Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[S:13]1(=[O:29])=[O:28]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([N:14]2[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[S:13]2(=[O:28])=[O:29])=[CH:22][CH:23]=1
Reactant: C1COCCN1
Reactant: O=S1(=O)N(CCCCBr)c2ccccc2N1c1ccc(Cl)cc1
Product: O=S1(=O)N(CCCCN2CCOCC2)c2ccccc2N1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.3 %

Procedure:
Morpholine (2 mL, 23 mmol) was added to a round bottom flask containing (50 mg, 0.12 mmol) of 1-(4-bromobutyl)-3-(4-chlorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (made in general procedure IV). The reaction flask was covered with a septum and stirred overnight at room temperature. The reaction solution was concentrated in vacuo and the crude product was pre-adsorbed onto Celite and purified via Isco chromatography (Redisep, silica, gradient 1-8% methanol in dichloromethane with ammonia) to afford 29 mg (78%) of 1-(4-chlorophenyl)-3-(4-morpholin-4-ylbutyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide. HPLC purity 100.0% at 210-370 nm, 8.2 minutes Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (ammonium formate buffer pH=3.5, acetonitrile/MeOH) for 10 minutes, hold 4 minutes.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].Cl[CH2:10][CH2:11][CH2:12][C:13]1([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[O:17]CCO1.[CH3:24][CH:25]1[CH:30]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH2:29][CH:28]([CH3:38])[CH2:27][NH:26]1>CN(C)C=O>[CH:18]1([C:13](=[O:17])[CH2:12][CH2:11][CH2:10][N:26]2[CH2:27][CH:28]([CH3:38])[CH2:29][CH:30]([C:31]3[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=3)[CH:25]2[CH3:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC1CNC(C)C(c2ccc(O)cc2)C1
Reactant: ClCCCC1(C2CCCCC2)OCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1CC(c2ccc(O)cc2)C(C)N(CCCC(=O)C2CCCCC2)C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 40.4 %

Procedure:
0.96 g (9 mmol) of sodium carbonate, 1.35 g (9 mmol) of sodium iodide and 2.1 g (9 mmol) of 2-(3-chloropropyl)-2-cyclohexyl-1,3-dioxolane were added to a solution of 1.7 g (8.3 mmol) of 2,5-dimethyl-3-(4-hydroxyphenyl)piperidine in 10 ml of dimethylformamide and the resulting reaction mixture was stirred at a temperature of 80° C. for 16 hours. After cooling, the reaction mixture was poured on ice and extracted three times with ethyl acetate. After evaporating the organic layer under reduced pressure, the residue was dissolved in a mixture of 20 ml of dimethylformamide and 40 ml of 2N hydrochloric acid and stirred for 1 hour so as to split the dioxolane group present. The solution was then extracted three times with diethyl ether, rendered basic by the addition of concentrated ammonia and extracted three times with ethyl acetate. The resulting organic layer was washed three times with water and once with a concentrated saline solution, dried on sodium sulphate an evaporated under reduced pressure. The resulting crude product (2.3 g) was purified by means of flash chromatography over 75 g of silicagel (Merck, grain size 0.040-0.063 mm) using a mixture of dichloromethane, methanol and concentrated ammonia (95:4.5:0.5) as an eluent. After combining and evaporating the desired fractions, totally 1.2 g (46%) of 1-(4-cyclohexyl-4 -oxobutyl)-2,5-dimethyl-3-(4-hydroxyphenyl)piperidine were obtained (compound no. 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[C:9]#[C:10][Si](C)(C)C.C([O-])([O-])=O.[K+].[K+]>CO>[C:9]([C:8]1[CH:7]=[CH:6][C:5]([NH2:15])=[CH:4][C:3]=1[O:2][CH3:1])#[CH:10]
Reactant: COc1cc(N)ccc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(N)cc1OC
Temperature: 25 °C
Yield: 41.8 %

