Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[Cl:16])[C:12](=[O:17])[C:11]1[C:10]([OH:18])=[CH:9][CH:8]=[C:7]([OH:19])[C:6]=1[C:5]2=[O:20].[NH4+].[OH-].S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[Cl:16])[C:12]([OH:17])=[C:11]1[C:6]([C:7]([OH:19])=[CH:8][CH:9]=[C:10]1[OH:18])=[C:5]2[OH:20]
Reactant: O=C1c2cc(Cl)c(Cl)cc2C(=O)c2c(O)ccc(O)c21
Agent: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Product: Oc1ccc(O)c2c(O)c3cc(Cl)c(Cl)cc3c(O)c12
Temperature: 55 °C

Procedure:
Ten grams (32.35 mmol) of 6,7-dichloro- 1,4-dihydroxyanthraquinone were pulverized with enough NH4OH to make a paste. This was transferred to a 500 mL round bottom (RB) flask, using additional NH4OH to make the reaction mixture 0.13-0.16 M. While stirring, 6.72 grams (38.60 mmol) sodium hydrosulfite were added portionwise over 1.5 hours. Immediately after addition, the mixture was heated slowly to 55° C. on a steam bath, then heated at 55° C. for about 1.5 hours. After cooling to room temperature, the mixture was filtered, washed twice with water, and pulled dry on the funnel for a brief period. The product was dried overnight in a vacuum oven at 55-65° C. FDMS showed a mixture of starting material and product. This mixture was carried on to compound 2 of Table 1.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]1[N:11]=[C:10]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=[C:8]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:7]=1)([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC(S(O[CH2:42][C:43](=[O:65])[C@@H:44]2[C@:61]3([CH3:62])[C@H:47]([C@H:48]4[C:58](=[CH:59][CH2:60]3)[C@:56]3([CH3:57])[C:51](=[CH:52][C:53](=[O:63])[CH:54]=[CH:55]3)[CH2:50][CH2:49]4)[CH2:46][C@H:45]2[CH3:64])(=O)=O)=CC=1)([O-])=O>CC(C)=O>[CH3:4][C:2]([NH:5][C:6]1[N:11]=[C:10]([NH:12][C:13]([CH3:14])([CH3:15])[CH3:16])[CH:9]=[C:8]([N:17]2[CH2:18][CH2:19][N:20]([CH2:42][C:43](=[O:65])[C@@H:44]3[C@:61]4([CH3:62])[C@H:47]([C@H:48]5[C:58](=[CH:59][CH2:60]4)[C@:56]4([CH3:57])[C:51](=[CH:52][C:53](=[O:63])[CH:54]=[CH:55]4)[CH2:50][CH2:49]5)[CH2:46][C@H:45]3[CH3:64])[CH2:21][CH2:22]2)[N:7]=1)([CH3:1])[CH3:3]
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)COS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)Nc1cc(N2CCNCC2)nc(NC(C)(C)C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CN1CCN(c2cc(NC(C)(C)C)nc(NC(C)(C)C)n2)CC1

Procedure:
After adding 1.40 g (4.57 moles) of 2,4-bis(1,1-dimethylethylamino)-6-(1-piperazinyl}pyrimidine and 0.63 g of potassium carbonate to a solution containing 2.00 g (3.805 mmoles) of 21-(4-nitrobenzenesulfonyloxy)-16α-methylpregna-1,4,9(11)-triene-3,20-dione in 100 ml of acetone, the reaction mixture is boiled under reflux for 8.5 hours, then evaporated. The residue is distributed between 40 ml of chloroform and 10 ml of water. The chloroform layer is dried and evaporated. The residue is purified on a silica gel column by using a 98:2 mixture of chloroform/methanol as eluent. After recrystallization the title compound is obtained in a yield of 1.53 g (64%), m.p.:145°-155° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:9])[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[S:10](Cl)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11]>N1C=CC=CC=1>[S:10]([O:8][CH:5]1[CH2:6][CH2:7][S:2](=[O:9])(=[O:1])[CH2:3][CH2:4]1)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=S1(=O)CCC(O)CC1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCS(=O)(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
1,1-Dioxo-tetrahydrothiopyran-4-ol (1.0 g, 6.6 mmol), pyridine (10 mL), and tosyl chloride (1.6 g, 8.4 mmol) were combined and stirred at room temperature overnight. The reaction mixture was concentrated, diluted in EtOAc and washed with aqueous HCl and brine. The organic layer was dried, concentrated and triturated with hexane to yield O-tosyl-1,1-dioxo-tetrahydrothiopyran-4-ol (1.073 g, 53%) as a white solid.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[N:10]=[C:11]([CH:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[S:12][CH:13]=1)=[O:8])C>C1COCC1.O>[C:19]([O:18][C:17](=[O:23])[NH:16][CH:14]([C:11]1[S:12][CH:13]=[C:9]([C:7]([OH:8])=[O:6])[N:10]=1)[CH3:15])([CH3:20])([CH3:21])[CH3:22]
Reactant: CCOC(=O)c1csc(C(C)NC(=O)OC(C)(C)C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)c1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54 %

