Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:39])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:38])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:36][C:34]([F:35])([F:37])[C:26]1[CH:25]=[C:24]([S:21]([N:18]2[CH2:19][CH2:20][CH:15]([C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([F:38])[CH:11]=4)[CH:6]=[C:5]([CH2:4][C:3]([OH:39])=[O:2])[CH:14]=3)[CH2:16][CH2:17]2)(=[O:23])=[O:22])[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=1
Reactant: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(C2CCN(S(=O)(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.4 %

Procedure:
To a stirred solution of {4-[1-(3,5-bis-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid methyl ester (80 mg, 0.14 mmol) in THF (4 mL) was added a solution of lithium hydroxide monohydrate (30 mg, 0.7 mmol) in water (1 mL) and the reaction mixture was stirred for 24 hours at room temperature. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether (3×5 mL). The washings were discarded. Water (5 mL) was added to the residue, and the mixture acidified (pH ˜2-3) with an aqueous solution of hydrochloric acid (2 N) and extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure to give {4-[1-(3,5-bis-trifluoromethyl-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-naphthalen-2-yl}-acetic acid (65 mg, 83%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.33 (br s, 1H), 8.64 (s, 1H), 8.38 (s, 2H), 7.91-8.01 (m, 1H), 7.84 (d, J=12.7 Hz, 1H), 7.69 (s, 1H), 7.31-7.44 (m, 2H), 3.94 (d, J=11.7 Hz, 2H), 3.71 (s, 2H), 2.68 (d, J=11.2 Hz, 2H), 1.88-1.98 (m, 2H), 1.77 (d, J=8.3 Hz, 2H); MS cald. for C25H21F7NO4S [(M+H)+]: 564, obsd. 564.0.
Reaction SMILES: [CH3:1][C:2]1[C:3]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:4][C:5]2[NH:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.C([O-])([O-])=O.[K+].[K+].N#N.[CH2:29](Br)[CH:30]=[CH2:31]>CN(C=O)C.O>[CH2:31]([N:10]1[CH2:9][CH2:8][O:7][C:6]2[CH:11]=[C:2]([CH3:1])[C:3]([B:12]3[O:13][C:14]([CH3:20])([CH3:19])[C:15]([CH3:18])([CH3:17])[O:16]3)=[CH:4][C:5]1=2)[CH:30]=[CH2:29]
Reactant: Cc1cc2c(cc1B1OC(C)(C)C(C)(C)O1)NCCO2
Reactant: C=CCBr
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN1CCOc2cc(C)c(B3OC(C)(C)C(C)(C)O3)cc21
Temperature: 70 °C
Yield: 52.9 %

Procedure:
A solution of 7-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.488 g, 1.774 mmol, prepared according to the procedures outlined for related compounds in Ref. WO20100130034) and K2CO3 (0.490 g, 3.55 mmol) in dry DMF (5 mL) was sparged with N2 for 5 min, treated with allyl bromide (0.773 mL, 8.87 mmol), then heated (70° C.) for 22 h. The reaction was diluted with water (50 mL) and extracted into EtOAc (50 mL) and washed with water, brine and then dried (Na2SO4), filtered, and concentrated. The crude was purified by biotage column chromatography (12 g SiO2, 0% (3 CV), 0-40% (10 CV), 40% (2 CV), EtOAc in hexanes). Product rich fractions were re-purified by biotage (0% (3 CV), 0-40% (15 CV), 40% (2 CV), EtOAc in hexanes) to afford the desired product (0.345 g, 0.938 mmol, 52.9% yield), as a colorless viscous oil. 1H NMR (500 MHz, CDCl3) δ 7.20 (s, 1H), 6.62 (d, J=0.5 Hz, 1H), 5.92 (ddt, J=16.9, 10.4, 5.9 Hz, 1H), 5.29 (dq, J=17.2, 1.6 Hz, 1H), 5.23 (dq, J=10.2, 1.4 Hz, 1H), 4.30-4.24 (m, 2H), 3.89 (dt, J=5.9, 1.3 Hz, 2H), 3.27-3.18 (m, 2H), 2.43 (s, 3H), 1.33 (s, 12H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])=[CH:3][CH:2]=1.[IH:12].CS[C:15]1[C:23]2[CH:24]=[CH:25][CH:26]=[C:21]3[C:22]=2[C:17](=[CH:18][CH:19]=[CH:20]3)[N:16]=1>C(O)C>[IH:12].[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:15]2[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]4[C:22]=3[C:17](=[CH:18][CH:19]=[CH:20]4)[N:16]=2)=[CH:3][CH:2]=1
Reactant: NCCCCc1ccncc1
Reactant: CSC1=Nc2cccc3cccc1c23
Agent: I
Solvent: CCO
Product: c1cc2c3c(cccc3c1)C(NCCCCc1ccncc1)=N2
Temperature: 25 °C