Procedure:
3-Methoxy-4-trimethylsilanylethynyl-phenylamine (1.86 g, 8.45 mmol) in MeOH (17 mL) was treated with solid K2CO3 (1.17 g, 8.45 mmol). After stirring at room temperature the volatiles were removed by evaporation, the residue was taken up with EtOAc (50 mL), washed with water (50 mL), brine, dried over sodium sulfate and evaporated. The crude was purified by flash chromatography on silica gel (heptane/EtOAc 65/35) to afford 520 mg of title compound (42% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:12]=[CH2:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].ClC1C=CC=C(C(OO)=[O:22])C=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:12]2[CH2:13][O:22]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1cc(Br)cc(C(=O)OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cc(Br)cc(C2CO2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 3-bromo-5-vinylbenzoate (1.00 g, 4.15 mmol) in CH2Cl2 (40 mL) at 0° C. was added m-chloroperbenzoic acid (70% purity, 1.43 g, 5.80 mmol) in portions over a 10 minute period. The mixture was warmed to room temperature and stirred for 2 hours upon which it was poured onto saturated sodium bicarbonate (250 mL). The mixture was extracted with ethyl acetate (3×100 mL) and the combined extracts were dried over Na2SO4 and concentrated. The residue was purified by column chromatography (0-50% EtOAc/hexane) to afford the title compound as a yellow oil. 1H NMR (400 MHz, DMSO-d6): 7.92 (t, 1H, J=1.7 Hz), 7.86 (t, 1H, J=1.5 Hz), 7.78 (t, 1H, J=1.7 Hz), 4.09 (q, 1H, J=2.5 Hz), 3.87 (s, 3H), 3.17-3.14 (m, 1H), 2.92-2.90 (m, 1H).
Reaction SMILES: Cl.[CH3:2][C:3]1([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)[CH:13]=2)=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.Cl[C:24]1[C:25]2[C:32]([CH3:33])=[CH:31][NH:30][C:26]=2[N:27]=[CH:28][N:29]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH3:2][C:3]1([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)[CH:13]=2)=[O:10])[CH2:4][CH2:5][N:6]([C:24]2[C:25]3[C:32]([CH3:33])=[CH:31][NH:30][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:7][CH2:8]1
Reactant: CC1(C(=O)Nc2cccc(-c3cnco3)c2)CCNCC1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)Nc4cccc(-c5cnco5)c4)CC3)c12
Temperature: 105 °C

Procedure:
A pressure vessel was charged with a solution of 4-methyl-N-(3-(oxazol-5-yl)phenyl)piperidine-4-carboxamide hydrochloride from step B (51.9 mg, 0.17 mmol) and isopropanol (3 mL), and to this solution was added 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (55.0 mg, 0.329 mmol) and N,N-diisopropylethylamine (297.9 mg, 0.40 mL, 2.31 mmol). The vessel was sealed, and the reaction was heated to 105° C. for 15 hours. The reaction was worked up by normal means, and the residue was purified by prep HPLC to afford the title compound as an off-white solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13]3)=[O:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].O.[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32]>CC(C)=O>[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13]3)=[O:9])[CH2:2][CH2:3]1)=[O:32]
Reactant: O=C1Cc2cc(C(=O)CN3CCNCC3)ccc2N1
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1Cc2cc(C(=O)CN3CCN(C(=O)c4cccc(Cl)c4)CC3)ccc2N1
Temperature: 0 °C

