Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]2[C:8]3[S:22][C:21]([CH2:23][CH3:24])=[CH:20][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N:11][CH2:12][C:6]2=[N:5][N:4]=1.[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>C(Cl)(Cl)Cl>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[C:9]2[CH:20]=[C:21]([CH2:23][CH3:24])[S:22][C:8]=2[N:7]2[C:3]([CH2:2][NH:1][C:33]([NH:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=3)=[O:34])=[N:4][N:5]=[C:6]2[CH2:12][N:11]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CCc1cc2c(s1)-n1c(CN)nnc1CN=C2c1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(s1)-n1c(nnc1CNC(=O)Nc1cccc(C)c1)CN=C2c1ccccc1Cl
Reaction time: 3 h
Yield: 100.1 %

Procedure:
9-Aminomethyl-4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (1.07 g) was dissolved in chloroform (50 ml). 3-Methylphenyl isocyanate (0.44 g) was added at room temperature, and the mixture was stirred for 3 hours. The reaction mixture was concentrated, and crystallized from ethyl acetate. The crude crystals were recrystallized from methanol to give 1.47 g of N-(4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepin-9-ylmethyl)-N'-(3-methylphenyl)urea.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:34])[C:18]2[CH:23]=[CH:22][C:21]([C@@H:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:25])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].O>O1CCCC1.CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH:17]([C:18]2[CH:19]=[CH:20][C:21]([C@@H:24]([NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH3:25])=[CH:22][CH:23]=2)[OH:34])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(=O)C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Agent: [Na]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)C2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.5 %

Procedure:
267 mg of the compound [22-1] was dissolved in a mixed solvent of 10 mL of tetrahydrofuran and 1 mL of methanol, then 22 mg of sodium boronhydride was added thereto, and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, which was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine in that order, and dried over anhydrous magnesium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0-30/70), to obtain 256 mg of benzyl-4-[(4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}phenyl)(hydroxy)methyl]piperidine-1-carboxylate [25-1] (hereinafter, referred to as the compound [25-1]).
Reaction SMILES: [CH3:1][C:2]12[CH2:17][CH:6]([N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:8]1=[O:9])[CH:5]=[CH:4][CH2:3]2.IC1C2CC(C)(C(=O)N2[C:27](OC(C)(C)C)=[O:28])CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[C:13]([O:12][C:10]([NH:7][CH:6]1[CH2:17][C:2]([CH3:1])([C:8]([O:28][CH3:27])=[O:9])[CH2:3][CH:4]=[CH:5]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2(C)CC=CC1C2
Reactant: CC(C)(C)OC(=O)N1C(=O)C2(C)CC=C(I)C1C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: COC(=O)C1(C)CC=CC(NC(=O)OC(C)(C)C)C1
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 1-methyl-7-oxo-6-azabicyclo[3.2.1]oct-3-ene-6-carboxylate, 52e, (4.93 g, 20.78 mmol) in MeOH (100 mL) was added cesium carbonate (13.54 g, 41.56 mmol). The reaction was stirred overnight and then concentrated in vacuo. The cesium salts were precipitated with Et2O and filtered. The ether filtrate was evaporated to give 5.5 g of a yellow oil that was used without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([NH2:21])=[N:9]2)=[CH:4][C:3]=1[CH3:22].Cl[C:24]1C=CC(N2C(C3C=CC(SC)=CC=3)=CC(N)=N2)=C[C:25]=1C>>[CH:3]([C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19][CH3:20])=[CH:17][CH:18]=3)=[CH:11][C:10]([NH2:21])=[N:9]2)=[CH:25][CH:24]=1)([CH3:22])[CH3:4]
Reactant: CSc1ccc(-c2cc(N)nn2-c2ccc(Cl)c(C)c2)cc1
Reactant: CSc1ccc(-c2cc(N)nn2-c2ccc(F)c(C)c2)cc1
Product: CSc1ccc(-c2cc(N)nn2-c2ccc(C(C)C)cc2)cc1