Procedure:
A mixture consisting of 3.3 grams of 4-(4-pyridinyl)butanamine, 6.5 grams of 2-methylthiobenz (cd)indole hydriodide, and 200 ml of ethanol. Cooling to room temperature failed to effect precipitation, so that solution was concentrated to 100 ml volume and cooled at -10° C. The precipitate that formed was collected, washed with ethanol, and dried. The yield of title compound was 6.1 grams; mp 197° C.-199° C. with decomposition.
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[C:9]([C:11]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][NH2:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]([C:30]1[CH:35]=[C:34](/[CH:36]=[CH:37]/[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:33]=[C:32]([CH3:44])[CH:31]=1)=[C:28]=[O:29]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([N:8]([CH3:26])[C:9]([C:11]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][NH:19][C:28]([NH:27][C:30]2[CH:35]=[C:34](/[CH:36]=[CH:37]/[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:33]=[C:32]([CH3:44])[CH:31]=2)=[O:29])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C(=O)C1(c2ccccc2)CCN(CCN)CC1
Reactant: Cc1cc(N=C=O)cc(/C=C/c2ccccc2)n1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cc(NC(=O)NCCN2CCC(C(=O)N(C)Cc3ccccc3)(c3ccccc3)CC2)cc(/C=C/c2ccccc2)n1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of 1-(2-amino-ethyl)-4-phenyl-piperidine-4-carboxylic acid benzyl-methyl-amide (Example B8., 0.25 mmol) in CH2Cl2 is added a freshly prepared solution of 4-isocyanato-2-methyl-6-(E)-styryl-pyridine (Example C2., 0.3 mmol) in toluene (2 mL). The mixture is stirred for 15 h at 20° C. Evaporation of the solvent and purification by HPLC provides the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9](=[O:11])[CH3:10])=[C:4]([CH3:12])[CH:3]=1.Cl[CH2:14][CH2:15][O:16][CH3:17]>[OH-].[Na+].O>[CH3:17][O:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([C:9](=[O:11])[CH3:10])=[C:6]([CH3:8])[CH:7]=1
Reactant: COCCCl
Reactant: CC(=O)c1c(C)cc(O)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCOc1cc(C)c(C(C)=O)c(C)c1
Temperature: 140 °C
Yield: 61.3 %

Procedure:
A pressure glass vessel charged with 1-(4-hydroxy-2,6-dimethylphenyl)ethanone (500 mg, 3.1 mmol, 1.0 equiv) and 1-chloro-2-methoxyethane (0.28 mL, 3.1 mmol, 1.0 equiv) in 50% aqueous NaOH solution (5.0 mL) was heated at 140° C. for 16 h. The residue was diluted with H2O (20 mL) and extracted with EtOAc (3×30 mL). The organic layer was separated, dried with MgSO4, and concentrated under reduced pressure to give 1-(4-(2-methoxyethoxy)-2,6-dimethylphenyl)ethanone (430.9 mg, 1.9 mmol) as yellow oil in 64% yield: 1H NMR (CDCl3, 500 MHz) δ 6.58 (s, 2 H), 4.09-4.10 (m, 2 H), 3.72-3.74 (m, 2 H), 3.44 (s, 3 H), 2.45 (s, 3 H), 2.23 (s, 6 H); ESI-MS: m/z 223.6 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.Br.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:20])=[C:17]([OH:19])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:20][C:16]1[CH:15]=[CH:14][C:13]([NH2:12])=[CH:18][C:17]=1[O:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Nc1ccc(F)c(O)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(F)c(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
A mixture of 2-chloro-5-nitropyridine (3.17 g, 20 mmol), 5-amino-2-fluorophenol hydrobromide (4.16 g, 20 mmol) and potassium carbonate (5.52 g, 40 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→50/50), and crystallized from diethyl ether to give the title compound (4.36 g, 88%) as an orange powder.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]([F:7])([F:6])[F:5].[N+]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1)([O-])=O>CS(C)=O.[Cl-].[Na+].O>[F:5][C:4]([F:7])([F:6])[CH2:3][O:8][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: OCC(F)(F)F
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(OCC(F)(F)F)cc1
Reaction time: 0.33 h
Yield: 43.4 %

