Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:11][CH2:12][C:13](=[O:15])[CH3:14])=[CH:5][CH:4]=1.[OH-].[K+].Cl.C1(=O)CCCC=C1>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:11][CH2:12][C:13](=[O:15])[CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)C(CCC(C)=O)c2ccc(OC)cc2)cc1
Agent: Cl
Agent: O=C1C=CCCC1
Agent: [K+]
Solvent: CCO
Product: COc1ccc(C2=CC(=O)CCC2c2ccc(OC)cc2)cc1

Procedure:
A solution of 212.0 g. of 1,2-bis(4-methoxyphenyl)-1,5-hexanedione and 650 ml. of 2N potassium hydroxide in three liters of 2B ethanol was heated to reflux for two hours. The solution was cooled and 110 ml. of concentrated hydrochloric acid were added. The solution was then concentrated in vacuo. One liter of water and 1.5 liters of ethyl acetate were added to the residue. The layers were separated. The aqueous layer was extracted three times each with 800 ml. of ethyl acetate. The combined organic layers were washed four times with water, dried over sodium sulfate, filtered and evaporated in vacuo to provide 195.6 g. of the desired cyclohexenone intermediate as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:15])[CH2:13]Br)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[N:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1>C(#N)C>[N:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:23][CH2:24][N:25]([CH2:13][C:12]([N:9]3[CH2:10][CH2:11][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]3)=[O:15])[CH2:26][CH2:27]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)C1CCN(C(=O)CBr)CC1
Reactant: c1cc(N2CCNCC2)ccn1
Solvent: CC#N
Product: CCOC(=O)C1CCN(C(=O)CN2CCN(c3ccncc3)CC2)CC1
Reaction time: 3 h
Yield: 32.4 %

Procedure:
A solution of ethyl-1-(bromoacetyl)-piperidin-4-carboxylate (0.84 g, 3 mMoles) in acetonitrile (10 ml) was added dropwise to a stirred solution of 1-(4-pyridyl)piperazine (0.5 g, 3 mMoles) in acetonitrile (20 ml) and the resulting mixture was allowed to stand for 3 hours. The white precipitate was removed by filtration and the mother liquors were concentrated under reduced pressure to give a yellow foam. The foam was purified by chromatography (flash column made with grade III neutral alumina and eluted with a gradient of 0-1% ethanol in dichloromethane) to give the title compound (350 mg) as a colourless oil which was crystallised from cyclohexane to give colourless prisms; mp 102°-104° C.; Microanalysis, found: C,63.5; H,8.1; N, 15.5%; C19H28N4O3 requires C,63.3; H,7.8; N,15.5%; NMR (d6DMSO+CD3COOD): 1.2 (t,3H), 1.3-1.7 (m,2H), 1.8 (m,2H), 2.5-2.8 (m,6H), 3.0-3.4 (m,3H), 3.6 (br s,4H), 3.9 (d,1H), 4.0 (q,2H), 4.2 (d,1H), 7.1 (d,2H), 8.2 (d,2H); m/e 361 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[N:6][C:7]=1[O:8][CH3:9]>ClCCl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[C:7]([O:8][CH3:9])=[N:6][CH:5]=[C:4]([CH:3]=1)[CH:10]=[O:11]
Reactant: COc1ncc(CO)cc1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ncc(C=O)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a solution of 0.54 g of (5-fluoro-6-methoxypyridin-3-yl)methanol in 5 mL of dichloromethane, 1.5 g of manganese dioxide was added. The mixture was stirred at room temperature for 3 hours, thereto were then added 0.89 g of manganese dioxide and 4 mL of dichloromethane, and the mixture was stirred for 1 hour. Thereto were further added 1.5 g of manganese dioxide and 2 mL of dichloromethane, and the mixture was stirred at room temperature for 2 hours 30 minutes. After leaving overnight, the insoluble substance was filtered off, and the filtration residue was washed with chloroform. The solvent was distilled off under reduced pressure to obtain 0.48 g of 5-fluoro-6-methoxynicotinaldehyde as a yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][CH:16]1[O:21][CH:20]([CH3:22])[CH2:19][NH:18][CH2:17]1>>[CH3:22][CH:20]1[O:21][CH:16]([CH3:15])[CH2:17][N:18]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:19]1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: CC1CNCC(C)O1
Product: CC1CN(c2nnc(N)nc2-c2ccccc2)CC(C)O1
Yield: 10.3 %

