Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:9]([C:13]([F:16])([F:15])[F:14])[O:10]2)=[CH:5][CH:4]=1.II.[I:24](O)(=O)(=O)=O>C(O)C.O>[I:24][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[O:10][CH:9]([C:13]([F:14])([F:15])[F:16])[C:8]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:7]2
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CCOC(=O)C1=Cc2ccc(OC)cc2OC1C(F)(F)F
Agent: II
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1=Cc2cc(I)c(OC)cc2OC1C(F)(F)F
Temperature: 70 °C
Yield: 86.4 %

Procedure:
To a solution of 8 g (26.5 mmol) of ethyl 7-methoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 60 mL of ethanol was added 2.8 g (11.2 mmol) of iodine, followed by addition of a solution of 9.0 g (39.5 mmol) of periodic acid in 25 mL of water. The resulting solution was heated to 70° C. for five hrs. After cooling to room temperature, the volatiles were removed, the residue was dissolved in ethyl acetate, and the organic phase washed with saturated aqueous sodium sulfite and satr' brine. The resultant solution was dried over anhydrous magnesium sulfate and the volatiles were removed. The residue was purified by silica gel chromatography with hexane/ethyl acetate mixture to afford 9.8 g (70%) of a light yellow solid: 1H NMR (CDCl3/300 MHz) 7.62(s, 1H), 7.60(s, 1H), 6.49(s, 1H), 5.69(q, J=6.9 Hz, 1H), 4.30(m, 2H), 3.89(s, 3H), 1.34(t, J=7.2 Hz, 3H). MS (ESI+) 428.9(M+1, 100). HRMS (EI) m/z calcd for (C14H12F3O4) 427.9732, found 427.9741.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[CH2:12][N:13]([CH3:30])[C:14](=[O:29])[N:15]([CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[C:5]=3[C:4]=2[N:3]=1.[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.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>[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[CH2:12][N:13]([CH3:30])[C:14](=[O:29])[N:15]([CH:16]5[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]5)[C:5]=4[C:4]=3[N:3]=2)=[CH:35][CH:34]=1
Reactant: CN1Cc2cnc3ccc(Cl)nc3c2N(C2CCN(C(=O)OC(C)(C)C)CC2)C1=O
Reactant: COc1ccc(B(O)O)cn1
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: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccc3ncc4c(c3n2)N(C2CCN(C(=O)OC(C)(C)C)CC2)C(=O)N(C)C4)cn1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
tert-butyl 4-(9-chloro-3-methyl-2-oxo-3,4-dihydropyrimido[5,4-c][1,5]naphthyridin-1(2H)-yl)piperidine-1-carboxylate (0.104 g, 0.241 mmol) and 6-methoxy-3-pyridine boronic acid (40.7 mg, 0.266 mmol) were dissolved in toluene (6 mL) and ethanol (2 mL), and to the system added tetrakis(triphenylphosphine)palladium (5 mg) and 2N sodium carbonate solution (0.36 mL), reacted under reflux under nitrogen for 16 h, cooled to room temperature, filtered and the organic layer was concentrated under reduced pressure and dissolved in 30 mL of dichloromethane, followed by washing sequentially with water and saturated brine, dried over anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (ethyl acetate:petroleum ether=2:1) to give 75 mg of the product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:12]([O:14][CH:15]=[CH:16][C:17](Cl)=[O:18])[CH3:13]>C(OCC)C>[CH3:8][O:7][C:5]([C:4]1[CH:3]=[C:2]([CH:11]=[CH:10][CH:9]=1)[NH:1][C:17](=[O:18])[CH:16]=[CH:15][O:14][CH2:12][CH3:13])=[O:6]
Reactant: CCOC=CC(=O)Cl
Reactant: COC(=O)c1cccc(N)c1
Solvent: CCOCC
Product: CCOC=CC(=O)Nc1cccc(C(=O)OC)c1
Yield: 63.8 %