Procedure:
The following compounds described in (1) to (2) were obtained according to a similar manner to that of Preparation 3.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH:10]2[CH2:12][O:11]2)=[CH:6][CH:5]=1)([O-])=O.[CH3:15][NH:16][CH3:17]>C(O)C>[NH2:1][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH:10]([OH:11])[CH2:12][N:16]([CH3:17])[CH3:15])=[CH:6][CH:5]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(OCC2CO2)cc1
Solvent: CCO
Product: CN(C)CC(O)COc1ccc(N)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-nitro-phenoxymethyl)-oxirane (0.2 g, 1 mmol) in 2 mL of ethanol was added a solution of dimethylamine (2 M in methanol, 2.5 mL). The solution was stirred at 80° C. for 2 hours in a capped vial. The solvent was removed in vacuo. Hydrogenation of the residue using the procedure described in Example 1(f) gave the title compound as a brown solid. 1H NMR (300 MHz, CD3OD) δ (ppm): 6.76 (m, 2H), 6.71 (m, 2H), 4.20 (m, 1H), 3.88 (d, 2H), 3.04 (m, 2H), 2.71 (s, 6H).
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[Na].[CH2:14](Br)[CH2:15][CH2:16][CH3:17]>>[CH2:14]([O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:15][CH2:16][CH3:17]
Reactant: OCCCCCCCCCCO
Reactant: CCCCBr
Agent: [Na]
Product: CCCCOCCCCCCCCCCO
Yield: 62 %

Procedure:
Monosodium decane-1,10-diol is reacted with n-butyl bromide to give oily 10-n-butoxydecanol in a yield of 62% of theory. This is brominated with phosphorus tribromide in the presence of pyridine to give an oily product in a yield of 37% of theory. After reaction of this 10-n-butoxydecyl bromide with monosodium ethylene glycol, there is obtained oily 10-n-butoxydecyloxyethanol in a yield of 36% of theory, which is reacted with phosphorus tribromide in the presence of pyridine to give oily 10-n-butoxydecyloxyethyl bromide in a yield of 52% of theory. This is then reacted with methyl β-mercaptopropionate in the presence of sodium methylate to give a yield of 49% of theory of oily methyl β-(10-n-butoxydecyloxyethylthio)-propionate, reduction of which with lithium aluminium hydride gives a yield of 90% of theory of 3-(10-n-butoxydecyloxyethylthio]-propanol; m.p, 23°-27° C.
Reaction SMILES: [CH3:1][C:2]1([C:9]([O:11]CC)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.Cl.NO.[N:17]1C=CC=CC=1>CCO>[CH3:1][C:2]12[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[N:17][O:11][C:9]2=[O:10]
Reactant: CCOC(=O)C1(C)CCCCC1=O
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Solvent: CCO
Product: CC12CCCCC1=NOC2=O
Temperature: 65 °C

Procedure:
To a mixture of ethyl 1-methyl-2-oxo-cyclohexanecarboxylate, 37a, (2.05 g, 11.10 mmol) in EtOH (20 mL) was added hydroxylamine hydrochloride (0.97 g, 13.96 mmol) and pyridine (0.99 mL, 12.20 mmol). The mixture was heated to 65° C. overnight. The solution was concentrated in vacuo and the crude material was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc twice more. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified via silica gel chromatography (0-35% EtOAc/hexanes) to afford the desired product, 37b.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:4]=2[N:3]=1.Cl.C[C:22]1[NH:23]C=CN=1.O.NN.C([O-])([O-])OCC>C(O)C.CO>[Cl:19][C:16]1[CH:17]=[CH:18][C:4]2[N:3]3[CH:22]=[N:23][N:1]=[C:2]3[CH2:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]=2[CH:15]=1
Reactant: Cc1ncc[nH]1
Reactant: NC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Agent: CCOC([O-])[O-]
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CO
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nncn1-2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 8.1 parts of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine in 180 parts by volume of methanol are added 3.6 parts of 2-methylimidazole hydrochloride and 2.25 parts by volume of 80% hydrazine hydrate. The suspension is stirred at room temperature for 1.5 hours, and then 25 parts of ethyl orthoformate is added. To the mixture is added dropwise with stirring 60 parts by volume of ethanol containing 10% hydrogen chloride. After stirring for a further 1 hour, the mixture is warmed for a while so as to complete the reaction. After evaporation of the solvent, an aqueous solution of sodium bicarbonate is added to the residue to neutralize it. The mixture is then extracted with methylene chloride. The methylene chloride layer is washed with water and dried over sodium sulfate, followed by evaporation of the solvent. The residue is recrystallized from a mixture of acetone and n-hexane to give 8-chloro-6-phenyl-4H-s-triazolo [4,3-a][1,4] benzodiazepine as colorless flakes. Melting point; 226° C to 227° C.
Reaction SMILES: [CH:1]([NH:5][C:6](=[O:9])[CH2:7]Cl)([CH2:3][CH3:4])[CH3:2].[OH-:10].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH:1]([N:5]1[CH2:7][C:6](=[O:10])[N:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH2:7][C:6]1=[O:9])([CH2:3][CH3:4])[CH3:2]
Reactant: [OH-]
Reactant: CCC(C)NC(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC(C)N1CC(=O)N(C(C)CC)CC1=O
Temperature: 75 °C
Yield: 61.9 %