Procedure:
To a suspension comprising 1.0 g of dihydrochloric acid salt of 5-[2-(1-piperazinyl)acetyl]oxindol, 0.63 gof potassium carbonate, 5 ml of water and 10 ml of acetone was added dropwise a solution of 0.63 g of m-chlorobenzoyl chloride in 2 ml of acetone under ice-cooling with stirring, and the mixture was stirred for 1.5 hours at the same temperature. After completion of reaction, the reaction mixture was poured into ice-water and extracted with chloroform. The chloroform layer was washed, in turn, with water and a saturated saline solution, and dried over sodium sulfate. The solvent was then distilled off under reduced pressure. The resultant residue was purified by silica-gel column chromatography (eluent: chloroform:methanol=20:1) and recrystallized from a mixture of ethanol and chloroform to give 0.34 g of 5-[2-[4-(3-chlorobenzoyl)-1-piperazinyl]acetyl]oxindol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30](=[O:50])[CH2:31][C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:50])[CH2:31][C:32]1([C:35]2[CH:36]=[CH:37][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:15])[C:16]4[O:17][C:18]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)=[N:19][N:20]=4)=[CH:4][CH:3]=3)=[CH:39][CH:40]=2)[CH2:33][CH2:34]1)[CH3:28]
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1nnc(-c2ccccc2)o1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4nnc(-c5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 28, Step 1, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-(5-phenyl-[1,3,4]oxadiazol-2-yl)-methanol and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1I)[CH2:8][C:9]1([CH3:13])[CH2:12][O:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:47][C:48]1[CH:53]=[CH:52][C:51](B(O)O)=[C:50]([O:57][CH3:58])[CH:49]=1.[NH4+].[Cl-]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O>[F:47][C:48]1[CH:53]=[CH:52][C:51]([C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[N:7]([CH2:8][C:9]2([CH3:13])[CH2:12][O:11][CH2:10]2)[C:6](=[O:21])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:50]([O:57][CH3:58])[CH:49]=1
Reactant: CC1(CN(C(=O)OC(C)(C)C)c2cnccc2I)COC1
Reactant: COc1cc(F)ccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1ccncc1N(CC1(C)COC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 298.8 %

Procedure:
To a solution of (4-iodo-pyridin-3-yl)-(3-methyl-oxetan-3-ylmethyl)-carbamic acid tert-butyl ester (0.878 g, 2.17 mmol) in DME (10 mL) under argon 4-fluoro-2-methoxyphenylboronic acid (424 mg, 2.5 mmol, CAS RN 179899-07-1) and 2M aqueous Na2CO3 solution (2.77 mL, 5.54 mmol) were added. After stirring for 30 min. at room temperature, palladium(II) acetate (24.4 mg, 0.109 mmol, CAS RN 3375-31-3) and triphenylphosphine polymer bound (73.0 mg, 0.217 mmol, CAS RN 39319-11-4) were added and the reaction was stirred at reflux (90° C. oil bath temperature) for 22 hours. Another 4-fluoro-2-methoxyphenylboronic acid (111 mg, 0.652 mmol) was added and reaction mixture was refluxed for another 4 hours before another 4-fluoro-2-methoxyphenylboronic acid (111 mg, 0.652 mmol) was added. After stirring at reflux temperature for 18 hours the reaction mixture was poured on saturated aqueous NH4Cl solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100) to give the title compounds as a light brown oil (0.784 g; 89%). MS (ESI): m/z=403.20 [M+H]+.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:93]=[CH:94][CH:95]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][C@@H:78]([OH:80])[CH3:79])[CH2:73][CH2:72]5)=[C:67]([O:81][CH3:82])[CH:66]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:93]=[CH:94][CH:95]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][C@@H:78]([OH:80])[CH3:79])[CH2:73][CH2:72]5)=[C:67]([O:81][CH3:82])[CH:66]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: COc1cc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)ccc1N1CCN(C[C@H](C)O)CC1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)ccc1N1CCN(C[C@H](C)O)CC1
Yield: 65 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-1-(4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl)piperazin-1-yl)propan-2-ol (70 mg, 0.100 mmol) was hydrolyzed with lithium hydroxide (13 mg, 0.302 mmol) in THF/methanol/water (2/2/1 mL) to yield 35 mg (65% yield). 1H NMR (CD3OD, 400 MHz): δ 8.48 (s, 1H), 8.34 (s, 1H), 8.20 (s, 1H), 7.95 (s, 1H), 7.39-7.36 (q, 1H), 7.30-7.28 (m, 2H), 7.13-7.11 (d, 2H), 7.07-7.02 (m, 2H), 5.45 (s, 2H), 4.20-4.30 (m, 1H), 3.99 (s, 3H), 3.60-3.80 (m, 4H), 3.1-3.3 (m, 3H), 1.29-1.28 (d, 3H). MS: m/z=541.6 (M+1), HPLC: 98.71% in method A.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]34[C:28]([F:30])([F:29])[CH:14]3[CH:15]3[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH:16]3[CH2:27]4)=[CH:10][CH:11]=2)[N:6]([CH3:31])[C:5]1=[O:32].FC(F)(F)C(O)=O>ClCCl>[F:30][C:28]1([F:29])[C:13]2([C:9]3[N:8]=[C:7]4[N:6]([CH3:31])[C:5](=[O:32])[N:4]([CH2:3][C:2]([CH3:34])([CH3:1])[CH3:33])[C:12]4=[CH:11][CH:10]=3)[CH2:27][CH:16]3[CH:15]([CH:14]12)[CH2:19][NH:18][CH2:17]3
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C34CC5CN(C(=O)OC(C)(C)C)CC5C3C4(F)F)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C34CC5CNCC5C3C4(F)F)nc21
Reaction time: 18 h

