroethane (5 ml) in one portion at -15° C. The mixture was stirred for one hour at the same temperature and then dichloromethylmethyl ether (0.6 g) was added therein. After stirring for 3 hours at 5° C., the reaction mixture was quenched with 10% hydrochloric acid. The separated organic layer was washed with 10% hydrochloric acid three times, dried, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted by 1% methanol in dichloromethane to yield 1-(4-ethoxycarbonylphenyl)-4-formylpyrrole-2-carbonitrile (2.96 g) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.OC=[C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C:15]1=[O:20]>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[C:8]2[C:6](=[CH:5][CH:4]=1)[NH:7][C:14]1[C:15](=[O:20])[CH2:16][CH2:17][CH2:18][C:19]2=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C1CCCCC1=CO
Product: O=C1CCCc2c1[nH]c1ccc(C(F)(F)F)cc21

Procedure:
6-(Trifluoromethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-one was prepared from 4-(trifluoromethyl)aniline (5.5 g, 34 mmol) and 2-(hydroxymethylene)cyclohexanone (3.9 g, 31 mmol) in a similar manner as described above to give 2.25 g (29%). of a dark brown solid. 1H-NMR (DMSO-d6): δ 12.05 (s, 1H), 8.11 (s, 1H), 7.56 (s, 2H), 3.00 (t, 2H), 2.58 (t, 2H), 2.19-2.13 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([O:12][Si](C)(C)C)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[Li+].[OH-].Cl>CO.O>[CH3:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(O[Si](C)(C)C)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(O)ccc1C(=O)O
Temperature: 0 °C
Yield: 31.6 %

Procedure:
A 100 mL round bottom flask equipped with magnetic stir bar was charged with 5.7 g methyl 2-methyl-4-trimethylsilyloxybenzoate and 2.0 g LiOH in 40 mL methanol and 10 mL water. After 2 hours at reflux the reaction was poured into 10 mL concentrated HCl and then 100 g ice. Extraction with ethyl acetate followed by concentration in vacuo gave a crude solid (70:30) product:starting material. Flash Chromatography using 50-50 ethyl acetate/hexanes as an eluent gave 1.15 g 2-methyl-4-hydroxybenzoic acid, m/e=193(M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([CH:14]=[O:15])=[CH:5][CH:4]=1.CC(=CC)C.[O-:21]Cl=O.[Na+]>CC(O)(C)C.O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([OH:21])=[O:15])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)c2c(C)cccc12
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(C(=O)O)c2c(C)cccc12