Procedure:
Toluene (75 ml), N-sec-butyl-2-chloracetamide (14.9 g, 0.10 mol), tetrabutylammonium hydrogen sulfate (1.7 g, 5×10-3 mol), and powdered sodium hydroxide (16.0 g, 0.40 mol) were charged into a 500 ml Morton flask equipped with a mechanical stirrer, thermometer and condenser. The reaction mixture was vigorously stirred and heated to 75° C. for one hour. The reaction mixture was cooled, filtered and solvent removed under reduced pressure. The resulting solids were recrystallized from ether to give 7.0 g (62%) of 1,4-di-sec-butyl-2,5-diketopiperazine as an off-white colored solid, mp 95.5°-97.5° C. Analytical results on the product were as follows: 1H NMR (CDCl3, TMS, 90 MHz) δ4.54 (septet, J=7 Hz, 2H), 3.78 (s, 4H), 1.45 (q, J=6 Hz, 4H), 1.10 (d, J=6 Hz, 6H), 0.83 (t, J=7 Hz, 6H) Mass spectrum, m/e =226 (parent). Anal. calcd. for C12H22N2O2 :C, 63.68; H, 9.80; N, 12.38. Found: C, 63,51; H, 9.82; N, 12.30.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:18]=[CH:19][C:20]3[N:21]([N:23]=[C:24]([NH2:26])[N:25]=3)[CH:22]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1.[N:33]1([CH2:39][C:40]2[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[CH2:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([C:17]2[CH:18]=[CH:19][C:20]3[N:21]([N:23]=[C:24]([NH:26][C:44](=[O:45])[C:43]4[CH:47]=[CH:48][C:40]([CH2:39][N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:41][CH:42]=4)[N:25]=3)[CH:22]=2)=[CH:4][C:3]=1[O:2][CH3:1])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1cc(-c2ccc3nc(N)nn3c2)ccc1OCc1ccccc1
Reactant: O=C(Cl)c1ccc(CN2CCCCC2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(-c2ccc3nc(NC(=O)c4ccc(CN5CCCCC5)cc4)nn3c2)ccc1OCc1ccccc1
Yield: 9.1 %

Procedure:
To a reaction vessel containing the 6-{3-(methyloxy)-4-[(phenylmethyl)oxy]phenyl}[1,2,4]triazolo[1,5-a]pyridin-2-amine (104 mg, 0.3 mmol, 1 equivalent) and pyridine (0.063 mL, 1.2 mmol, 4 eq.) in dichloromethane (1 mL) was added 4-piperidin-1-ylmethyl-benzoyl chloride (142 mg, 0.6 mmol, 2 eq.) as a solution in dichloromethane (2 mL), dropwise. The vessel was capped and heated to reflux for approximately 16 hours. The reaction mixture was cooled and the solvent removed in vacuo. The residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give N-[6-(4-benzyloxy-3-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-4-piperidin-1-ylmethyl-benzamide as a white solid (14.9 mg, 9%).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:13][C:12]2[C:11]3[S:14][C:15]4[C:19]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[C:18]([C:30]([O:32]CC)=[O:31])[S:17][C:16]=4[C:10]=3[S:9][C:8]=2[C:7]=1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:5])C.[Li+].[OH-].C1COCC1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>[CH2:20]([C:19]1[C:15]2[S:14][C:11]3[C:12]4[S:13][C:6]([C:4]([OH:5])=[O:3])=[C:7]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:8]=4[S:9][C:10]=3[C:16]=2[S:17][C:18]=1[C:30]([OH:32])=[O:31])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCCCCc1c(C(=O)OCC)sc2c1sc1c3sc(C(=O)OCC)c(CCCCCCCCCC)c3sc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCc1c(C(=O)O)sc2c1sc1c3sc(C(=O)O)c(CCCCCCCCCC)c3sc21
Yield: 95.9 %

Procedure:
Compound 74 (14.0 g, 0.021 mol) is mixed with LiOH (1.24 g, in 15 mL water), THF (100 mL), MeOH (20 mL) and a catalytic amount of tetrabutylammonium iodide. This mixture is heated at reflux overnight and most of the solvent is evaporated. The residue is acidified with concentrated HCl (30 mL). The resultant solid is collected by filtration, washed thoroughly with water and vacuum dried to yield compound 75 (12.5 g, 97.4% yield). M.P.: 315.6-318.5° C.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:8]=[C:9]([C:18]([O:20]CC)=[O:19])[C:10](=[O:17])[N:11]2[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[OH-].[Na+].Cl>CN(C)C=O>[N:29]1([CH2:6][C:7]2[CH:8]=[C:9]([C:18]([OH:20])=[O:19])[C:10](=[O:17])[N:11]3[C:16]=2[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cc(COS(C)(=O)=O)c2ccccn2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(CN2CCOCC2)c2ccccn2c1=O
Reaction time: 16 h

