Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][O:25][CH2:26][O:27][CH3:28])=[CH:19][CH:18]=2)=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH2:35]([O:42][C@@H:43]1[C@@H:49]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:48]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C@@H:47]([CH2:66][O:67][CH2:68][C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[O:46][C:44]1=[O:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:35]([O:42][C@@H:43]1[C@@H:49]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@H:48]([O:58][CH2:59][C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)[C@@H:47]([CH2:66][O:67][CH2:68][C:69]2[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=2)[O:46][C:44]1([C:10]1[CH:11]=[C:12]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][O:25][CH2:26][O:27][CH3:28])=[CH:21][CH:22]=2)[C:13]([Cl:15])=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:45])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: COCOCCc1ccc(Cc2cc(Br)c(OCc3ccccc3)cc2Cl)cc1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOCCc1ccc(Cc2cc(C3(O)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCc3ccccc3)cc2Cl)cc1
Reaction time: 0.08 h
Yield: 21.8 %

Procedure:
To a tetrahydrofuran solution (3 mL) of 1-(benzyloxy)-2-bromo-5-chloro-4-[4-[2-(methoxymethoxy)ethyl]benzyl]benzene (290 mg, 0.609 mmol) was added dropwise under nitrogen atmosphere at −78° C. a 2.6 M hexane solution of n-butyllithium (234 μL, 0.609 mmol), and the mixture was stirred for 5 minutes at the same temperature. Then a tetrahydrofuran solution (3 mL) of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (328 mg, 0.609 mmol) was added dropwise, and the mixture was stirred for an hour at the same temperature. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (124 mg, 22%) as a colorless oily compound.
Reaction SMILES: OS(O)(=O)=O.[C:6]1([C@@H:12]2[CH2:14][C@H:13]2[C:15]([OH:17])=[O:16])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[I:18]I>O.CC(O)=O>[I:18][C:9]1[CH:10]=[CH:11][C:6]([C@@H:12]2[CH2:14][C@H:13]2[C:15]([OH:17])=[O:16])=[CH:7][CH:8]=1
Reactant: II
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.1 %

Procedure:
A solution of H2SO4 (0.1 mL) in water (1 mL) and AcOH (4 mL) in a 25 mL flask was added trans-2-phenylcyclopropanecarboxylic acid (200 mg, 1.23 mmol), iodine (173 mg, 0.68 mmol) and KIO3 (61 mg, 0.28 mmol). The reaction mixture was heated to reflux, and added AcOH (6 mL) in portions of 2 mL to rinse iodine down the condenser. After 4 hours, when no further color changes appeared, the reaction was cooled to room temperature, quenched with 1M Na2S2O4 and added water. The mixture was extracted with EtOAc (3×), and the combined extracts were washed with brine, dried over MgSO4 and concentrated under vacuum. The crude product containing minor impurities of starting material and the ortho-iodinated product, was recrystallized from PE to provide 157 mg (44%) trans-2-(4-iodophenyl)cyclopropanecarboxylic acid as a pure and white crystalline product: Rt=11.33 min (HPLC method I); 1H NMR (CDCl3) δ 7.62-7.58 (m, 2H), 6.87-6.84 (m, 2H), 2.56-2.51 (m, 1H), 1.89-1.84 (m, 1H), 1.69-1.64 (m, 1H), 1.39-1.34 (m, 1H); 13C NMR (CDCl3) δ 179.3, 139.2, 137.6, 128.3, 91.7, 26.5, 23.9, 17.4; ESI-MS m/z 311.0 (M+Na+).
Reaction SMILES: O[C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C@H:9]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:10][N:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH3:12])[CH2:4][CH2:3]1.CCN(CC)CC.[F:38]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.C1COCC1>>[F:38][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][C@H:9]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:10][N:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH3:12])[CH2:4][CH2:3]1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CN(C[C@H](C[C@H]1CC[C@H](O)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C[C@H](C[C@H]1CC[C@H](F)CC1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 39.2 %