Procedure:
To a solution of 4-methoxy-8-methyl-1-naphthaldehyde (above Step-4 intermediate) (4.4 g, 22 mmol) in tBuOH (50 mL) and 2-methyl-2-butene (23.3 mL, 220 mmol) at 0° C. was added, a solution of NaClO2 (6.0 g, 66 mmol) and NaH2PO4 (9.1 g, 66 mmol) in water (40 mL) drop wise and the reaction mixture was stirred at RT overnight. After completion (TLC), the solvent was evaporated and the residue was basified with 10% NaOH solution and washed with CH2Cl2 (2×50 mL). The aqueous layer was then acidified with 1 N HCl and extracted with EtOAc (4×100 mL). The combined organic layer was washed with water (100 mL), brine (100 mL), dried and filtered. After removal of solvent, the desired compound was obtained (4.5 g, 95%) as an off white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[C:2]1=[N:11][OH:12].[H-].[Na+].Br[CH2:16][CH2:17][OH:18].O>CN(C)C=O>[OH:18][CH2:17][CH2:16][O:12][N:11]=[C:2]1[C:3](=[O:10])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:1]1
Reactant: O=C1C(=NO)Oc2ccccc21
Reactant: OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C(=NOCCO)Oc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
11.8 g (0.0725 mol) of benzofuran-2,3-dione 2-oxime (XI-1) (Stoermer, Kahlert, B. 35, 1644) are dissolved in 75 ml of dimethylformamide. With cooling, 3 g (0.075 mol) of 60% strength sodium hydride (mineral oil suspension) are added a little at a time and stirring is continued at a temperature of 25° C. for about one hour until the formation of gas has ceased. The mixture is then cooled to 0° C., and at this temperature 9.3 g (0.0744 mol) of 2-bromoethanol are added dropwise and stirring is continued at 25° C. for a further 24 hours. The reaction mixture is poured into water and the resulting mixture is extracted with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is distilled off under reduced pressure. The residue is recrystallized from a mixture of 150 ml of toluene and 100 ml of cyclohexane. 11.5 g (64% of theory) of benzofuran-2,3-dione 2-[O-(2-hydroxy-ethyl)-oxime] (VII-1) are obtained (content according to HPLC analysis: 83.5%). A sample recrystallized from toluenes has a melting point of 110-111° C.
Reaction SMILES: C([N:4]1[C:9]2=[CH:10][C:11]3[C:12](=[N:14][O:15][N:16]=3)[CH:13]=[C:8]2[O:7][C:6]([CH3:18])([CH3:17])[CH2:5]1)(=O)C.CO.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:17][C:6]1([CH3:18])[CH2:5][NH:4][C:9]2=[CH:10][C:11]3[C:12](=[N:14][O:15][N:16]=3)[CH:13]=[C:8]2[O:7]1
Reactant: CC(=O)N1CC(C)(C)Oc2cc3nonc3cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC1(C)CNc2cc3nonc3cc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
A mixture of 1.22 g 8-acetyl-7,8dihydro-6,6-dimethyl-6H-[1,2,5]oxadiazolo[3,4-g][1,4]benzoxazine, 40 ml methanol, 4 ml water and 1.37 g potassium carbonate was stirred at room temperature for one hour, the reaction mixture was poured into 300 ml ice water, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvents were distilled off from the dried solution, and the residue was subjected to column chromatography on silica gel. Elution was conducted by the use of a 2:1 mixture of hexane and ethyl acetate, giving 1.02 g of 7,8-dihydro-6,6-dimethyl-6H-[1,2,5]oxadiazolo[3,4-g][1,4]benzoxazine.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([NH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([N:23]2[CH2:22][CH2:21][CH:20]([NH:19][C:12](=[O:13])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:25][CH2:24]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Product: Cc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Yield: 87 %

Procedure:
Method 1 was followed using 4-fluoro-3-nitrotoluene (1.0 eq), 4-(N-Boc-amino) piperidine (1.2 eq), and TEA (1.5 eq) at 55° C. for 48 hours yielding tert-butyl 1-(4-methyl-2-nitro phenyl)piperidin-4-ylcarbamate (87%). LCMS (m/z): 336.1 (MH+); LC Rt=3.32 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][N:20]=1.O>C1COCC1>[CH3:26][O:25][C:23](=[O:24])[C:22]1[CH:27]=[CH:28][C:19]([O:14][CH2:13][C:12]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[N:10][C:11]=2[CH3:15])=[N:20][CH:21]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(C)nnn2-c2ccc(F)cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
A solution of [3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-yl]-methanol (425 mg, 2.05 mmol) in THF (3 mL) was added dropwise at 0° C. to a suspension of NaH (55% in oil, 100 mg, 2.05 mmol) in THF (6 mL) and the reaction mixture was then stirred at room temperature for 30 min. Then a solution of methyl 6-chloronicotinate (390 mg, 8.0 mmol) in THF (3 mL) was added dropwise at 0° C. and the reaction mixture stirred at room temperature for 20 h. The mixture was then poured into water extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 10 to 50% ethyl acetate in heptane) afforded the title compound (621 mg, 88%) as a white solid. MS: m/e=343.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=O>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:27][C:26]1[CH:29]=[CH:30][CH:31]=[C:24]([C:23]([F:22])([F:32])[F:33])[CH:25]=1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: O=Cc1cccc(C(F)(F)F)c1
Product: O=C(C=Cc1cccc(C(F)(F)F)c1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared from a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol) and 3-(trifluoromethyl)benzaldehyde (85 ul, 0.633 mmol) similar to Example 6 and isolated as a yellow solid (88 mg, 30%). 1H NMR (CDCl3): 7.86 (s, 1H), 7.76-7.50 (m, 5H), 7.35 (d, J=3.0 Hz, 1H), 7.14 (dd, J=3.3, 9.3 Hz, 1H), 6.94 (d, J=9.0 Hz, 1H), 4.47-4.32 (m, 4H).