Procedure:
6-(2,6-Dimethylmorpholin-4-yl)-5-phenyl-1,2,4-triazin-3-amine (35 mg, 10%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 2,6-dimethylmorpholine (0.27 g, 2.39 mmol) according to the general procedure of Example 2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)=O)[N:5]=[C:4]2[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:12](=[O:15])[NH:13][CH2:14][C:3]=12.[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:28][CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])[N:5]=[C:4]2[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:12](=[O:15])[NH:13][CH2:14][C:3]=12
Reactant: CS(=O)c1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: CN(C)CCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCNc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 85.5 %

Procedure:
To a solution of 5-chloro-1-(2,6-difluorophenyl)-7-(methylsulfinyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (800 mg, 2.23 mmol) in DCM (45 mL) were added N,N-dimethylethylenediamine (0.36 mL, 3.23 mmol) and triethylamine (0.63 mL, 4.5 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (730 mg, 85%). LC-MS m/z 383 (M+H)+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:37](=[O:36])[CH2:38][OH:39])[CH2:31][CH2:32]4)=[O:25])=[C:21]([CH3:23])[NH:22][C:15]=23)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ccnc2c1C(=O)NC1CCN(C(=O)CO)CC1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluorophenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f7) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH3:24][N:25]([CH3:27])[NH2:26]>>[CH3:24][N:25]([CH3:27])[NH:26][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Reactant: CN(C)N
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NN(C)C)[nH]n1
Yield: 24 %

Procedure:
As described for example 1b, 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.32 mmol) was converted, using N,N-dimethylhydrazine instead of morpholine, to the title compound (26 mg, 24%), which was obtained as a white solid. MS: m/e=342.1 [M+H]+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[O:5]([P:12]1(=[O:20])[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18]I)[O:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1.CN(C=O)C>[O:5]([P:12]1(=[O:20])[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][N:1]=[N+:2]=[N-:3])[O:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=P1(Oc2ccccc2)CCCC(CI)O1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CCCP(=O)(Oc2ccccc2)O1
Yield: 96 %

Procedure:
A suspension containing two equivalents of sodium azide, one equivalent of the above-prepared iodonated oxaphosphorinane and a catalytic amount of about 0.1 equivalent of tetrabutylammonium bromide in benzene/DMF (1:1) was heated to 60-80 degrees C. for 16 hours to produce 2-phenoxy-2-oxo-6-(azidomethyl)-1,2-oxaphosphorinane in 96 percent yield as a white solid.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:24]1([C:35](O)=[O:36])[CH:25]=[CH:26][CH:27]=[C:28]2[CH2:34][CH2:33][CH2:32][CH:31]=[CH:30][C:29]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:35]([C:24]2[CH:25]=[CH:26][CH:27]=[C:28]3[CH2:34][CH2:33][CH2:32][CH:31]=[CH:30][C:29]=23)=[O:36])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1cccc(SC(F)(F)F)c1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(SC(F)(F)F)c1)C(O)c1ccc(F)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-{3-[(trifluoromethyl)thio]phenyl}propan-1-ol (450 mg, 1.51 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (284 mg, 1.51 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (435 mg, 2.27 mmol) and 1-hydroxybenzotriazole hydrate (231 mg, 1.51 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-ethyl acetate). Recrystallization from ethyl acetate-hexane gave the objective substance (396 mg, 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[C:4]([CH3:29])[CH:3]=1.Br[CH2:31][CH2:32][OH:33].C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH2:31][CH2:32][OH:33])[CH:17]=2)=[O:11])=[C:4]([CH3:29])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)[nH]c1)c1ccc(S(C)(=O)=O)cc1
Reactant: OCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Product: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(CCO)c1)c1ccc(S(C)(=O)=O)cc1