Procedure:
A 25 mL round bottom flask was charged with 0.75 mL of N,N-dimethylformamide, which was evacuated for 5 minutes and purged with nitrogen. To this flask was added ethyl 1-{[(methylsulfonyl)oxy]methyl}-4-oxo-4H-quinolizine-3-carboxylate, potassium carbonate (25 mg, 0.18 mmol), and then morpholine (0.016 mL, 0.18 mmol), which was stirred for 45 minutes. The reaction mixture was charged with 2.5 N NaOH (0.15 mL, 0.36 mmol), which was stirred for 16 hours. The mixture was acidified with 3 N HCl (1 mL) and then reduced in volume under vacuum, providing material, which was purified by reverse phase HPLC to yield the title compound that gave a proton NMR spectrum consistent with theory and a high resolution mass spectrum (ES+) m/z of 289.1205 calculated for M+H+ [C15H16N2O4: 289.1183]: 1H NMR (500 MHz, DMSO-d6) δ 13.76 (bs, CO2H), 9.81 (bs, 1H), 9.44 (s, 1H), 8.66 (m, 1H), 8.54 (m, 1H), 8.21 (m, 1H), 7.74 (t, J=6.8 Hz, 1H), 4.77 (s, 2H), 3.96 (m, 2H), 3.09-3.64 (m, 6H).
Reaction SMILES: [CH3:1][C:2]([SiH2:5][O:6][CH:7]1[CH2:12][C:11]2([CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[O:10][CH:9]([CH2:18]/[CH:19]=[C:20](\[CH3:26])/[C:21](OCC)=[O:22])[CH2:8]1)([CH3:4])[CH3:3].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCOCC>[CH3:4][C:2]([SiH2:5][O:6][CH:7]1[CH2:12][C:11]2([CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[O:10][CH:9]([CH2:18]/[CH:19]=[C:20](\[CH3:26])/[CH:21]=[O:22])[CH2:8]1)([CH3:1])[CH3:3]
Reactant: CCOC(=O)/C(C)=C/CC1CC(O[SiH2]C(C)(C)C)CC2(CCCCO2)O1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: C/C(C=O)=C\CC1CC(O[SiH2]C(C)(C)C)CC2(CCCCO2)O1