Procedure:
To a solution containing 29.5 g of methyl m-aminobenzoate in 300 ml of diethyl ether, 11.53 g of β-ethoxyacrylic acid chloride was added dropwise at 17°-27° C. under stirring condition. After the addition was finished, the reaction mixture was further stirred at a room temperature for 1 hour, then the crystals thus precipitated were collected by filtration. The crystals were washed with ether, and the crude crystals were dissolved in chloroform, then the chloroform solution was washed with 0.5N-hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride. The chloroform solution was dried and then chloroform was removed by distillation, and the residue thus obtained was purified by a silica gel column chromatography, then recrystallized from methanol to obtain 13.63 g of m-methoxycarbonyl-N-(β-ethoxyacryloyl)aniline in the form of colorless prism-like crystals.
Reaction SMILES: [C:1]([CH2:6][C@:7]12[C:31]3[CH2:30][CH2:29][C@@H:28]4[C@:23]([CH3:33])([CH2:24][CH2:25][C@H:26]([OH:32])[CH2:27]4)[C:22]=3[CH2:21][CH2:20][C@:19]1([CH3:34])[C@@H:10]([C@H:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9][CH2:8]2)([O:3]CC)=[O:2]>COCCOCCOC.[OH-].[Li+]>[C:1]([CH2:6][C@:7]12[C:31]3[CH2:30][CH2:29][C@@H:28]4[C@:23]([CH3:33])([CH2:24][CH2:25][C@H:26]([OH:32])[CH2:27]4)[C:22]=3[CH2:21][CH2:20][C@:19]1([CH3:34])[C@@H:10]([C@H:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:9][CH2:8]2)([OH:3])=[O:2]
Reactant: CCOC(=O)C[C@@]12CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CCC1=C2CC[C@H]2C[C@@H](O)CC[C@]12C
Agent: [Li+]
Agent: [OH-]
Solvent: COCCOCCOC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@@]2(CC(=O)O)C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C[C@@H]1CC3
Temperature: 130 °C
Yield: 69.1 %

Procedure:
A mixture of 14α-carbethoxymethyl-5α-cholest-8-en-3β-ol (100 mg) in diglyme (3 mL) and 1N lithium hydroxide (3 mL) was heated at 130° C. for 2 hours under argon. The cooled reaction was partitioned between methylene chloride and iced dilute HCl, and the dried and concentrated organic layer provided 65 mg of 14α-carboxymethyl-5α-cholest-8-en-3β-ol; mp 191°-193° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.Cl[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21]>O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1N1CCCCC1
Reaction time: 18.5 h
Yield: 96.4 %

Procedure:
Piperidine (660 μl, 6.66 mmol, commercially available product) was added at room temperature to an N,N-dimethylformamide (DMF; 1 ml) solution of 1,4-dichloro-2-nitrobenzene (390 mg, 2.03 mmol, commercially available product). The resulting mixture was stirred for 18.5 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 g, hexane/ethyl acetate=10/1). Thus, 1-(4-chloro-2-nitrophenyl)piperidine (471 mg, 96.4%) was yielded as an orange-colored oily material.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4](O)=[O:5].S(Cl)([Cl:16])=O>>[CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4]([Cl:16])=[O:5]
Reactant: CC(C)(CC(=O)O)c1ccccc1
Reactant: O=S(Cl)Cl
Product: CC(C)(CC(=O)Cl)c1ccccc1
Yield: 98.1 %

Procedure:
3-Methyl-3-phenylbutanoic acid (1.78 g, 10.0 mmol) was dissolved in thionyl chloride (5 mL, 68.5 mmol). The reaction mixture was heated at reflux for 6 hours. Concentration of the reaction mixture provided the title compound (1.93 g, 98%), which was used without additional purification.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=1)C.Cl>C1COCC1>[O:3]=[CH:4][CH2:5][CH2:6][O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=1
Reactant: CCOC(CCOc1ccc(C(N)=O)cc1)OCC
Agent: Cl
Solvent: C1CCOC1
Product: NC(=O)c1ccc(OCCC=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
5 g of the product obtained in Step A, 100 ml of THF and 94 mL of 1N hydrochloric acid solution are added to a flask. The mixture is stirred at ambient temperature for 1 hour. The aqueous phase is extracted with dichloromethane, and then the organic phases are concentrated under reduced pressure. The product is obtained in the form of a solid in a yield of 96% and with a chemical purity of 93%.
Reaction SMILES: CN(C=O)C.O=[C:7]1[NH:12][C:11]([CH2:13][O:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17])=[N:10][C:9]2[S:23][C:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=3[C:8]1=2.S(Cl)([Cl:32])=O>>[Cl:32][C:7]1[C:8]2[C:25]3[CH2:26][CH2:27][CH2:28][CH2:29][C:24]=3[S:23][C:9]=2[N:10]=[C:11]([CH2:13][O:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17])[N:12]=1
Reactant: CCCCOC(=O)COCc1nc2sc3c(c2c(=O)[nH]1)CCCC3
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCOC(=O)COCc1nc(Cl)c2c3c(sc2n1)CCCC3
Reaction time: 2 h