Procedure:
In analogy to example 161, step 1, 5-(3-(4-chloro-2-methylphenyl)-3-(4-(methylsulfonyl)phenyl)propanoyl)pyridin-2(1H)-one (example 339, step 2) was reacted with 2-bromoethanol in the presence of potassium carbonate and a catalytic amount of tetrabutylammonium iodide to give the title compound as a light yellow solid, MS (ESI+): m/z=474.2 [M+H]+.
Reaction SMILES: O1C2(CCC(N3CCN([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)CC3)CC2)OCC1.[OH-:24].[Na+]>Cl.O1CCOCC1>[F:23][C:20]1[CH:19]=[CH:18][C:17]([CH:17]2[CH2:22][CH2:21][C:20](=[O:24])[CH2:19][CH2:18]2)=[CH:22][CH:21]=1
Reactant: [OH-]
Reactant: Fc1ccc(N2CCN(C3CCC4(CC3)OCCO4)CC2)cc1
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C1CCC(c2ccc(F)cc2)CC1
Temperature: 0 °C

Procedure:
A solution of 1-(1,4-dioxa-spiro[4.5]dec-8-yl)-4-(4-fluoro-phenyl)-piperazine (3.13 gm) (C18H25FN2O2) in 100 ml 3N hydrochloric acid and 100 ml dioxane was stirred at ambient temperature for 2 hours. The mixture is cooled to 0° C., neutralized with 2N sodium hydroxide and extracted with 2×100 ml ethyl acetate. The ethyl acetate layer was washed with water and brine (each 2×40 ml), dried over sodium sulfate and concentrated to a solid. This material, which was recrystallized from ethyl ether (1.5 gm), has a melting point of 104-106° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:25])([CH:22]([CH3:24])[CH3:23])[CH2:18][C:19]([OH:21])=[O:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26]O>>[CH3:26][O:20][C:19](=[O:21])[CH2:18][C:17]([CH2:16][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)([OH:25])[CH:22]([CH3:23])[CH3:24]
Reactant: CC(C)C(O)(CCc1ccc(OCc2ccccc2)cc1)CC(=O)O
Reactant: CO
Product: COC(=O)CC(O)(CCc1ccc(OCc2ccccc2)cc1)C(C)C

Procedure:
A solution of 3-[2-(4-benzyloxy-phenyl)-ethyl]-3-hydroxy-4-methyl-pentanoic acid from Example RRRR (10.1 g, 29.5 mmol), MeOH (300 mL), and H2 SO4 (0.2 mL) was refluxed for 3 days. The reaction was stripped to dryness and the product was partitioned between ethyl acetate and 5% NaHCO3. The solution was dried (MgSO4), and concentrated to give the title compound.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].N12CCCN=C1CCCCC2.[CH3:16][O:17][C@@H:18]1[C@H:22]([OH:23])[C@@H:21]([CH2:24][OH:25])[O:20][C@H:19]1[N:26]1[C:35]2[N:34]=[CH:33][N:32]=[C:30]([OH:31])[C:29]=2[N:28]=[CH:27]1.OCC(CO)O>CC(N(C)C)=O.CO>[CH3:16][O:17][C@@H:18]1[C@H:22]([OH:23])[C@@H:21]([CH2:24][OH:25])[O:20][C@H:19]1[N:26]1[C:35]2[N:34]=[CH:33][N:32]([CH2:3][C:2]#[CH:1])[C:30](=[O:31])[C:29]=2[N:28]=[CH:27]1
Reactant: C#CCBr
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(O)ncnc21
Solvent: OCC(O)CO
Solvent: CO
Solvent: CC(=O)N(C)C
Product: C#CCn1cnc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OC)c1=O
Reaction time: 6 h

Procedure:
Propargyl bromide (2.2 ml, 19.7 mmol) and 1,8 diazabicyclo[5.4.0]undec-7-ene (DBU) (2.7 ml, 17.7 mmol) were added to a suspension of 2'-O-methylinosine (5.4 g, 19.0 mmol) in dimethylacetamide (100 ml). The reaction mixture was stirred at room temperature under argon for 18 hours at which time an additional 1 ml of DBU was added. After 6 hours, the reaction solution was evaporated in vacuo to an oil and dried onto 20 g of silica gel. Pure product was isolated by silica gel chromatography with a 2-5% gradient of methanol in chloroform. FABMS (glycerol & methanol) m/z 321 (MH+). 1H-NMR (DMSO-d6): 8.50 (1H,s, H2); 8.41 (1H, s, H8); 5.96 (1H, d, H1'); 5.28 (1H, d, 2'--OH); 5.09 (1H, t, 5'--OH); 4.82 (2H, s, CH2); 4.27 (2H, m, H2', H3'); 3.94 (1H, m, H4'); 3.60 (2H, m, H5', H5"); 3.41 (1H, s, CH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:29])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[N:5][CH:4]=1.[ClH:30].CO>C(Cl)(Cl)Cl.O1CCOCC1>[ClH:30].[ClH:30].[NH2:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[N:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:29])[CH2:20][CH2:19]1
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Reaction time: 1 h