Procedure:
Lithium hydroxide monohydrate (165 mg, 3.9 mmol) was added to a solution of tert-butyl (1-(4-(ethyloxycarbonyl)thiazol-2-yl)ethyl)carbamate (1.4 g crude material) in THF (25 ml) and water (20 ml) and stirred at room temperature for 18 h. A further amount of lithium hydroxide monohydrate was added (165 mg) and stirring continued for 4 h. The THF was removed in vacuo, the aqueous residue acidified with 1N hydrochloric acid and extracted twice with chloroform. The combined organic layers were washed with brine, dried and reduced. Chromatography (50:2:1 chloroform, methanol, acetic acid) and recrystallisation (EtOAc/hexanes) afforded tert-butyl(1-(4-carboxythiazol-2-yl)ethyl)carbamate (686 mg, 64% over two steps).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4].CC#N.[N:27]1([CH2:33][CH2:34][OH:35])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.[I-].[Na+]>Cl.CO>[NH2:23][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:21])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:30]1[CH2:31][CH2:32][N:27]([CH2:33][CH2:34][OH:35])[CH2:28][CH2:29]1
Reactant: OCCN1CCNCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCCN3CCN(CCO)CC3)c2n1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
An aliquot (0.2 mL, 0.1 mmol) of a solution of 2-(butyloxy)-9-(5-chloropentyl)-8-(methyloxy)-9H-purin-6-amine (for example, as prepared for Intermediate 44) in MeCN (prepared by dissolving 410 mg, 1.2 mmol in MeCN (2.4 mL)) was added to 2-(1-piperazinyl)ethanol (commercially available, for example, from Aldrich) (0.1 mmol) in a test tube. DIPEA (50 μl, 3 equivalents) and sodium iodide (5 mg) were added. The reaction mixture was heated to 60° C. for 18 hours in a Radleys greenhouse. The samples were filtered then DMSO (0.3 mL) was added and the solution and purified MDAP on Xbridge column using Acetonitrile Water with an ammonium carbonate modifier. The solvent was evaporated in vacuo using the Genevac to give an intermediate. 2N HCl/MeOH (200 μL) added to each vial, capped and stood at room temperature for 4 hours. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus. The residue was redissolved in methanol (0.5 mL) and applied to top of an aminopropyl SPE (0.1 g, 3 mL, preconditioned in methanol (1.5 mL)). The cartridge was washed methanol (2×1.5 mL). The solvent was removed to give the title compound (0.0175 g).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:22])=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)(=[O:14])=[O:13])[S:4][C:3]=1[CH3:23].CC1(C)C(C)(C)OB([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.O.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>[Cl:21][C:17]1[CH:16]=[C:15]([S:12]([NH:11][C:9]2[CH:8]=[C:7]([CH3:22])[N:6]=[C:5]3[S:4][C:3]([CH3:23])=[C:2]([CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:10]=23)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Br)c(C)sc2n1
Reactant: CC1(C)OB(Cc2ccccc2)OC1(C)C
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: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(Cc3ccccc3)c(C)sc2n1
Temperature: 100 °C
Yield: 32.4 %