Procedure:
A mixture of tert-butyl (S)-1-(trans-4-hydroxycyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate (3 g, 7 mmol), Et3N (12 mL, 88 mmol), NEt3(HF)3 (4.71 mL, 29 mmol) and perfluorobutanesulfonyl fluoride (5.21 mL, 29 mmol) was stirred in THF (70 mL, 1 mmol/10 mL) at 50° C. until HPLC revealed complete conversion. The reaction mixture was quenched with water and extracted with EtOAc (2×100 mL), dried over MgSO4 and evaporated. The residue was then purified by prep HPLC to give tert-butyl (S)-1-(trans-4-fluorocyclohexyl)-3-(N-(benzyloxycarbonyl)-N-methylamino)propan-2-ylcarbamate (1.16 g, 40%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 1.41 (d, 9H), 1.68 (m, 6H), 1.96 (m, 3H), 2.98 (d, 3H), 3.20 (m, 1H), 3.52 (m, 1H), 3.90 (m, 1H), 5.13 (d, 2H), 7.33 (m, 5H).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:25][O:26][C@@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]=[CH2:36])[CH3:28])[CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([F:24])[CH:18]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C12BC(CCC1)CCC2.[O:46]1CCCC1>O>[Si:1]([O:8][C@H:9]([CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([F:24])[CH:18]=1)[CH2:25][O:26][C@@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][CH2:36][OH:46])[CH3:28])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: C=Cc1ccccc1[C@@H](C)OC[C@@H](CN1CCC[C@H]1Cc1ccc(C)c(F)c1)O[Si](C)(C)C(C)(C)C
Agent: B1C2CCCC1CCC2
Solvent: O
Product: Cc1ccc(C[C@@H]2CCCN2C[C@H](CO[C@H](C)c2ccccc2CCO)O[Si](C)(C)C(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
(2S)-1-{(2R)-2-{[Tert-butyl(dimethyl)silyl]oxy}-3-[(1R)-1-(2-ethenylphenyl)ethoxy]propyl}-2-(3-fluoro-4-methylbenzyl)pyrrolidine (1.20 g, 2.35 mmol), which had been obtained in Example 180 (180c), was dissolved in tetrahydrofuran (20 mL) and added with a 0.5 M solution of 9-borabicyclo[3,3,1]nonane in tetrahydrofuran (5.6 mL, 2.82 mmol). After raising the temperature to room temperature, the mixture was stirred for 16 hours. Separately, the reaction solution was added dropwise in small portions to a solution in which sodium perborate hydrate (1.40 g, 14 mmol) was dissolved in water (20 mL), and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by basic silica gel chromatography (n-hexane/ethyl acetate=3/1) to give the title compound as a colorless oily substance (1.05 g, yield 84%).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH:7]([CH3:12])[C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:12])[C:8]([NH:10][CH3:11])=[O:9])=[CH:13][CH:14]=1
Reactant: Fc1ccccc1CBr
Reactant: CNC(=O)C(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CNC(=O)C(C)Oc1ccc(OCc2ccccc2F)cc1

Procedure:
In analogy to the procedure described in Example 3b), the alkylation of (RS)-2-(4-hydroxy-phenoxy)-N-methyl-propionamide with 2-fluoro-benzylbromide in 2-butanone using potassium carbonate as the base yielded the (RS)-2-[4-(2-fluoro-benzyloxy)-phenoxy]-N-methyl-propionamide as white crystals; MS: m/e=304 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[O:6][CH:7]=1)=[O:2].I[C:12]1[C:20]2[C:15](=[N:16][CH:17]=[N:18][C:19]=2[NH2:21])[N:14]([CH:22]([CH3:24])[CH3:23])[N:13]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:21][C:19]1[N:18]=[CH:17][N:16]=[C:15]2[N:14]([CH:22]([CH3:24])[CH3:23])[N:13]=[C:12]([C:5]3[O:6][CH:7]=[C:3]([CH:1]=[O:2])[CH:4]=3)[C:20]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: O=Cc1coc(B(O)O)c1
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: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2cc(C=O)co2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 38.3 %