Procedure:
tert-butyl 4a-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo-[4,5-b]pyridin-5-yl]-4,4-difluorooctahydro-2H-cyclopropa[3,4]cyclopenta[1,2-c]pyrrole-2-carboxylate (30-2, 100 mg, 0.21 mmol) was added to a mixture of dichloromethane (2.0 mL) and trifluoroacetic acid (0.5 mL) at room temperature. After stirring for 18 h, the solvent was removed in vacuo. The resulting residue was then diluted with ethyl acetate (100 mL) and washed sequentially with saturated sodium bicarbonate (2×50 mL), water (1×50 mL) and brine (1×50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to give 1-[(2,2-Difluorocyclopropyl)methyl]-5-(1,2,3,3a,4,6a-hexahydrocyclopenta-[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (30-3) as a white solid. This material was carried on without further purification.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:34]1([N:40]2[C:44]3([CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[C:43](=[O:50])[NH:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([N:47]3[CH2:46][CH2:45][C:44]4([N:40]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH2:41][NH:42][C:43]4=[O:50])[CH2:49][CH2:48]3)=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc2[nH]ccc2c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reaction time: 0.17 h
Yield: 67.8 %

Procedure:
To a mixture of indole-5-carboxylic acid (300 mg, 1.86 mmol) and HOBT (278 mg, 2.05 mmol) in dry DMF (10 mL) was added EDAC (464 mg, 2.42 mmol). The resulting mixture was stirred for 10 min followed by addition of a mixture of TEA (0.78 ml, 5.58 mmol) and 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (473 mg, 2.04 mmol). The reaction mixture was stirred for an additional 16 hrs. To the reaction mixture was added water (25 ml) and the resulting precipitate was filtered and washed with water. The resulting solid was recrystalised from a mixture of EtOH-water (4:1, 10 mL) the precipitate was filtered off, washed with water and dried in vacuo at 40° C. affording 472 mg (67%) of the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[N:11]=[C:10](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:19])[CH:9]=1)([CH3:4])[CH3:3].[H][H]>[Pd].CO>[CH3:3][C:2]([Si:5]([CH3:25])([CH3:26])[O:6][CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[N:11]=[C:10]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:19])[CH:9]=1)([CH3:1])[CH3:4]
Reactant: CCCCOC(=O)/C=C/c1cc(CO[Si](C)(C)C(C)(C)C)cc(OC)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCOC(=O)CCc1cc(CO[Si](C)(C)C(C)(C)C)cc(OC)n1
Yield: 99.9 %

Procedure:
A mixture of butyl (2E)-3-[4-({[(1,1 dimethylethyl)(dimethyl)silyl]oxy}methyl)-6-(methyloxy)-2-pyridinyl]-2-propenoate (4.84 g, 12.49 mmol) and 10% palladium on carbon in methanol (200 ml) was stirred at rt over one atmosphere of hydrogen for 3 h. The mixture was filtered through Celite and evaporated to give the desired product (4.76 g, 98%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:6][CH2:5]1)[CH3:3].Br[C:18]1[CH:19]=[CH:20][C:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:22][CH:23]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH3:3][CH:2]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:22][CH:23]=3)[CH2:15][CH2:16]2)[CH2:6][CH2:5]1)[CH3:1]
Reactant: CC(C)N1CCC(CC2CCNCC2)CC1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(C)N1CCC(CC2CCN(c3ccc(C(=O)OC(C)(C)C)nc3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.9 %