Procedure:
Under nitrogen, N-(3-bromo-2,6-dimethylthieno[2,3-b]pyridin-4-yl)-3-chlorobenzenesulfonamide (100 mg, 0.232 mmol) (Example 61) was dissolved in 1,4-dioxane (1.5 mL) and water (0.7 mL). 4,4,5,5-Tetramethyl-2-(phenylmethyl)-1,3,2-dioxaborolane (0.077 mL, 0.347 mmol), tetrakis(triphenylphosphine)palladium(0) (26.8 mg, 0.023 mmol) and potassium carbonate (96 mg, 0.695 mmol) were added and the mixture heated at 100° C. overnight. Ethyl acetate (10 mL) was added and the mixture washed with water (2×5 mL). The organic layer was dried over MgSO4, filtered and the solvent removed in vacuo. Purification by chromatography on silica gel, eluting with a gradient of 70% ethyl acetate in cyclohexane, afforded the title compound (33.3 mg). LCMS (A) m/z: 443 [M+1]+, Rt 1.28 min (acidic), Rt 0.97 min (basic).
Reaction SMILES: C[C@@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[NH:3][CH2:4][C:5]1C=C[CH:8]=[CH:7][CH:6]=1.C([Li])CCC.C(OCC)(=[O:26])/C=C/C>C1COCC1>[CH2:2]([N:3]1[C@@H:7]([CH3:8])[CH2:6][C:5](=[O:26])[CH2:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C/C=C/C(=O)OCC
Reactant: C[C@H](NCc1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H]1CC(=O)CN1Cc1ccccc1
Reaction time: 0.33 h
Yield: 158.3 %

Procedure:
To a stirred solution of 20.394 g (96.513 mmol) of (S)-alpha-methyl-N-(phenylmethyl)-benzenemethanamine (from Example 5) in 400 mL of THF, cooled to 0° C., was added, over a 10 minute period, 38.61 g (96.525 mmol) of n-butyllithium, and the reaction was stirred for an additional 15 minutes. To this solution was added 10.00 mL (80.427 mmol) of ethyl crotonate with stirring over a 20 minute period, and the solution was stirred for an additional 20 minutes. The reaction was quenched by addition of an excess of saturated ammonium chloride solution, and the mixture was extracted with ether. The ether extract was washed with saturated brine, dried over MgSO4 and concentrated to give a colorless liquid. The crude product was chromatographed on silica gel, eluting with 1:4 ethyl acetate:hexane, and the solvent was removed to afford 24.10 g (92.1%) of the title product as a colorless oil. MS M/Z: 326 (M+H). NMR (CDCl3) δ: 1.13 (d, 3 H, J=7 Hz), 1.16 (t, 3H, J=7 Hz), 1.35 (d, 3H, J=7 Hz), 2.10 (dd, 1H, J=14 Hz, J=6 Hz), 2.36 (dd, 1H, J=14 Hz, J=6 Hz), 3.44 (m, 1H), 3.67 (d, 1H, J=14 Hz), 3.74 (d, 1H, J=14 Hz), 3.88-4.07 (m, 3H), 7.19-7.42 (10H). Anal calc. for C21H27NO2 : C, 77.50; H, 8.36 N, 4.30; found: C, 77.46; H, 8.37; N, 4.28.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].[O:12]([CH2:19][C:20](Cl)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>[OH-].[Na+]>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH:11][C:20](=[O:21])[CH2:19][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: O=C(Cl)COc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(C(=O)O)c1NC(=O)COc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
3-Methylanthranilic acid 5 g (33 mmol) was dissolved in 10% aqueous sodium hydroxide solution 27 ml and to this solution, phenoxyacetyl chloride 6.2 g (36 mmol) was added dropwise at 0° C. The resulting solution was stirred at room temperature for 1 hour and acidified with 10% hydrochloric acid solution. Deposited crystals were collected by filtration, washed with water and recrystallized from ethanol to obtain 3-methyl-N-(phenoxyacetyl)anthranilic acid (melting point: 174° to 176° C.) 4.4 g (yield: 47%).
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1[C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(Cl)(=O)C(C)(C)C.Cl.[CH:31]1([CH:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40][CH2:39][NH:38]2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.Cl>ClCCCl.CCOC(C)=O>[CH:31]1([CH:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:40][CH2:39][N:38]2[C:17]([C@@H:16]2[CH2:20][CH2:21][CH2:22][N:15]2[C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])=[O:19])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: c1ccc2c(c1)CCNC2C1CCCCC1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCc2ccccc2C1C1CCCCC1
Reaction time: 1 h
Yield: 109.2 %