Procedure:
A solution of 4-Formylfuran-2-boronic acid (20 mg, 0.14 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 ml). Pd(PPh3)4 (16 mg, 0.014 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA35 (13.5 mg, 39% yield). ESI-MS (M+H)+ m/z calcd 272.1, found 272.1.
Reaction SMILES: [CH3:1][C:2]1([CH:5]([O:9][CH2:10][CH:11]=O)[CH2:6][CH:7]=[CH2:8])[CH2:4][CH2:3]1.C([O-])(=O)C.[Na+].Cl.[NH2:19][OH:20]>C(O)C.O>[OH:20][NH:19][CH2:11][CH2:10][O:9][CH:5]([C:2]1([CH3:1])[CH2:4][CH2:3]1)[CH2:6][CH:7]=[CH2:8]
Reactant: NO
Reactant: C=CCC(OCC=O)C1(C)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C=CCC(OCCNO)C1(C)CC1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
{[1-(1-Methylcyclopropyl)but-3-en-1-yl]oxy}acetaldehyde (C54) (27.7 g from the previous step, ≦165 mmol) was dissolved in a 2:1 mixture of ethanol and water (39 mL). Sodium acetate (63.1 g, 770 mmol) was added; after the reaction mixture had been stirred for 15 minutes, hydroxylamine hydrochloride (98%, 32.1 g, 462 mmol) was added. The reaction mixture was heated to 60° C. for 24 hours. The reaction mixture was concentrated under reduced pressure to remove ethanol and extracted with dichloromethane (2×140 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo at 22° C. Silica gel chromatography (Gradient: 0% to 12% ethyl acetate in petroleum ether) provided the product as a colorless oil. By 1H NMR analysis, this material consisted of a roughly 1:1 mixture of E and Z oxime isomers. Yield: 4.1 g, 22.4 mmol, 48% over two steps. 1H NMR (400 MHz, CDCl3) δ [7.49 (t, J=5.6 Hz) and 6.91 (t, J=3.6 Hz), total 1H], 5.82-5.92 (m, 1H), 5.00-5.10 (m, 2H), {[4.52 (dd, half of ABX pattern, J=16.4, 3.2 Hz) and 4.35 (dd, half of ABX pattern, J=16.4, 3.6 Hz)] and [4.27 (dd, half of ABX pattern, J=13.2, 5.6 Hz) and 4.09 (dd, half of ABX pattern, J=12.8, 6.0 Hz)], total 2H}, 2.59-2.64 (m, 1H), 2.25-2.45 (m, 2H), 1.02 (s, 3H), 0.42-0.56 (m, 2H), 0.18-0.29 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH:32]1([S:38](Cl)(=[O:40])=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:38]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)(=[O:40])=[O:39]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)C1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)C1CCCCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. cyclohexanesulfonyl chloride (10 mg, 0.052 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 24 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)9H-purin-6-yl)pyridin-2-ylamino)phenyl)cyclohexanesulfonamide (percentage yield: 91%), was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([O:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([O:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[CH2:23][CH2:24][CH2:25][N:26]3[C:30](=[O:31])[C:29]4[C:28](=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:27]3=[O:36])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(Oc2ccc(OC[C@@H]3CCCN3)cc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCN1CCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 60 °C
Yield: 61246.2 %

Procedure:
(S)-2-[4-(4-Chloro-phenoxy)-phenoxymethyl]-pyrrolidine (200 mg, 0.658 mmol) was taken into anhydrous DMF (2 mL) in a nitrogen flushed 20 mL vial. N-(3-Bromopropyl)phthalimide (194 mg, 0.724 mmol) was added to the mixture followed by potassium carbonate (364 mg, 2.43 mmol). The reaction was sealed and heated at 60° C. for 24 h. The mixture was then cooled to room temperature and partitioned between ethyl acetate and water. The water layer was washed with ethyl acetate (3×). The combined ethyl acetate layers were then washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was then purified by silica gel flash chromatography (20:1 silica ratio, eluted with 40% methanol in dichloromethane). The overlap from the purification was repurified by silica gel flash chromatography (20:1 silica ratio, eluted with 1% methanol in dichloromethane followed by 5% methanol in dichloromethane) to obtain the title product (198 mg, 403 mmol, 61%); MS; m/z 491 (M); 1H NMR (400 MHz, DMSO-d6) δ 1.5-1.67 (m, 3H), 1.75-1.82 (m, 2H), 1.86-1.91 (m, 1H), 2.13-2.14 (m, 1H), 2.34-2.37 (m, 1H), 2.72-2.73 (m, 1H), 2.89-2.94 (m, 1H), 3.02-3.06 (m, 1H), 3.60-3.70 (m, 3H), 3.88-3.91 (m, 1H), 6.89-6.98 (m, 6H), 7.38 (d, J=9.2, 2H), 7.82-7.85 (m, 4H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([O:14][C:15]1[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[CH:17][C:16]=1[OH:23])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27](F)[N:26]=1>C(#N)C>[CH2:7]([O:14][C:15]1[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[CH:17][C:16]=1[O:23][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[N:26]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Fc1cccc(F)n1
Reactant: CCc1ccc(O)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1ccc(Oc2cccc(F)n2)c(OCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a suspension of K2CO3 (0.25 mmol; 35 mg) in anhydrous acetonitrile (2 mL) under argon, was added 2-Benzyloxy-4-ethyl-phenol (48 mg; 0.21 mmol) followed by 2,6-difluoropyridine (100 μL; 1.10 mmol). The reaction mixture was stirred at 80° C. overnight.
Reaction SMILES: [C:1]([CH2:5][C:6](Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)CCC>C1(C)C=CC=CC=1.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:2][C:1]([CH3:4])([CH3:3])[CH2:5][C:6]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:7]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CC(C)(C)CC(=O)Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC(C)(C)CC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
A mixture of t-butylacetyl chloride (1 ml, 7.2 mmol), 2-(tributylstannyl)thiophene (2.4 ml, 7.56 mmol) and PdCl2(PPh3)2 (98 mg, 0.14 mmol) in toluene (50 ml) was heated at reflux until the starting material disappeared. After cooling at room temperature, the brown-black solution was diluted with ether and washed with a 0.1 N aqueous HCl solution. The organic phase was separated and stirred vigorously with a 10% w/v aqueous KF solution for 30 minutes. After filtration, the layers were separated and the organic one washed with water, brine, dried over MgSO4 and concentrated. The residual brown oil was chromatographied on silica gel (hexane/AcOEt 97/3) to give 3,3-dimethyl-1-(2-thienyl)-1-butanone 10 as a colorless oil (810 mg, 62%).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[N:20]1([C:26]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:28][N:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(OCC)(=O)C>C(#N)C>[S:28]1[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:26]([N:20]2[CH2:21][CH2:22][N:23]([C:9]([C:8]3[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:7]=3[N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[O:11])[CH2:24][CH2:25]2)=[N:27]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2nsc3ccccc23)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 2-morpholin-4-yl-5-nitro-benzoic acid (Example 2.1) and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (CA=87691-88-1) in acetonitrile. Chromatography (SiO2; ethyl acetate) yields the title compound as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]O.[Cl:11]C(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][Cl:11]
Reactant: COc1ccccc1CO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccccc1CCl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 290.5 %