Procedure:
To a solution of ethyl 4-[4-[(1,1-dimethylethyl)silyl]oxy-1,7-dioxaspiro[5.5]undec-2-yl]-2-methyl-2E-butenoate, (10.0 g; 27.0 mmoles) in methylene chloride (160 ml) is added finely powdered pyridinium chlorochromate (PCC; 8.7 g; 40.5 mmoles) in a single portion with stirring under nitrogen at 25°. After twenty minutes the reaction mixture is diluted with ether (800 ml) and filtered through celite. The chromium salt residue is washed several times with ether, the washes filtered through celite, and the combined filtrates reduced in volume to 100 ml, filtered through silica gel and concentrated in vacuo to an oil. Chromatography (7.5% ethyl acetate/hexane yields the title compound, 4-[4-[(1,1-dimethylethyl)silyl]oxy-1,7-dioxaspiro[5.5]undec-2-yl]-2-methyl-2E-butenealdehyde; (5.42 g; 54.5%0 as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:13]([CH2:14][CH2:15][O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH:27][C:28]1[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=1[F:35])=O.[OH-].[Na+].[Cl-].[NH4+].C([N:43](C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(O)C>[F:35][C:29]1[CH:30]=[C:31]([I:34])[CH:32]=[CH:33][C:28]=1[NH:27][C:6]1[C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:12]=2[N:13]([CH2:14][CH2:15][O:16][Si:17]([CH:18]([CH3:19])[CH3:20])([CH:21]([CH3:22])[CH3:23])[CH:24]([CH3:26])[CH3:25])[C:5]=1[C:3]([NH2:43])=[O:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1CCO[Si](C(C)C)(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCO
Product: CC(C)[Si](OCCn1c(C(N)=O)c(Nc2ccc(I)cc2F)c2cnccc21)(C(C)C)C(C)C
Temperature: 65 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a suspension of 3-(2-fluoro-4-iodo-phenylamino)-1-(2-triisopropylsilanyloxy-ethyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester (132 mg, 0.22 mmol) in ethanol (3 mL) was added a 1M aqueous solution of sodium hydroxide (0.23 mL, 0.23 mmol). The reaction mixture was heated at 65° C., stirred for 1 hour, cooled to room temperature, concentrated and azeotroped with toluene. The residue was suspended in DMF and ammonium chloride (24 mg, 0.44 mmol), diisopropylethylamine (0.15 mL, 0.88 mmol) then HATU (167 mg, 0.44 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours before being partitioned between ethyl acetate and water. The organic layer was isolated and washed with water then a saturated solution of sodium hydrogencarbonate and then brine, dried (Na2SO4), filtered and evaporated to give the title compound as a yellow solid (105 mg, 80%). LCMS (method B): RT=3.03 min, M+H+=597.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:45])[O:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1.C(=O)(O)[O-].[Na+]>ClCCl.O>[C:18]1([C:17]([NH:16][CH:12]2[CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:26])=[CH:9][CH:8]=3)[CH2:15][N:14]([C:34]([O:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:45])[CH2:13]2)=[O:24])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(NC1CNCC(c2ccc(OC(F)(F)F)cc2)C1)c1ccccc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(NC1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At 0° C., 200 mg (0.55 mmol) of N-{5-[4-(trifluoromethoxy)phenyl]piperidin-3-yl}benzamide and 153 μl (1 l mmol) of triethylamine were initially charged in 17 ml of dichloromethane, and 111 mg (0.55 mmol) of 4-nitrophenyl chlorocarbonate were added slowly. The mixture was stirred at 0° C. for 2 h and then warmed to RT. Water and saturated aqueous sodium bicarbonate solution were added, and the reaction mixture was extracted. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 254 mg (87% of theory)
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([CH3:16])=[N:7][O:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].C([Li])CCC.[C:22](#N)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH3:1][N:2]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:16][C:6]2=[N:7][O:8][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:5]2[C:3]1=[O:4]
Reactant: CNC(=O)c1c(C)noc1-c1ccccc1
Reactant: N#Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(-c2ccccc2)cc2noc(-c3ccccc3)c2c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
159 mg (0.73 mmol) of 3-methyl-5-phenyl-isoxazole-4-carboxylic acid methylamide is suspended in 4 ml of THF under argon. At −5° C. a solution of butyl lithium (1.0 ml, 1.6M in hexane, 1.6 mmol, 2.2 eq.) is slowly added. After 1 h at this temperature, the solution is warmed to 0° C. and 0.92 ml (0.88 mmol, 1.2 eq.) of benzonitrile is slowly added. Under warming to room temperature, the red solution is stirred for another 2 h, then quenched with 0.1 ml of water and concentrated. The residue is then taken up in 4 ml of a 4M solution of HCl in dioxane and the suspension stirred for 16 h at room temperature. Then, the solvent is removed and the residue dissolved in ethyl acetate and carefully neutralised with sat. NaHCO3-solution. The phases are separated and the organic phases washed with brine, dried over Na2SO4 and concentrated. Chromatographic purification (hexane/ethyl acetate 90:10) yields 108 mg (48%) of 5-methyl-3,6-diphenyl-5H-isoxazolo[4,3-c]pyridin-4-one as a white solid. Mass spectrum: m/z (M+H)+: 303.2
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][S:4]([CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)(=[O:6])=[O:5].[BH4-].[Na+]>CO.O.O.O.O.O.O.O.[Co](Cl)Cl>[CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][S:4]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][NH2:13])=[CH:14][CH:15]=1)(=[O:6])=[O:5]
Reactant: CC(C)(C)CS(=O)(=O)Cc1ccc(C#N)cc1
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)CS(=O)(=O)Cc1ccc(CN)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 18.4 %

Procedure:
Add cobalt(II) chloride hexahydrate (1.83 mg, 7.7 mmol) to a solution of 4-(2,2-dimethylpropane-sulfonylmethyl)-benzonitrile (966 mg, 3.85 mmol) in methanol (25 mL). Cool the mixture to 0° C. and stir for 15 min. Carefully add sodium borohydride (1.46 g, 38.49 mmol) in small batches, allow the mixture to warm to room temperature and stir for 2 h. Dilute the mixture with water and partition between water and chloroform. Extract the aqueous phase three times with chloroform/iso-propanol (3:1). Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (80 g) eluting with DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) (1:0 over 5 min, 19:1 over 5 min, 9:1 over 35 min, 85:15; 50 mL/min) to give the title compound (181 mg, 49%). MS (APCI+) m/z: 256 (M+H)+.