Procedure:
To a stirred suspension of sodium hydride (60% dispersion in mineral oil, 0.87 g, 21.8 mmol) in DMSO (20 ml) was added trifluoroethanol (3.97 g, 39.7 mmol) at 10-15° C. under an atmosphere of argon. The reaction mixture was stirred at this temperature for 20 min then 4-nitrobenzaldehyde (3.0 g, 19.85 mmol) was added in one portion. The reaction mixture was stirred at 10-15° C. for 3 h then at room temperature for 60 h. Brine (100 ml) was added cautiously to the reaction mixture followed by extraction with Et2O (3×70 ml). The combined organic extracts were washed with water, dried (MgSO4) and the solvent removed under reduced pressure to give an oil which was purified by flash chromatography (3:1 Hexane/EtOAc) to give a yellow oil which solidified on standing at room temperature to give the title compound (1.76 g, 43%) as a yellow solid.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:9]=[C:10]([C:11]#[N:12])[C:5]2=[N:4][CH:3]=1.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>>[F:20][C:19]([F:22])([F:21])[C:16]1[CH:17]=[CH:18][C:13]([C:8]2[CH:9]=[C:10]([C:11]#[N:12])[C:5]3[N:6]([C:2]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])=[CH:3][N:4]=3)[CH:7]=2)=[CH:14][CH:15]=1
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(I)cnc12
Product: C[Si](C)(C)C#Cc1cnc2c(C#N)cc(-c3ccc(C(F)(F)F)cc3)cn12
Yield: 65.2 %