Procedure:
N-methylmorpholine (0.873 mL) was added to a solution of 1-(tert-butoxycarbonyl)-L-proline (1.28 g) in 1,2-dichloroethane (10 mL) under ice-cooling, followed by further addition of pivaloyl chloride (0.734 mL). The reaction liquid was stirred for 1 hour, and N-methylmorpholine (1.09 mL) and 1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.00 g) were then added thereto. The mixture was stirred at room temperature for 15 hours. To the reaction solution were added EtOAc and an aqueous 1 M HCl solution. The organic layer was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain tert-butyl (2S)-2-[(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]pyrrolidine-1-carboxylate (1.79 g).
Reaction SMILES: [CH3:1][C:2]([NH:4][C@H:5]1[C@H:10]([C@H:11]([OH:16])[C@H:12]([OH:15])[CH2:13][OH:14])[O:9][C@:8]([O:20]P(OC[C@H]2O[C@@H](N3C(=O)N=C(N)C=C3)[C@H](O)[C@@H]2O)(O)=O)([C:17]([OH:19])=[O:18])[CH2:7][C@@H:6]1[OH:41])=[O:3].OC(C1(O[C@@H]([C@@H]([C@@H](CO)O)O)[C@H](NC(C)=O)[C@@H](O)C1)O)=O.[O:63]([C@@H]1[C@@H](CO)O[C@@H](O)[C@H](NC(C)=O)[C@H]1O)[C@@H:64]1[O:72][C@H:71]([CH2:73][OH:74])[C@H:69]([OH:70])[C@H:67](O)[C@H:65]1[OH:66].O=C[C@@H]([C@H]([C@H]([C@@H](CO)O)O)O)O>>[OH:19][C:17]([C@@:8]1([O:9][C@@H:10]([C@@H:11]([C@@H:12]([CH2:13][OH:14])[OH:15])[OH:16])[C@H:5]([NH:4][C:2]([CH3:1])=[O:3])[C@@H:6]([OH:41])[CH2:7]1)[O:20][C@H:67]1[C@@H:69]([OH:70])[C@@H:71]([CH2:73][OH:74])[O:72][C@@H:64]([OH:63])[C@@H:65]1[OH:66])=[O:18]
Reactant: CC(=O)N[C@@H]1[C@@H](O)[C@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@@H](CO)O[C@H]1O
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)O[C@](OP(=O)(O)OC[C@H]2O[C@@H](n3ccc(N)nc3=O)[C@H](O)[C@@H]2O)(C(=O)O)C[C@@H]1O
Agent: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(O)(C(=O)O)C[C@@H]1O
Agent: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Product: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)O[C@@](O[C@@H]2[C@@H](O)[C@H](O)O[C@H](CO)[C@@H]2O)(C(=O)O)C[C@@H]1O