Procedure:
1-(1-Methylethyl)-4-(4-piperidinylmethyl)piperidine (may be prepared as described in Description 4) (0.25 g), 1,1-dimethylethyl 5-bromo-2-pyridinecarboxylate (may be prepared as described in Description 12) (0.29 g), BINAP (0.06 g) and Cs2CO3 (1.82 g) were added to toluene (50 ml) under argon and the reaction mixture degassed by sequential freezing in dry ice followed by warming to room temp under vacuum (3×). After stirring for 5 min Pd(OAc)2 (0.05 g) was added, degassed again, and the reaction mixture heated at 100° C. for 24 h. The reaction mixture was filtered and evaporated, after which chromatography (silica gel, eluting with methanol/dichloromethane, 0-20%) afforded the title compound (E4) as a yellow solid (0.25 g). MS electrospray (+ion) 424 (MNa+)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[N:3]=1.[CH2:12]([C:14]1[CH:15]=[C:16]([CH3:26])[C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:18][CH:19]=1)[CH3:13]>>[Br:1][C:2]1[N:3]=[C:4]([CH3:11])[C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:17]3[C:16]([CH3:26])=[CH:15][C:14]([CH2:12][CH3:13])=[CH:19][N:18]=3)[CH2:21][CH2:22]2)=[O:8])=[CH:9][CH:10]=1
Reactant: CCc1cnc(N2CCNCC2)c(C)c1
Reactant: Cc1nc(Br)ccc1C(=O)O
Product: CCc1cnc(N2CCN(C(=O)c3ccc(Br)nc3C)CC2)c(C)c1
Yield: 55.3 %

Procedure:
Using 6-bromo-2-methylnicotinic acid (675 mg) and 1-(5-ethyl-3-methylpyridin-2-yl)piperazine (611 mg) described in Preparation Example 81 and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (664 mg) was obtained.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].I[C:27]1[CH:28]=[C:29]([CH3:35])[C:30]([O:33][CH3:34])=[N:31][CH:32]=1.C([Mg]Cl)(C)C>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4]([C:27]3[CH:32]=[N:31][C:30]([O:33][CH3:34])=[C:29]([CH3:35])[CH:28]=3)=[O:5])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: COc1ncc(I)cc1C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1ncc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1C

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 120 mg (0.30 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 164 mg (0.66 mmol) of 5-iodo-2-methoxy-3-methyl-pyridine in 1 mL THF with 0.34 mL 2M isopropylmagnesium chloride. Yield: 40 mg of a white powder. LC-MSD, m/z for C23H18BrN3O3 [M+H]+=464.0, 466.0; HPLC retention time: 2.4 min.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.O[CH2:11][C:12]([CH3:24])([CH3:23])[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[CH2:16]([O:15][C:13]([C:12]([CH3:24])([CH3:23])[CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(CO)C(=O)OCc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(COc1ccc(C=O)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 14 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (2.7 g), benzyl hydroxypivalate (4.7 g) and triphenylphosphine (6.4 g) in tetrahydrofuran (22 mL) was added diethyl azodicarboxylate (40% toluene solution, 11 mL), and the mixture was stirred at room temperature for 2 days. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=6/1-4/1) to give the title compound (0.97 g).
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@H:17]([CH:28]=[CH2:29])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H](CO)C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:31]1>>[CH2:11]1[CH2:10][O:9][C:8]23[O:13][CH2:14][CH2:1][O:2][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@H:17]([CH2:28][CH2:29][OH:31])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:12]1
Reactant: C=C[C@H]1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Reactant: C[C@]12CCCCC1[C@@H](CO)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCCCC1[C@@H](CCO)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Yield: 96 %

Procedure:
17,17-Bis(ethylendioxy)-6α-(2-hydroxyethyl)androstane was prepared in 96% yield from 3,3:17,17-bis(ethylendioxy)-6α-vinylandrostane by the procedure described above for the preparation of 3,3:17,17-bis(ethylendioxy)-6α-hydroxymethyl-androstane (Prepn. 14). The crude was purified by flash chromatography (SiO2, n-hexane/acetone 80/20). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.25 (1H, t), 3.86-3.70 (8H, m), 3.35 (2H, m), 1.91-0.42 (23H, m), 0.75 (3H, s), 0.74 (3H, s).