Procedure:
Prepared from 3-iodo-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-8-carbonitrile (example C.23 step 4) (1.3 g, 4 mmol) and trimethylsilylacetylene (0.87 mL, 6 mmol) as described in example C.20 step 4. Obtained the title compound as a light brown solid (1.0 g, 82%). MS (ISP) 384.1 [(M+H)+].
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15](=[O:18])[CH2:16][CH3:17])[CH2:9]1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].O.BrC[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([N:14]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:15](=[O:18])[CH2:16][CH3:17])[CH2:9]1)[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCC(=O)N(c1ccccc1)[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N(c1ccccc1)[C@H]1CCCN(CCc2ccccc2)C1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
3(S)-(Phenyl-propionyl-amino)-piperidine-1-carboxylic acid tert-butyl ester (168) (100 mg) was dissolved in a mixture of TFA-CH2Cl2 (1 ml, 20%) and stirred for 1 hr. After removal of solvent, the residue was dried under vacuum for 30 min and dissolved in 5 ml of CH2Cl2, washed with sat. K2CO3, dried (Na2SO4), filtered. After evaporation of the solvent, the residue was dissolved in CH3CN (1 ml). Then K2CO3 (125 mg, 3 eq), water (1 ml) and (2-bromoethyl)benzene (0.05 ml, 1.2 eq) was added. The mixture was heated at 70° C. for 12 hr. After cool to room temperature, the mixture was diluted with sat. NaHCO3 (5 ml), extracted with CH2Cl2 (2×10 ml). The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by silica gel chromatography (100% CH2Cl2, 2%-4%MeOH in CH2Cl2) to give 171 as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 7.40 (m, 3H), 7.10 (m, 2H), 4.80 (m, 1H), 0.20 (m, 1H), 4.00 (m, 1H), 2.40 (m, 2H), 1.95 (m, 3H), 1.61 (m, 1H), 1.51 (m, 1H), 1.50 (s, 9H), 1.30 (m, 1H), 1.00 (t, 3H) ppm; LRMS (calculated for C22H28N2O2)+ 336, found 336; IR (film) 2978, 2937, 2860, 1693, 1662, 1698, 1494, 1422, 1363, 1264, 1151, 1386, 1182 cm−1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][CH:5]=[C:4]([Cl:10])[C:3]=1[CH2:11]O.P(Br)(Br)[Br:14].O.C([O-])(O)=O.[Na+]>CCOCC.CCOC(C)=O>[Br:14][CH2:11][C:3]1[C:2]([Cl:1])=[C:7]([CH2:8][CH3:9])[CH:6]=[CH:5][C:4]=1[Cl:10]
Reactant: BrP(Br)Br
Reactant: CCc1ccc(Cl)c(CO)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCc1ccc(Cl)c(CBr)c1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
The required 2-bromomethyl-1,3-dichloro-4-ethyl-benzene was prepared as follows: To a mixture of 2′,4′-dichloroacetophenone (4.85 g; 25.66 mmol) suspended in diethylene glycol (20 mL) was added KOH (2.37 g; 35.92 mmol) and hydrazine hydrate (2.9 mL). The resulting mixture was heated at 100° C. (for 1 hour) and subsequently overnight, at 200° C. After cooling to RT, the mixture was partitioned between Et2O and water. The layers were separated and the organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexanes) to afford the product: 2,4-dichloro-1-ethylbenzene (2.24 g). To a solution 2,2,6,6-tetramethylpiperidine (2.36 mL; 14 mmol), dissolved in THF (40 ml) was added a solution of n-BuLi in hexanes (5.6 mL; 2.50 mol/l; 14 mmol), at −78° C. The reaction mixture was stirred for 90 minutes, allowing the temperature to reach 0° C. Subsequently, a solution of 2,4-dichloro-1-ethylbenzene (2.23 g; 12.74 mmol), dissolved in THF (5 mL) was added at −78° C. The resulting mixture was stirred for 2.5 hours. Subsequently, DMF (1.48 mL; 19.11 mmol) was added dropwise and the resulting mixture was stirred for 30 minutes. The reaction was quenched by the addition of a saturated aqueous NH4Cl solution, at −50° C. The resulting mixture was extracted with Et2O. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo to afford the crude 2,6-dichloro-3-ethylbenzaldehyde, which was redissolved in MeOH (100 mL). Subsequently, NaBH4 (1.45 g; 38.22 mmol) was added, in small portions, at 0° C. After the addition was complete the mixture was allowed to warm to RT and stirred for one hour. Subsequently, the mixture was cooled to 0° C., water was added, and the MeOH evaporated in vacuo. To the aqueous solution was added a 5% aqueous NaHCO3 solution and Et2O. The layers were separated and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O:hexanes 1:7 followed by 1:1) to afford (2,6-dichloro-3-ethylphenyl)methanol (2.11 g). To a solution of (2,6-dichloro-3-ethylphenyl)methanol (0.79 g; 3.85 mmol) in Et2O (25 mL) was added dropwise PBr3 (0.47 ml; 5.01 mmol), at 0° C., and the resulting mixture was stirred overnight, at RT. Subsequently, water was added, at 0° C., followed by EtOAc en 5% aqueous NaHCO3. The layers were separated and the organic layer was dried (MgSO4), filtered, and concentrated in vacuo to afford 2-bromomethyl-1,3-dichloro-4-ethylbenzene (0.57 g), which was used as such.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:20][CH2:21][CH2:22][CH3:23])=[C:8]([C:10]2[N:18]=[C:17]3[C:13](=[N:14][N:15]=[N:16]3)[C:12](=[O:19])[N:11]=2)[CH:9]=1)([O-])=O>C(OCCO)C.[Pt]=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:20][CH2:21][CH2:22][CH3:23])=[C:8]([C:10]2[N:18]=[C:17]3[C:13](=[N:14][N:15]=[N:16]3)[C:12](=[O:19])[N:11]=2)[CH:9]=1
Reactant: CCCOc1ccc([N+](=O)[O-])cc1C1=NC(=O)C2=NN=NC2=N1
Agent: O=[Pt]
Solvent: CCOCCO
Product: CCCOc1ccc(N)cc1C1=NC(=O)C2=NN=NC2=N1
Reaction time: 24 h
Yield: 41.5 %