Procedure:
The resulting CMP-sialic acid analogue, illustrated in FIG. 28 as the CMP derivative of Neu5Ac (i.e., CMP-Neu5Ac), is then combined with the derivatized βGal(1→4)βGlcNAc-OR compound in the presence of the βGal(1→3/4)βGlcNAc α(2→3)sialyltransferase under conditions wherein sialic acid is transferred to the 3 position of the galactose to form a αNeu5Ac(2-3)βGal- linkage. Suitable conditions, known in the art, include the addition of the sialyltransferase to a mixture of the derivatized βGal(1→4)βGlcNAc-OR compound and of the CMP-sialic acid in a appropriate buffer such as 0.1M sodium cacodylate in appropriate conditions of pH and temperature such as at a pH of 6.5 to 7.5 and a temperature between 25° and 45° C., preferably 35°-40° C., while incubating for 12 hours to 4 days. The resulting sialylated product can be isolated and purified using conventional methodology comprising HPLC, ion exchange-, gel-, reverse-phase-or adsorption chromatography.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[C:7]([F:31])[CH:6]=[CH:5][C:4]=1[NH:32][S:33]([C:36]1[C:37]2[CH:38]=[CH:39][N:40]([CH3:45])[C:41]=2[CH:42]=[CH:43][CH:44]=1)(=[O:35])=[O:34]>>[N:24]1[C:16]([C:15]2[C:10]([NH:9][C:8]3[C:3]([F:2])=[C:4]([NH:32][S:33]([C:36]4[C:37]5[CH:38]=[CH:39][N:40]([CH3:45])[C:41]=5[CH:42]=[CH:43][CH:44]=4)(=[O:34])=[O:35])[CH:5]=[CH:6][C:7]=3[F:31])=[N:11][CH:12]=[CH:13][CH:14]=2)=[C:17]2[C:21]([NH:20][CH:19]=[N:18]2)=[N:22][CH:23]=1
Reactant: Cn1ccc2c(S(=O)(=O)Nc3ccc(F)c(Nc4ncccc4-c4ncnc5c4ncn5C4CCCCO4)c3F)cccc21
Agent: Cl
Product: Cn1ccc2c(S(=O)(=O)Nc3ccc(F)c(Nc4ncccc4-c4ncnc5[nH]cnc45)c3F)cccc21
Reaction time: 2 h

Procedure:
1M aqueous hydrochloric acid solution was added into the N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-1-methyl-1H-indole-4-sulfonamide (20 mg, 0.033 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: Cl.[CH:2]([N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][C:20]=2[CH3:21])[NH:17][C:16]([C:22]([OH:24])=O)=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])[CH3:3].[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[CH:2]([N:5]1[CH2:6][CH2:7][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][C:20]=2[CH3:21])[NH:17][C:16]([C:22]([N:32]2[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]2)=[O:24])=[CH:15]3)[CH2:9][CH2:10]1)([CH3:3])[CH3:4]
Reactant: Cc1cc2[nH]c(C(=O)O)cc2cc1OC1CCN(C(C)C)CC1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: Cl
Product: Cc1cc2[nH]c(C(=O)N3CCN(S(C)(=O)=O)CC3)cc2cc1OC1CCN(C(C)C)CC1
Yield: 49 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(1-isopropyl-piperidin-4-yloxy)-6-methyl-1H-indole-2-carboxylic acid hydrochloride and 1-methanesulfonylpiperazine to afford the title compound as a light-yellow solid (49%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[OH:16].[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:4][C:3]=1[O:16][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][O:17]1
Reactant: CC(C)(C)C(=O)Nc1cc(O)c(F)cc1F
Reactant: C1=COCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc(OC2CCCCO2)c(F)cc1F
Temperature: 25 °C
Reaction time: 4.3 h
Yield: 85 %

Procedure:
2.15 g (9.39 mmol) of the resulting 2,4-difluoro-5-pivaloylaminophenol was dissolved in 40 ml of dichloromethane, 4.3 ml of 3,4-dihydro-2H-pyrane and 44 mg of camphorsulfonic acid were added and the mixture was stirred at room temperature for 4.3 hours. The reaction solution was added to a 5% aqueous solution of potassium carbonate and the mixture was extracted with chloroform. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent Was distilled off under reduced pressure and the residue was triturated with n-hexane to give 2.51 g (85%) of 2,4-difluoro-5-pivaloylamino-O-(2-tetrahydropyranyl)phenol.
Reaction SMILES: C([NH:3][C:4]1[S:5][C:6]([N+:12]([O-:14])=[O:13])=[CH:7][C:8]=1[C:9](=O)[NH2:10])=O.C(NC1SC([N+]([O-])=O)=CC=1C(=O)N)(=O)C1C=CC=CC=1>>[NH2:3][C:4]1[S:5][C:6]([N+:12]([O-:14])=[O:13])=[CH:7][C:8]=1[C:9]#[N:10]
Reactant: NC(=O)c1cc([N+](=O)[O-])sc1NC=O
Agent: NC(=O)c1cc([N+](=O)[O-])sc1NC(=O)c1ccccc1
Product: N#Cc1cc([N+](=O)[O-])sc1N
Reaction time: 0.25 h
Yield: 60 %