Procedure:
A solution of 1,1-dimethylethyl (1-{2-[7-(methyloxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]ethyl}-4-piperidinyl)carbamate (5.453 g, 13.565 mmol) in chloroform (30 ml) was added 4M HCl in 1,4-dioxane (30 ml) and the reaction was stirred at rt for 0.5 h before addition of MeOH (30 ml). The reaction was stirred for a further 1 h before evaporation to provide the desired compound as a slightly impure white solid (5.323 g, 105%), which was used without further purification.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([NH:13][C:14](OC)=[O:15])[N+:10]([O-:18])=[C:9]([NH:19][C:20]([O:22][CH3:23])=[O:21])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.[OH-].[Na+]>O>[N:1]1([C:7]2[CH:8]=[C:9]([NH:19][C:20]([O:22][CH3:23])=[O:21])[N:10]3[O:18][C:14](=[O:15])[N:13]=[C:11]3[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)Nc1cc(N2CCCCC2)nc(NC(=O)OC)[n+]1[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)Nc1cc(N2CCCCC2)nc2nc(=O)on12

Procedure:
5 G. of dimethyl 6-piperidino-2,4-pyrimidine-dicarbamate-3-oxide are dissolved in 200 ml. of methylene chloride and mixed with 100 ml. of water. While stirring vigorously, the mixture is adjusted with concentrated sodium hydroxide to pH 12.5 and stirred at this pH for 3 hours. The two phases are separated and the aqueous phase is adjusted to pH 4 with concentrated hydrochloric acid. The resulting white precipitate is filtered off, washed with water, pre-dried slightly and recrystallized from a mixture of methylene chloride and methanol, there being obtained pure methyl 5-piperidino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]pyrimidine-7-carbamate, having a melting point of 210°-214° C. (decomposition).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[Mg].[CH3:10][C:11]1[O:16][C:15](=[O:17])[C:14]2[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:13]=2[N:12]=1.Cl>CCOCC>[C:11]([NH:12][C:13]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:14]=1[C:15]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8])=[O:17])(=[O:16])[CH3:10]
Reactant: Clc1ccccc1Br
Reactant: Cc1ccc2nc(C)oc(=O)c2c1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CC(=O)Nc1ccc(C)cc1C(=O)c1ccccc1Cl

Procedure:
The Grignard reagent prepared from 312.5 g (1.63 mol) of 2-bromochlorobenzene and 39.6 g (1.63 mol) of magnesium in 1.2 liters of anhydrous ether is added dropwise, in 2.5 hours, to a stirred solution of 270 g (1.54 mol) of 2,6-dimethyl-4H-3,1-benzoxazin-4-one in 4 liters of absolute ether at room temperature. The mixture is then allowed to react for a further 2 hours at the same temperature. While cooling in ice, the mixture is cautiously hydrolysed with 2N hydrochloric acid and then the aqueous phase is separated off. The organic phase is washed first with dilute sodium hydroxide solution and then with water. The organic phase is dried and concentrated. The resulting residue is induced to crystallise with isopropyl ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccco2)cc1[N+](=O)[O-]
Agent: [Ni]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccco2)cc1N

Procedure:
Prepared from (4-furan-2-yl-2-nitrophenyl)-carbamic acid tert.-butyl ester (Example B3) by catalytic hydrogenation with Raney-Ni according to the general procedure G (method a). Obtained as a grey powder (212 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20]CC)=[O:19])=[CH:14]2>O1CCCC1.C(O)C.[OH-].[Na+]>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][C:9]1[CH:10]=[C:11]([O:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OCc3nccn3C)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1ccnc1COc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2cc(C(=O)O)[nH]c12
Temperature: 50 °C
Reaction time: 0.83 h
Yield: 85.1 %