Procedure:
2-(5-Nitro-2-propoxyphenyl)-8-azapurin-6-one (32 g) was dissolved in 2-ethoxyethanol (400 ml) and the solution was hydrogenated under a hydrogen pressure of 5 kg/cm2 at 30° C. using platinum oxide (3 g) as catalyst. After 3 hours when reaction was complete, the catalyst was filtered off and the solvent was removed from the filtrate in vacuo. The resulting brown oil was heated at reflux with hydrochloric acid (600 ml; 2 N) and the mixture was then treated with charcoal and filtered. The filtrate was cooled and treated with concentrated aqueous ammonia solution until alkaline, and then was again treated with charcoal and filtered. The filtrate was acidified to pH 4 by treatment with glacial acetic acid and left to stand at 0° C. for 24 hours. The resulting yellow solid was filtered off and recrystallised from ethanol to give 2-(5-amino-2-propoxyphenyl)-8-azapurin-6-one (12.0 g), m.p. 225°-227° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]([OH:15])=[O:14].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([S:22]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:6]([CH2:12][C:13]([OH:15])=[O:14])=[CH:7]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc2[nH]cc(CC(=O)O)c2c1
Product: COc1ccc2c(c1)c(CC(=O)O)cn2S(=O)(=O)c1ccccc1

Procedure:
(1-Benzenesulfonyl-5-methoxy-1H-indol-3-yl)-acetic acid 100 was prepared from commercially available (5-methoxy-1H-indol-3-yl)-acetic acid and benzene sulfonyl chloride using the protocol as described in step 8, example 4. (M−1=344.4)
Reaction SMILES: [C:1]([CH:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:5]([O:7]C)=O)(=[O:3])[CH3:2].C(C(CCCCCC)C(O)=O)(=O)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.[NH2:57][CH:58]([C:60]1[C:61](=[O:75])[NH:62][C:63]([CH2:66][C:67]2[CH:72]=[CH:71][C:70]([O:73][CH3:74])=[CH:69][CH:68]=2)=[N:64][N:65]=1)[CH3:59]>ClCCl>[C:1]([CH:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:5]([NH:57][CH:58]([C:60]1[C:61](=[O:75])[NH:62][C:63]([CH2:66][C:67]2[CH:72]=[CH:71][C:70]([O:73][CH3:74])=[CH:69][CH:68]=2)=[N:64][N:65]=1)[CH3:59])=[O:7])(=[O:3])[CH3:2]
Reactant: CCCCCCC(C(C)=O)C(=O)OC
Reactant: COc1ccc(Cc2nnc(C(C)N)c(=O)[nH]2)cc1
Agent: CCCCCCC(C(C)=O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCCCCC(C(C)=O)C(=O)NC(C)c1nnc(Cc2ccc(OC)cc2)[nH]c1=O

Procedure:
1.18 g (5.91 mmol) of methyl 2-acetyloctanoate (Example 18A) are hydrolysed to 2-acetyloctanoic acid according to Example 19A. The acid in 20 ml of dichloromethane is reacted analogously to Example 23A with 800 mg (5.90 mmol) of 1-hydroxy-1H-benzotriazole, 1.66 g (16.4 mmol) of 4-methylmorpholine, 1.13 g (5.9 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 900 mg (3.5 mmol) of 6-(1-aminoethyl)-3-(4-methoxybenzyl)-1,2,4-triazin-5(4H)-one (Example 10A) to give 2-acetyl-N-{1-[3-(4-methoxybenzyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]ethyl}octanamide.
Reaction SMILES: C([O:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([C:16]2[C:24]3[C:23]([OH:25])=[C:22]([C:26]#[N:27])[C:21](=[O:28])[NH:20][C:19]=3[S:18][CH:17]=2)=[CH:11][C:10]=1[Cl:29])C1C=CC=CC=1>Br.CC(O)=O>[Cl:29][C:10]1[CH:11]=[C:12]([C:16]2[C:24]3[C:23]([OH:25])=[C:22]([C:26]#[N:27])[C:21](=[O:28])[NH:20][C:19]=3[S:18][CH:17]=2)[CH:13]=[C:14]([Cl:15])[C:9]=1[OH:8]
Reactant: N#Cc1c(O)c2c(-c3cc(Cl)c(OCc4ccccc4)c(Cl)c3)csc2[nH]c1=O
Agent: Br
Solvent: CC(=O)O
Product: N#Cc1c(O)c2c(-c3cc(Cl)c(O)c(Cl)c3)csc2[nH]c1=O
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 64.1 %