Procedure:
In place of the 83.9 parts of 2-formylamino-3-carbamoyl-5-nitrothiophene used in Example 1 there are used 113.6 parts of 2-benzoylamino-3-carbamoyl-5-nitrothiophene, the first stage of the reaction being carried out for 15 minutes at 60° C. (instead of at 70°-75° C. as in Example 1). 2-Amino-3-cyano-5-nitrothiophene is obtained in an overall yield of 60%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([O:24]C(C)C)=[CH:17][C:11]=3[C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.B(Cl)(Cl)Cl>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([OH:24])=[CH:17][C:11]=3[C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(OC(C)C)cc12
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(O)cc12
Temperature: 0 °C

Procedure:
To a stirred solution of methyl 2-(4-fluorophenyl)-5-[(1-methylethyl)oxy]-6-nitro-1-benzofuran-3-carboxylate (5.237 g, 14.03 mmol) in dry dichloromethane (70 mL) at −15° C., under an atmosphere of nitrogen, was added a 1M solution of boron trichloride in dichloromethane (23.85 mL, 23.85 mmol) over 30 minutes using a syringe pump. The dark brown-red reaction mixture was poured over ice (˜250 mL). The ice was allowed to melt and the mixture extracted with dichloromethane (˜450 mL). The organic phase was separated by hydrophobic filter tube and evaporated under vacuum to give the methyl 2-(4-fluorophenyl)-5-hydroxy-6-nitro-1-benzofuran-3-carboxylate. 1H NMR (d6-DMSO): δ 10.97 (1H, br. s), 8.34 (1H, s), 8.07 (2H, dd), 7.67 (1H, s), 7.43 (2H, t), 3.86 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([NH2:15])([CH:12]([F:14])[F:13])[CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:11])[CH3:10].[C:17](Cl)(=[O:20])[CH2:18][CH3:19].C(N(CC)CC)C>CCOCC>[CH3:1][O:2][C:3](=[O:16])[C:4]([CH:12]([F:14])[F:13])([NH:15][C:17](=[O:20])[CH2:18][CH3:19])[CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:11])[CH3:10]
Reactant: COC(=O)C(N)(CCCNC(C)=O)C(F)F
Reactant: CCC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCC(=O)NC(CCCNC(C)=O)(C(=O)OC)C(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.47 g of 5-acetylamino-2-amino-2-difluoromethylpentanoic acid methylester in 10 ml of ether is added simultaneously at 0° C. 0.18 g of propionylchloride and 0.2 g of triethylamine. The reaction mixture is stirred at room temperature for 2 hours then extracted with ethylacetate. The organic phase is washed with a solution of sodium bicarbonate, water, then brine and dried over magnesium sulfate. Evaporation of the solvent gives 5-acetylamino-2-difluoromethyl-2-propionylaminopentanoic acid methylester.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[CH:13][N:14]2[CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][CH:9]=1)(C)(C)C.Cl[C:28]1[CH:33]=[CH:32][N:31]=[C:30]([NH:34][CH:35]2[CH2:40][C:39]([CH3:42])([CH3:41])[NH:38][C:37]([CH3:44])([CH3:43])[CH2:36]2)[N:29]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:41][C:39]1([CH3:42])[CH2:40][CH:35]([NH:34][C:30]2[N:29]=[C:28]([C:12]3[C:11]4[C:15](=[CH:16][C:8]([CH2:7][OH:6])=[CH:9][CH:10]=4)[N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:22])([CH3:23])[CH3:24])[CH:13]=3)[CH:33]=[CH:32][N:31]=2)[CH2:36][C:37]([CH3:44])([CH3:43])[NH:38]1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc2ccn(COCC[Si](C)(C)C)c2c1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3cn(COCC[Si](C)(C)C)c4cc(CO)ccc34)n2)CC(C)(C)N1

Procedure:
[3-[2-(2,2,6,6-Tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-6-yl]-methanol was prepared as described in Example 215, starting from 6-(tert-butyl-dimethyl-silanyloxymethyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by selective cleavage of the TBDMS-protecting group with TBAF. Yield: 7.1 g (93%).