Procedure:
1.7 g of sodium hydride (50% suspension) are added to a solution of 5.0 g of “AB” and 2.8 g of butyl glycolate in 100 ml of THF, and the mixture is refluxed for 3 hours. The solvent is removed, and the mixture is subjected to conventional work-up, giving 5.0 g of butyl (4-oxo-3,4,5,6,7,8-hexahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethoxy)acetate (“AC”). 1 ml of DMF is added to a solution of 5.0 g of “AC” in 50 ml of thionyl chloride, and the mixture is stirred at 45° for 2 hours. After the solvent has been removed, the mixture is subjected to conventional work-up, giving 4.5 g of butyl (4-chloro-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-2-ylmethoxy)acetate (“AD”).
Reaction SMILES: [CH:1](=[C:3]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:4]#[N:5])[CH3:2].C(O[CH:17](N(C)C)[N:18]([CH3:20])[CH3:19])(C)(C)C>O1CCCC1>[CH3:17][N:18]([CH3:20])[CH:19]=[CH:2][CH:1]=[C:3]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[C:4]#[N:5]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC=C(C#N)c1cccnc1
Solvent: C1CCOC1
Product: CN(C)C=CC=C(C#N)c1cccnc1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
A 0.2 g portion of α-ethylidene 3-pyridine acetonitrile and 0.315 ml of t-butoxy-bis-dimethylaminomethane were dissolved in tetrahydrofuran and stirred at 20° C. for 20 hours. The solvent was removed at reduced pressure and the orange oil was purified by chromatography, eluting with ethyl acetate:hexane (10:3). The eluate was concentrated to a solid which was recrystallized from methylene chloride-hexane, giving α-[3-(dimethylamino)-2-propenylidene]-3-pyridineacetonitrile as yellow crystals, mp 117°-120° C.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([S:24]([CH2:27][CH:28]([NH:38][OH:39])[CH2:29][CH2:30][C:31]3[CH:32]=[N:33][CH:34]=[C:35]([Cl:37])[CH:36]=3)(=[O:26])=[O:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>C1COCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:19][CH2:20][N:21]([S:24]([CH2:27][CH:28]([N:38]([OH:39])[CH:1]=[O:3])[CH2:29][CH2:30][C:31]3[CH:32]=[N:33][CH:34]=[C:35]([Cl:37])[CH:36]=3)(=[O:25])=[O:26])[CH2:22][CH2:23]2)=[CH:14][CH:13]=1
Reactant: O=S(=O)(CC(CCc1cncc(Cl)c1)NO)N1CCN(c2ccc(Cl)cc2)CC1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=CN(O)C(CCc1cncc(Cl)c1)CS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
To formic acid (400 μl, 10.8 mmol) at 0° C. was added acetic anhydride (102 μl, 1.1 mmol) and the mixture was then stirred at RT for 15 minutes. The mixture was then re-cooled to 0° C., and a solution of 1-(4-chlorophenyl)-4-{[4-(5-chloropyridin-3-yl)-2-(hydroxyamino)butyl]sulfonyl}piperazine (100 mg, 0.22 mmol) in THF was added dropwise via syringe. After stirring at RT for 1.5 hours, volatiles were removed in vacuo, and the residue was azeotroped with toluene (2 mL). The residue was then dissolved in methanol (5 mL) and stirred at 40° C. for 1 hour. After cooling to RT, the solvent was evaporated, and the residue dissolved in methanol (0.5 mL). Diethyl ether (5 mL) was then added and the cloudy suspension stirred at RT for 1 hour. The solid that precipitated was filtered, washed with diethyl ether and dried in vacuo, to give the title compound as an off-white solid (48 mg, 0.099 mmol).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]([CH3:34])([CH3:33])[C:30](O)=[O:31]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:30](=[O:31])[C:29]([F:28])([CH3:34])[CH3:33])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CC(C)(F)C(=O)O
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)C(C)(C)F)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F2) and 2-fluoro-2-methyl-propionic acid followed by deprotection of the intermediate yielded the title compound as a colorless amorphous solid. MS (ESI): m/z=367.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[NH:5][N:4]=1.I[CH2:16][CH3:17].CN(C=O)C.[H-].[Na+]>O>[CH2:16]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)[C:3]([O:2][CH3:1])=[N:4]1)[CH3:17]
Reactant: CCI
Reactant: COc1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(OC)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-methoxy-5-nitro-1H-indazole (100 mg) and iodoethane (0.1 ml) were added to a DMF (1 ml) suspension containing sodium hydride (60% in oil) (23 mg), followed by stirring at room temperature for 0.5 hours. Water was added to the reaction solution. A solid precipitate was collected by filtration and purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:1). 1-Ethyl-3-methoxy-5-nitro-1H-indazole (80 mg) was thus obtained.
Reaction SMILES: CO.[OH:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1.[CH:14](N(C(C)C)CC)(C)C.C[Si](C=[N+]=[N-])(C)C.CCCCCC>C(#N)C>[CH3:14][O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Oc1ccnc2ccccc12
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CO
Solvent: CC#N
Product: COc1ccnc2ccccc12
Reaction time: 13 h

Procedure:
To 15 mL of methanol containing 4.02 g of 4-hydroxyquinoline and 130 mL of an acetonitrile solution, 5.01 g of diisopropylethylamine and 19.4 mL of a 2.0 mol/L trimethylsilyldiazomethane/hexane solution were added at room temperature, and the mixture was stirred for 13 hours, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [silica gel; Chromatorex-NH, manufactured by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate 2:1] to obtain 1.79 g of a yellow oily substance, 4-methoxyquinoline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[N:26](COCC[Si](C)(C)C)[C:25]4[C:24](=[O:35])[N:23]([CH2:36][CH2:37][CH3:38])[CH:22]=[N:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.Cl>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[NH:26][C:25]4[C:24](=[O:35])[N:23]([CH2:36][CH2:37][CH3:38])[CH:22]=[N:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCCn1cnc2nc(-c3ccc(OCC#Cc4ccc(F)cc4)cc3)n(COCC[Si](C)(C)C)c2c1=O
Agent: Cl
Solvent: CCO
Product: CCCn1cnc2nc(-c3ccc(OCC#Cc4ccc(F)cc4)cc3)[nH]c2c1=O
Temperature: 85 °C
Yield: 79.9 %

Procedure:
A mixture of 8-{4-[3-(4-Fluoro-phenyl)-prop-2-ynyloxy]-phenyl}-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.03 g, 0.056 mmol), 2N HCl (1 ml), ethanol (2 ml) was heated at 85° C. for 2 hours. The mixture was cooled and the solvent was evaporated. The residue was washed with n-pentane to obtain 8-{4-[3-(4-fluoro-phenyl)-prop-2-ynyloxy]-phenyl}-1-propyl-1,7-dihydro-purin-6-one (0.018 g, 78%) as off white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([OH:14])[C:8]=3[O:7][C:6]=2[CH:15]=1.C(N(CC)CC)C.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].C(OCC)(=O)C>C1COCC1.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([O:14][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C:8]=3[O:7][C:6]=2[CH:15]=1
Reactant: Oc1cccc2c1oc1cc(Br)ccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1cccc2c1oc1cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of 3-bromo-6-hydroxydibenzofuran (309 mg, 1.17 mmol) in 8 ml THF at room temperature were added triethylamine (0.23 ml, 1.6 mmol), 4-dimethylaminopyridine (14 mg, 0.12 mmol) and t-butyldimethylsilyl chloride (229 mg, 1.5 mmol). The mixture was stirred at room temperature overnight and then diluted into ethyl acetate and washed successfully with NH4Cl (sat.), H2O, and brine. Drying (MgSO4) and evaporation gave 421 mg of brown solid which was purified by flash chromatography through 40 g silica gel (10% EtOAc/hexane) to yield 388 mg (87%) of the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6]2.[N+:17]([O-])([OH:19])=[O:18]>ClCCl>[OH:2][C:3]1[C:4]([N+:17]([O-:19])=[O:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6]2
Reactant: CCOC(=O)c1cc2cc(OC)ccc2[nH]1
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: CCOC(=O)c1cc2c([N+](=O)[O-])c(O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59 %

Procedure:
A mixture of ethyl 5-methoxyindole-2-carboxylate (8.15 g, 37.2 mmol), (prepared by the method described in Heterocycles Vol. 43, No. 2, p. 263-266), nitric acid adsorbed on silica gel (24 g) and dichloromethane (150 ml) was stirred at ambient temperature for 18 hours. The dichloromethane was removed in vacuo and the product washed off the silica with acetone. The acetone was evaporated in vacuo. The residue was treated again with nitric acid on silica (1 g) as above and the work up procedure repeated to give ethyl 5-hydroxy-4-nitroindole-2-carboxylate (5.8 g, 59%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](C(Cl)(Cl)Cl)[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1.[CH2:16]([O-:19])[CH2:17][CH3:18].[Na+].Cl>C(O)CC>[NH2:1][C:2]1[N:7]=[C:6]([O:19][CH2:16][CH2:17][CH3:18])[N:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[N:3]=1
Reactant: CCC[O-]
Reactant: Nc1nc(C(F)(F)F)nc(C(Cl)(Cl)Cl)n1
Agent: Cl
Agent: [Na+]
Solvent: CCCO
Product: CCCOc1nc(N)nc(C(F)(F)F)n1
Temperature: 75 °C

Procedure:
20.0 g (71 mmol) of 2-amino-4-trichloromethyl-6-trifluoromethyl-1,3,5-triazine were added at 22° C. to a solution of 0.58 g (7.1 mmol) of sodium propanolate in 40 ml of propanol. The resulting yellow mixture was then heated at 75° C. for 30 minutes, after which a further 0.58 g (7.1 mmol) of sodium propanolate in 10 ml of propanol was added and the mixture was heated at 75° C. for 10 minutes. The reaction mixture was cooled to 20° C. and then neutralized with 2 normal aqueous hydrochloric acid. After this, most of the solvent was removed under reduced pressure, and the residue was slowly diluted with 40 ml of water. The solid which formed was separated off, washed with 5 ml of water and dried at 40° C. under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH3:12]N(C=O)C.C(Cl)(=O)C(Cl)=O>ClCCl.C(OCC)(=O)C>[CH3:12][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][N:10]=[C:2]([Cl:1])[C:3]=1[Cl:11]
Reactant: O=C(O)c1ccnc(Cl)c1Cl
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccnc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 2,3-dichloro-isonicotinic acid (7.7 g, 40 mmol) in dichloromethane (45 mL) were added DMF (0.1 mL) and oxalyl chloride (17.5 mL, 200 mmol). The reaction mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The resultant residue was azeotroped with toluene, then cooled to 0° C. and dissolved in methanol (135 mL). The mixture was allowed to warm to room temperature and then concentrated under reduced pressure to give a residue. The residue was dissolved in ethyl acetate and the resulting solution was washed with a saturated solution of sodium hydrogen carbonate, water and brine, dried (Na2SO4), filtered and concentrated to give the title compound as a colourless oil that crystallised on standing (7.9 g, 96%). 1H NMR (CDCl3, 400MHz) 8.38 (d, J=5.0 Hz, 1H), 7.52 (d, J=5.0 Hz, 1H), 3.99 (s, 3H).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:11][NH:10][CH2:9][C:4]32[O:8][CH2:7][CH2:6][O:5]3)[CH2:2]1.Br[CH2:13][CH2:14][CH2:15][OH:16].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[OH:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:11][C:3]2([CH2:1][CH2:2]2)[C:4]2([O:5][CH2:6][CH2:7][O:8]2)[CH2:9]1
Reactant: C1COC2(CNCC23CC3)O1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCCN1CC2(CC2)C2(C1)OCCO2

Procedure:
The compound (B) (100 mg) was mixed with 3-Bromopropanol (120 mg) and K2CO3 (120 mg) in Acetonitrile. The reaction was refluxed overnight and filtered; the filtrate was evaporated and purified on silica gel column to give the titled product. Mass: (M+1), 214
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].Cl[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.[OH-].[K+].[NH4+].[Cl-]>CN(C=O)C>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([S:13][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(S)cc(OC)c1OC
Reactant: COc1ccc(CCl)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc(CSc2cc(OC)c(OC)c(OC)c2)cc1

Procedure:
A room temperature solution of Example 85A (194 mg, 0.97 mmol), 1-(chloromethyl)-4-methoxybenzene (162 mg, 1.03 mmol), and KOH (70 mg, 1.25 mmol) in DMF (5 mL) was stirred for 2 hours, treated with saturated NH4Cl, and extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 25% ethyl acetate/hexanes to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[Cl:28][C:29]1[CH:30]=[C:31]([N:37]([CH:39]2[CH2:41][CH2:40]2)[CH3:38])[C:32]([NH2:36])=[CH:33][C:34]=1[F:35]>CCCCCCC.C(OCC)(=O)C>[Cl:28][C:29]1[C:34]([F:35])=[CH:33][C:32]([NH:36][C:11](=[O:12])[C:6]2[C:5]([O:4][C:3]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=3[Cl:1])=[CH:10][CH:9]=[N:8][CH:7]=2)=[C:31]([N:37]([CH:39]2[CH2:40][CH2:41]2)[CH3:38])[CH:30]=1
Reactant: CN(c1cc(Cl)c(F)cc1N)C1CC1
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(c1cc(Cl)c(F)cc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl)C1CC1

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 4-chloro-N2-cyclopropyl-5-fluoro-N2-methyl-benzene-1,2-diamine and using a gradient of n-heptane:ethyl acetate (100:0 to 30:70) for the chromatographic purification. Colorless solid (70%). MS (ESI): m/z=446.083 [M+H]+.