Procedure:
2-Methoxybenzyl alcohol (1.01 g, 7.31 mmol) and triphosgene (757 mg, 2.55 mmol) were dissolved in tetrahydrofuran (5 ml). The solution was added with pyridine (1.18 ml, 14.6 mmol) under ice cooling, and then warmed to room temperature. After 20 minutes, insoluble solids were removed by filtration, and the solvent was evaporated under reduced pressure. The resulting oil was diluted with ethyl acetate and insoluble solids were further removed. The solvent was evaporated under reduced pressure to obtain the title compound as pale yellow oil (1.16 g, yield: 100%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][O:32][CH2:31]1>>[CH3:8][C@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH2:29][CH:30]2[CH2:34][CH2:33][O:32][CH2:31]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: BrCCCC1CCOC1
Reactant: CCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 220 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(3-bromopropyl)tetrahydrofuran.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])/[C:6](=[CH:19]/[C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([C:15]([F:14])([F:24])[F:25])[CH:17]=1)/[CH2:5]2
Reactant: COc1cc2c(cc1Br)CCC2=O
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Br)C/C(=C\c1cccc(C(F)(F)F)c1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 11 (200 mg, 0.829 mmol) in toluene was added 3-(trifluoromethyl)benzaldehyde 99 (158.86 mg, 0.9128 mmol). PTSA (285.5 mg, 172.20 mmol) was added to the reaction mass, then stirred at 120° C. for 6 h, diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 152 which was purified through flash chromatography by using 100-200 mesh silica gel. The compound (E)-5-bromo-6-methoxy-2-(3-(trifluoromethyl)benzylidene)-2,3-dihydro-1H-inden-1-one 152 was eluted at 30% ethyl acetate in hexane to afford yellow coloured solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7](CCC(O)=O)[NH:8]2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:22]1C[O:25][CH2:24][CH2:23]1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: O=C(O)CCc1cc2ccc(F)cc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCCCc1c[nH]c2cc(F)ccc12
Temperature: 20 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
To a solution of 3-(6-fluoroindolyl)propionic acid (235 mg, 1.13 mmol) in THF (5.3 mL) was added LiAlH4 (86 mg, 2.26 mmol) slowly at 0° C. under N2. The reaction mixture was warmed to 20° C. and stirred for 15 h. The reaction was quenched by addition of H2O (0.5 mL) and diluted with EtOAc. The resulting solution was dried over MgSO4, filtered through Celite and concentrated in vacuo. The residue was chromatographed to give 6-fluoro-3-(3-hydroxypropyl)indole (142 mg, 65%) as a colorless oil.