Procedure:
The 3-(4-benzyloxy-3,5-dichloro-phenyl)-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile (125 mg, 0.281 mmol) was dissolved in 30% HBr/AcOH (1.3 mL) and sealed in a reaction tube with stirring for 40 minutes at 70° C. The reaction is cooled to room temperature and concentrated in vacuo. The resulting solid is washed with Et2O and filtered, then placed under high vacuum for 2 hours. The solid is taken up in NH4OH (2 mL) and stirred at room temperature for 1 hour. The reaction mix is concentrated and taken up in 1M HCl. The resulting solid is filtered and rinsed with water to give 66 mg of a white solid (0.18 mmol, 66% yield). 1H NMR (300 MHz, DMSO-D6) δ 12.45 (bs, 1H), 10.18 (bs, 1H), 7.42 (s, 2H), 7.08 (s, 1H), 4.60 (bs, 1H). MS (ESI APCI) positive ion 353 (M+H)+; negative ion 351 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][N:9]([C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[C:20]([O:22]CC)=O)[C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[CH2:1]([O:8][N:9]1[C:18]2[C:19](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:20]([OH:22])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]1=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)N(OCc1ccccc1)c1ccccc1C(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1c(O)c2ccccc2n(OCc2ccccc2)c1=O
Reaction time: 1 h
Yield: 58 %

Procedure:
To a stirring solution of ethyl 2-(N-(benzyloxy)-3-ethoxy-3-oxopropanamido)benzoate (1.3 g, 3.37 mmol) in MeOH (10 mL) was added sodium methoxide (0.255 g, 4.72 mmol) slowly at 20-25° C. Reaction mixture was stirred for 1 h. Excess methanol was distilled out and then reaction mixture diluted with NH4CJ solution. Precipitated product was filtered and dried to get titled compound in 58% yield.
Reaction SMILES: C([O-])(=O)C.[Na+].BrC(Br)C(C(F)(F)[F:11])=O.Cl.[Cl:16][C:17]1[C:27](F)=[CH:26][C:25]([NH:29][NH2:30])=[CH:24][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])O.[Na+]>O.C(OCC)C>[Cl:16][C:17]1[CH:27]=[C:26]([F:11])[C:25]([NH:29][NH2:30])=[CH:24][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=C(C(Br)Br)C(F)(F)F
Reactant: CCOC(=O)c1cc(NN)cc(F)c1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1cc(NN)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixed aqueous solution of 5.3 g (53.5 mmol) of sodium acetate and about 100 ml of water was added under ice cooling 6.6 g (24.3 mmol) of 1,1-dibromo-3,3,3-trifluoroacetone, and the reaction was allowed to proceed at 70° C. for 20 minutes. Then, the reaction mixture was cooled to room temperature. Separately, 5.8 g (21.5 mmol) of crude ethyl 2-chloro-fluoro-5-hydrazinobenzoate hydrochloride was dissolved in 30 ml of water, to which 100 ml of diethyl ether was added, and while cooling, the mixture was neutralized by the addition of saturated sodium hydrogencarbonate solution, followed by washing with saturated sodium chloride solution, which afforded a solution of ethyl 2-chloro-4-fluoro-5-hydrazinobenzoate in diethyl ether. This solution was added to the above reaction mixture, followed by vigorous stirring at room temperature for 2 hours. The ether layer was separated, washed once with 10 ml of saturated sodium chloride solution, and dried with magnesium sulfate. The diethyl ether was distilled out. The residue was dissolved in 50 ml of THF, to which 8.3 g (23.0 mmol) of carbethoxyethylidenetriphenylphosphorane was added, and the mixture was heated under reflux for 2 hours. The THF was distilled out under reduced pressure, and the residue was subjected to silica gel column chromatography, which afforded 3.8 g (10.0 mmol) of compound 1-642.