Procedure:
Ethyl 7-[(1-methyl-1H-imidazol-2-yl)methoxy]-5-[4-(methylsulfonyl)phenoxy]-1H-indole-2-carboxylate (100 mg) was dissolved in a mixed solvent of tetrahydrofuran (2 mL)-ethanol (2 mL), 1M aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at 50° C. for 50 min. The reaction. solution was allowed to cool to room temperature, and concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1M hydrochloric acid. The obtained crystals were collected by filtration, and washed successively with water and diethyl ether to give the title compound (80 mg, yield 86%) as a white solid. The white solid was recrystallized from N,N-dimethylformamide-water to give colorless crystals. melting point 209-210° C. (decomposition).
Reaction SMILES: [Na].CO.[CH:4]1[C:9]([CH:10]=[O:11])=[CH:8][C:7]2[O:12][CH2:13][O:14][C:6]=2[CH:5]=1.[N+:15]([CH:18]([CH3:20])[CH3:19])([O-:17])=[O:16]>C(O)(=O)C>[CH2:13]1[O:14][C:6]2[CH:5]=[CH:4][C:9]([CH:10]([OH:11])[C:18]([CH3:20])([N+:15]([O-:17])=[O:16])[CH3:19])=[CH:8][C:7]=2[O:12]1
Reactant: CC(C)[N+](=O)[O-]
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C(O)c1ccc2c(c1)OCO2)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
7.7 g of sodium are added to 220 ml of anhydrous methanol, and 50 g of piperonal and 90 g of 2-nitropropane are added thereto. The mixture is stirred at room temperature for one hour, and then refluxed for 4 hours. After cooling, the reaction mixture is poured into ice-water containing 21 g of acetic acid, and then extracted with ether. The extract is washed with a saturated sodium chloride solution, a saturated sodium bisulfite solution and a saturated sodium chloride solution, successively. The washed extract is dried and then evaporated to remove solvent. 15 g of 1-(3,4-methylenedioxyphenyl)-2-methyl-2-nitropropanol are thereby obtained as a crude oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[SiH4].[S-:12][C:13]#[N:14].[Na+]>C(O)C>[S:12]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])[C:13]#[N:14]
Reactant: N#C[S-]
Reactant: O=C(CBr)c1ccccc1
Agent: [Na+]
Agent: [SiH4]
Solvent: CCO
Product: N#CSCC(=O)c1ccccc1
Reaction time: 5 h

Procedure:
Bromoacetophenone-modified aminopropylsilylated glass surfaces (2.5×7.5 cm; Sigma, Silane-Prep™, S4651) (see Example 13) were coated with a 0.1M solution of sodium thiocyanate in ethanol and incubated for five hours at 50° C. The glass surfaces thus treated were then washed five times using respectively 30 mL of ethanol for 3 minutes each at room temperature. After washing three times for three minutes each using respectively 30 mL of DCM at room temperature, the glass surfaces were dried and stored at 4° C. until further use.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].[C:36](=[O:48])([O:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[O:37][CH:38](Cl)[CH3:39]>C1COCC1>[C:36](=[O:48])([O:41][CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[O:37][CH:38]([N:14]1[C:11]2=[N:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]2[C:16]([C:17](=[O:18])[C:19]2[C:24]([F:25])=[CH:23][CH:22]=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:20]=2[F:33])=[CH:15]1)[CH3:39]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(C)OC(=O)OC3CCCCC3)c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.8 %

Procedure:
To a solution of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide (5 g, 10.2 mmol) in THF (36 mL) was added KOH (1.1 g, 20.4 mmol). The reaction was stirred at rt for 0.5 h, followed by the addition of a solution of 1-chloroethyl cyclohexyl carbonate (2.3 g, 11.2 mmol) in THF (9 mL). The mixture was refluxed for 16 h, then cooled to rtand diluted with THF (50 mL). The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=8/1) to give the title compound as a white solid (3.49 g, 51.9%). The title compound was characterized by LC-MS and 1H NMR as shown below: