Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](O)=[O:12].CCN=C=NCCCN(C)C.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1>ClCCl>[CH:14]1[C:10]2[C:11](=[O:12])[NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8][C:9]=2[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1Sc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1Nc2ccccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-((2-aminophenyl)thio)benzoic acid, prepared as described in the previous step, (30 g, 0.122 mol) in dichloromethane (300 mL) was added EDCI (35.2 g, 0.183 mol), triethylamine (51 mL, 0.366 mol) and HOBT (24.7 g, 0.183 mol). The reaction mixture was stirred at room temperature for 12 hours, washed with 1M aq.HCl, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, and dried over MgSO4. The solution was filtered, concentrated, and purified by column chromatography to provide the title compound. ESI-MS (M+1): 228 calc. for C13H9NOS 227. 1H NMR: (CDCl3, 400 MHz): δ (ppm) 7.70-7.67 (m, 1H), 7.58-7.52 (m, 2H), 7.50-7.42 (m, 2H), 7.39-7.35 (m, 1H), 7.24-7.22 (m, 1H), 7.17-7.13 (m, 1H).
Reaction SMILES: I[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]([F:28])([F:27])[C:17]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:25]([O:24][C:22]([C:20]1[N:19]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[N:18]=[C:17]([C:16]([F:27])([F:28])[F:15])[CH:21]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)c1cc(C(F)(F)F)n[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(I)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(C(F)(F)F)nn1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 39.9 %

Procedure:
tert-Butyl 4-iodopiperidine-1-carboxylate (5.683, 18.26 mmol, E.G. Corley et al, JOC, 2004, 69, 5120-5123) in DMF (30.7 ml) was added to a mixture of ethyl 3-(trifluoromethyl)-1H-pyrazole-5-carboxylate (3.2 g, 15.37 mmol, M.-A. Plancquaert et al, Tetrahedron, 52, 4383-4396) and potassium carbonate 95.31 g, 38.4 mmol) and the mixture was stirred at 80° C. for 16 h. After cooling, water was added and the mixture was extracted with EtOAc, and the organic extraxts were dried, filtered and concentrated. Chromatographic purification of the residue by Biotage (5-20% EtOAc in Hexanes, 25M column) gave compound 93 as colorless oil (2.4 g, 39.9% yield). LRMS (ESI): calc. 391.4; found 414.1 (M+Na)+.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].O.C1(C)C=CC(S(O[CH2:22][CH:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH3:24])(=O)=O)=CC=1>C(O)C>[CH2:26]([O:25][CH:23]([CH3:22])[CH2:24][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: Oc1ccc(O)cc1
Reactant: CCCCCCCCOC(C)COS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCOC(C)COc1ccc(O)cc1

Procedure:
17.0 g of hydroquinone, 11.4 g of 85% KOH, 7.5 ml of water and 200 ml of ethanol were added into a four-necked flask, and after the reaction for 5 hours, the mixture was elevated in temperature to 50° C. and 33 g of (2'-octyloxypropyl) p-toluenesulfonate was added dropwise thereto. After the reaction for 5 hours, the mixture was heated at reflux for 11 hours and thereafter ethanol was evaporated. The residue was added into 600 ml of water and acidified with hydrochloric acid. The mixture was extracted with 500 ml of hexane and the extract was dried over anhydrous Na2SO4, followed by recrystallization. Yield: 4.2 g (16%). Optical rotation [α]D26.2° =-11.3°.
Reaction SMILES: [CH3:1]/[C:2](=[CH:5]\[CH2:6][C@H:7]1[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]1([CH3:14])[CH3:13])/[CH:3]=[O:4].CC1[C@H]2C(C)(C)[C@H](C2)CC=1.NCCCN.[OH-].[K+]>C(O)(C)C>[CH3:1]/[C:2](=[CH:5]\[CH2:6][C@H:7]1[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]1([CH3:14])[CH3:13])/[CH2:3][OH:4]
Reactant: CC1=CC[C@H](C/C=C(\C)C=O)C1(C)C
Agent: CC1=CC[C@H]2C[C@@H]1C2(C)C
Agent: NCCCN
Agent: [K+]
Solvent: CC(C)O
Product: CC1=CC[C@H](C/C=C(\C)CO)C1(C)C

Procedure:
In a 100 ml stainless steel autoclave were charged 3.84 g (0.02 mol) of (E)-(R)-2-methyl-4-(2,2,3-trimethylcyclopent-3-en-1-yl)-2-buten-1-al synthesized from (1S,5S)-α-pinene having an optical purity of 97% e.e. (available from Aldrich) in a conventional manner, 38.4 mg (0.04 mmol) of RuCl2 (PPh3)3, 4 ml of a 0.02M 1,3-diaminopropane (0.08 mmol) solution in isopropyl alcohol, and 12 ml of a 0.1M potassium hydroxide (1.2 mmol) solution in isopropyl alcohol in a nitrogen atmosphere, and the mixture was stirred at 0° C. for 3 hours under a hydrogen pressure of 50 atm.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH:22]=O)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].CC(O)=O.[CH3:28][C:29]1([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[BH3-]C#N.[Na+]>C(Cl)Cl>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:32]2[CH2:33][CH2:34][C:29]([CH3:28])([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:30][CH2:31]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1(C)CCNCC1
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1(C)CCN(Cc2ccc3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 6-(trans-4-tert-butylcyclohexyloxy)-2-naphthaldehyde (500 mg, 1.6 mmol), AcOH (288 mg, 4.8 mmol, 3.0 eq) and ethyl 4-methylpiperidine-4-carboxylate (410 mg, 2.4 mmol, 1.5 eq) in DCM (5 mL) was stirred at room temperature for 10 min. Then NaBH3CN (300 mg, 4.8 mmol, 3.0 eq) was added. The reaction mixture was stirred at room temperature for 12 h, quenched with water (5 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (Petroleum ether:ethyl acetate=3:1) to give ethyl 1-((6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)-4-methylpiperidine-4-carboxylate (480 mg, yield: 30%) as a yellow oil. ESI-MS (M+1)+: 466.2. 1HNMR (400 MHz, CDCl3) δ: 7.75˜7.73 (m, 3H), 7.48 (d, 1H), 7.18˜7.15 (m, 2H), 4.28˜4.26 (m, 1H), 4.19˜4.12 (q, 2H), 4.01 (s, 2H), 3.17˜3.15 (m, 2H), 2.59 (br, 2H), 2.29˜2.17 (m, 4H), 1.91˜1.82 (m, 4H), 1.46˜1.43 (m, 3H), 1.30˜1.18 (m, 8H), 0.88 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([S:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)(=[O:14])=[O:13])[C:9]([O:24]C)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([S:12]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)(=[O:13])=[O:14])[C:9]([OH:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COc1c(S(=O)(=O)NCc2ccc(Cl)cc2)cc(Cl)c2cccnc12
Solvent: ClCCl
Product: O=S(=O)(NCc1ccc(Cl)cc1)c1cc(Cl)c2cccnc2c1O

Procedure:
Under N2, a flame-dried, 50-mL, two-necked flask is charged with 5-chloro-N-[(4-chlorophenyl)methyl]-8-methoxy-7-quinolinesulfonamide (0.322 g), which is the first title compound of Preparation 9, and CH2Cl2 (20 mL) and is cooled in a dry ice/acetone bath. 1.0 M BBr3 (1.05 mL) is added dropwise. The cooling bath is removed and the reaction mixture is allowed to stir for 1.5 hrs. It is then poured into 75 mL 5% NaHCO3 aqueous solution, and the layers are separated. The aqueous layer is extracted twice with CH2Cl2. The combined organic layers are washed with H2O and then brine, dried over MgSO4, filtered and concentrated to a brown residue. Purification by column chromatography (elution with 2-5% MeOH/CH2Cl2 with <1% AcOH) yields 0.037 g of the title compound as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8](C(OC(C)(C)C)=O)[C:9]1[C:17]([C:18]([O-:20])=[O:19])=[C:12]2[N:13]=[CH:14][CH:15]=[CH:16][N:11]2[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[C:17]([C:18]([OH:20])=[O:19])=[C:12]2[N:13]=[CH:14][CH:15]=[CH:16][N:11]2[N:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nn2cccnc2c1C(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1nn2cccnc2c1C(=O)O
Temperature: 70 °C
Yield: 99.8 %

Procedure:
To a solution of 2-(bis(tert-butoxycarbonyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (220 mg, 0.54 mmol) in ethanol (15 mL) was added 4 mL of a 10% aqueous lithium hydroxide solution. The reaction mixture was heated to 70° C. for 18 hrs, then cooled to room temperature. 15 mL of a 10% aqueous solution of citric acid was added and the reaction mixture concentrated in vacuo. The residue was partitioned between EtOAc and a saturated aqueous solution of citric acid, then the organic layer was washed with water and brine, then dried over Na2SO4, filtered and concentrated in vacuo to afford 150 mg of 2-(tert-butoxycarbonylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid. 1H NMR (400 MHz, DMSO) δ 9.34 (s, 1H), 9.12 (dd, J=6.9, 1.7, 1H), 8.71 (dd, J=4.3, 1.7, 1H), 7.20 (dd, J=6.9, 4.3, 1H), 1.49 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23]C3CCCCO3)[CH:17]=2)=[C:11]([CH3:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[CH:17]=2)=[C:11]([CH3:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OCc2ccccc2)cc(C)c1-c1cccc(COC2CCCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: Cc1cc(OCc2ccccc2)cc(C)c1-c1cccc(CO)c1
Yield: 83.5 %

Procedure:
A solution of 2-{[4′-(benzyloxy)-2′,6′-dimethylbiphenyl-3-yl]methoxy}tetrahydro-2H-pyran (1.71 g, 4.25 mmol) and p-toluenesulfonic acid monohydrate (80.8 mg, 0.425 mmol) in methanol (15 mL) was stirred at room temperature for 20 hrs. The reaction solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-50% ethyl acetate/hexane) to give the title compound (1.13 g, yield 84%) as a colorless oil.
Reaction SMILES: C(OC([N:8]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:9]([C:15]([OH:17])=O)[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=O)(C)(C)C.[NH2:25][CH:26]1[CH2:32][CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[NH:28][C:27]1=[O:37]>>[C:21]([O:20][C:18]([NH:8][C@@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:15]([NH:25][CH:26]1[CH2:32][CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[NH:28][C:27]1=[O:37])=[O:17])=[O:19])([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](CCCCN)C(=O)O
Reactant: NC1CCc2ccccc2NC1=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CCc2ccccc2NC1=O

Procedure:
Prepared from Na, Ne -di(t-butoxycarbonyl)L-lysine and 3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (Example 1, Step A) by the procedure described in Example 25, Step A. 1H NMR (200 MHz, CDCl3): 1.2-2.1 (m,24 H), 2.6-3.3 (m,6 H), 4.20 (m,1 H), 4.62 (m,2H), 5.26 (m,1H), 7.0-7.4 (m,4 H). FAB-MS: calculated for C26H40N4O6 504; found 505 (M+H,20%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]([CH:12]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][O:14][C:15](=[O:18])[CH:16]=[CH2:17])[CH3:11]>[Pd].C(N(CC)CC)C>[CH3:22][CH2:21][CH2:20][CH2:19][CH:12]([CH2:13][O:14][C:15](/[CH:16]=[CH:17]/[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)=[O:18])[CH2:10][CH3:11]
Reactant: C=CC(=O)OCC(CC)CCCC
Reactant: COc1ccc(I)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Product: CCCCC(CC)COC(=O)/C=C/c1ccc(OC)cc1
Temperature: 142.5 °C
Reaction time: 3 h

Procedure:
Charge 6.8 gallons of molten 4-iodoanisole from step 1, 11.4 gallons 2-ethylhexylacrylate (83.8 pounds), 7.3 gallons triethylamine (44 pounds), and 0.6 pounds of 5% palladium on carbon catalyst (dry) to a 50 gallon tank. With good agitation, begin heating. Heat to 100° -105° C. to reflux. The reflux temperature will gradually increase to about 140-145° C. The total time of reaction above 100° C. will be about 2-4 hours. After the reaction is complete, as determined by gas chromatography, cool the reaction mixture to 25° -30° C. Filter to collect the palladium catalyst and the resulting triethylamine hydroiodide salt. Wash the filtered product with 20 gallons of water to remove any soluble salt. Allow the phases to separate. The top organic product phase is ready for distillation. Its volume is about 15 gallons containing about 119 pounds of product.
Reaction SMILES: O[CH2:2][C:3]1[NH:22][C:6]2=[CH:7][C:8]3[C:9]([CH3:21])([CH3:20])[C:10](=[O:19])[N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:12]=3[CH:13]=[C:5]2[N:4]=1.S(Cl)([Cl:25])=O>C(Cl)(Cl)Cl>[Cl:25][CH2:2][C:3]1[NH:22][C:6]2=[CH:7][C:8]3[C:9]([CH3:21])([CH3:20])[C:10](=[O:19])[N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:12]=3[CH:13]=[C:5]2[N:4]=1
Reactant: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(CO)nc3cc21
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCCCN1C(=O)C(C)(C)c2cc3[nH]c(CCl)nc3cc21
Temperature: 60 °C
Reaction time: 15 h

Procedure:
E1 (330 mg) is dissolved in CHCl3 (5 ml), thionyl chloride (1.2 ml) is added and the mixture is stirred at 60° C. for 15 h. The reaction mixture is concentrated in vacuo to give the compound.
Reaction SMILES: Cl[C:2]1[C:6]2[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:5]=2[S:4][N:3]=1.[Na].[CH3:13][OH:14]>>[CH3:13][O:14][C:2]1[C:6]2[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:5]=2[S:4][N:3]=1
Reactant: CO
Reactant: O=C1CCCc2snc(Cl)c21
Agent: [Na]
Product: COc1nsc2c1C(=O)CCC2

Procedure:
A mixture of 3-chloro-4,5,6,7-tetrahydro-1,2-benzisothiazol-4-one 24a (600 mg) and a solution of sodium (506 mg) in methanol (22 mL) was stirred at 90° C. for 1 h. The reaction mixture was evaporated and water (20 mL) was added to the residue. Extractions with methylene chloride (3×30 mL), drying and evaporation gave an oil. Column chromatography on silica gel (eluent:toluene-ethyl acetate 4:1) gave the title compound (251 mg). Mp 45-46° C.
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.[C:22]([CH:24]([C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)[CH2:25][C:26]([O:28]C)=[O:27])#[N:23]>>[C:22]([CH:24]([C:30]1[CH:35]=[CH:34][C:33]([O:14][CH2:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][CH2:5]/[C:4](/[C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)=[N:3]\[O:2][CH3:1])=[CH:12][CH:11]=2)=[CH:32][CH:31]=1)[CH2:25][C:26]([OH:28])=[O:27])#[N:23]
Reactant: COC(=O)CC(C#N)c1ccc(O)cc1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1cccc(F)c1
Product: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)O)cc2)cc1)c1cccc(F)c1
Yield: 18.73 %

Procedure:
Compound 35 was synthesized from (1Z)-1-(3-fluorophenyl)-2-[4-(hydroxymethyl)phenoxy]ethanone O-methyloxime (0.5 g, 1.8 mmol) and methyl 3-cyano-3-(4-hydroxyphenyl)propanoate (0.372 g, 1.8 mmol) by following the procedure described in scheme 18 (0.1 g, yield: 18.73%); Purity: 95.1%.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8]([Cl:14])=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1>>[Cl:14][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[CH:13][C:4]=2[NH:1][S:23]([C:18]2[CH:17]=[C:16]([F:15])[CH:21]=[C:20]([F:22])[CH:19]=2)(=[O:25])=[O:24])[N:9]=1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Product: O=S(=O)(Nc1cccc2nc(Cl)ccc12)c1cc(F)cc(F)c1

Procedure:
The intermediate N-(2-chloro-quinolin-5-yl)-3,5-difluoro-benzenesulfonamide was prepared in accordance with the general method of example 61, step A and B from 5-nitro-2-chloroquinoline, 3,5-difluorobenzenesulfonylchloride.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[N:10]([CH3:35])[C:11](=[O:34])[CH2:12][N:13]([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[CH3:27])[N:23](C1CCCCO1)[N:22]=[CH:21]2)[CH2:14][C:15]([OH:17])=[O:16].S(=O)(=O)(O)O.[CH2:41](O)[CH3:42]>>[CH2:41]([O:17][C:15](=[O:16])[CH2:14][N:13]([CH2:12][C:11]([N:10]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[CH3:35])=[O:34])[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[CH3:27])[NH:23][N:22]=[CH:21]2)[CH3:42]
Reactant: CCO
Reactant: Cc1cc2c(cnn2C2CCCCO2)cc1N(CC(=O)O)CC(=O)N(C)N1Cc2ccccc2C1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CN(CC(=O)N(C)N1Cc2ccccc2C1)c1cc2cn[nH]c2cc1C
Yield: 83 %

Procedure:
The compound (2.23 g, 4.67 mmol) of step A was dissolved in ethanol (60 ml), concentrated sulfuric acid (0.5 ml) was added at room temperature, and the mixture was heated under reflux for 80 min. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (1.64 g, yield 83%) as a colorless amorphous solid.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:21]=[CH:22][C:15]=12.CN(C)[CH:34]=[O:35]>O1CCCC1>[Br:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]2[N:20]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:21]([CH:34]=[O:35])=[CH:22][C:15]=12
Reactant: CN(C)C=O
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=Cc1cc2c(Br)ccnc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
n-Butyllithium (2.5M in hexanes, 3.56 mmol) was added dropwise to a solution of diisopropylamine (3.56 mmol) in anhydrous tetrahydrofuran (5 mL) at −78° C. under nitrogen. The reaction was stirred for 30 minutes at −78° C. and then a solution of 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.97 mmol) in anhydrous tetrahydrofuran (1 mL) was added dropwise via syringe. The resulting reaction was stirred at −78° C. for 2 h and then a solution of N,N-dimethylformamide (11.88 mmol) in tetrahydrofuran (1 mL) was added dropwise by syringe. The reaction was stirred at −78° C. for 2 h and then quenched with saturated aqueous ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate (2×20 mL), and the combined organic layers were dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography (Analogix IF280, 70-100% CH2Cl2/hexanes) afforded the title compound as a white solid (66%). ESMS [M+H]+: 365.0
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@@H:12]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[O:11][C@H:10]1[N:31]1[C:40]2[N:39]=[CH:38][N:37]=[C:35]([NH2:36])[C:34]=2[N:33]=[C:32]1[NH:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[C:45]([OH:55])[CH:44]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:63][CH2:64][CH2:65][Cl:66]>CN(C)C=O>[Si:1]([O:8][C@@H:9]1[C@H:13]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17])[C@@H:12]([CH2:22][O:23][Si:24]([C:27]([CH3:28])([CH3:29])[CH3:30])([CH3:25])[CH3:26])[O:11][C@H:10]1[N:31]1[C:40]2[N:39]=[CH:38][N:37]=[C:35]([NH2:36])[C:34]=2[N:33]=[C:32]1[NH:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)=[C:45]([O:55][CH2:63][CH2:64][CH2:65][Cl:66])[CH:44]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: ClCCCBr
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(NCc3ccc(-c4ccccc4)c(O)c3)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(NCc3ccc(-c4ccccc4)c(OCCCCl)c3)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 40 °C
Reaction time: 42 h

Procedure:
To a solution of 2′,3′,5′-tris-O-(tert-butyl-dimethylsilyl)-8-(2-hydroxybiphenyl-4-ylmethylamino)-adenosine (0.85 g) in N,N-dimethylformamide (5.3 mL) was added potassium carbonate (0.44 g). Then 1-bromo-3-chloropropane (0.16 mL) was added, and the resulting mixture was stirred at 40° C. for 42 hours. The reaction mixture was partitioned between diethyl ether (45 mL) and water (10 mL). The organic layer was washed successively with water (10 mL×2), and brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (0.91 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:29][N:30]1[CH:34]=[CH:33][C:32]([NH:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[C:43]([OH:46])[CH:44]=3)[N:39]=[CH:38][N:37]=2)=[N:31]1>O>[CH2:12]([O:11][CH:10]([O:14][CH2:15][CH3:16])[CH2:9][O:8][C:5]1[CH:4]=[N:3][C:2]([O:46][C:43]2[CH:44]=[C:45]3[C:40](=[CH:41][CH:42]=2)[N:39]=[CH:38][N:37]=[C:36]3[NH:35][C:32]2[CH:33]=[CH:34][N:30]([CH3:29])[N:31]=2)=[N:7][CH:6]=1)[CH3:13]
Reactant: CCOC(COc1cnc(Cl)nc1)OCC
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(COc1cnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)nc1)OCC
Temperature: 200 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
2-Chloro-5-(2,2-diethoxyethoxy)pyrimidine (225 mg, 0.91 mmol) obtained in Example 7 and potassium tert-butoxide (116 mg, 1.04 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (100 mg, 0.42 mmol), and stirred at 200° C. for 18 hours under a nitrogen atmosphere in a sealed tube. The reaction solution was cooled with ice, water was added, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Moritex, acetone:hexane=2:3) to obtain 6-{[5-(2,2-diethoxyethoxy)pyrimidin-2-yl]oxy}-N-(1-methyl-1H-pyrazol-3-yl)quinazoline-4-amine (177 mg, yield: 95%) as a pale orange amorphous solid.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[NH:6][CH:5]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[N:14]1([CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=3)[NH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: Fc1ccc2[nH]cc(CCBr)c2c1
Reactant: c1c[nH]cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Fc1ccc2[nH]cc(CCn3ccnc3)c2c1

Procedure:
A solution of 3-(2-bromo-ethyl)-5-fluoro-1H-indole (4.84 g, 20 mmol), imidazole (1.36 g, 20 mmol) and ethyl-diisopropylamine (3.4 ml, 20 mmol) in abs. dioxane (50 ml) was stirred at 90° C. for 8 h until according to TLC educt was no longer present. The solvent was then removed i. vac., CHCl3 (100 ml) was added to the residue and the organic phase was washed twice with water. The organic phase was dried over Na2SO4 and concentrated i. vac. and the residue which remained was purified by flash chromatography with CHCl3/MeOH (9:1).