Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=2)=[O:11])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl.C(Cl)(Cl)Cl.CO>O.[Sn]>[OH:9][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1)=[O:11]
Reactant: O=C(C(=O)c1cccc(O)c1)c1cccc(O)c1
Agent: Cl
Agent: [Sn]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(c1cccc(O)c1)C(O)c1cccc(O)c1
Reaction time: 1 h

Procedure:
To a hot stirred solution of 3,3'-dihydroxybenzil (5 g.) in water (200 ml) and tin (30 mesh) was slowly added concentrated hydrochloric acid (10 ml.). Heating on a steam bath with efficient mechanical stirring was continued for 1 hour. Thin layer chromatography on Silica AR 7GF plates (Mallinckrodt) with chloroform-methanol (9:1) showed the reaction was largely complete after 15 minutes. The mixture was filtered, while hot, through Celite and the filtrate was evaporated to smaller volume. The resulting crystals (4.60 g.), m.p. 159°-162° were recrystallized from hot water with decolorization to give white crystals, m.p. 173°-175°, M+ 244 (E. I. mode), pmr (DMSO-d6) δ 5.97 [s, --CH(OH)].
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1.NC(N)=[S:15].[OH-].[Na+]>C(O)C.O>[O:8]1[C:7]2[CH:11]=[CH:12][C:4]([CH2:3][CH2:2][SH:15])=[CH:5][C:6]=2[O:10][CH2:9]1
Reactant: BrCCc1ccc2c(c1)OCO2
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: SCCc1ccc2c(c1)OCO2
Yield: 95.5 %

Procedure:
750 g of 5-(2-bromoethyl)-1,3-benzodioxole was dissolved in 1 l of ethanol. 312 g of thiourea was added to the solution and the mixture was heated under reflux on a boiling water bath for 2 h. The reaction mixture was cooled. A solution of 300 g of sodium hydroxide in 1 l of water was added thereto and the mixture was heated under reflux on a boiling water bath for 45 min. After cooling, 3 l of water was added thereto and the product was extracted with 5 l of ethyl acetate. The extract was washed with dilute hydrochloric acid. It was then washed with water until the washing became substantially neutral and dried over anhydrous sodium sulfate. The solvent was distilled off at 40° C. to obtain about 570 g of a faint yellow oil. It was purified according to column chromatography with about 3 kg of silica gel (hexane : benzene=2:1) to obtain 310 g of the intended compound in the form of a colorless oil.
Reaction SMILES: Cl[C:2]1[C:3](=[O:12])[N:4]([CH3:11])[N:5]=[CH:6][C:7]=1[N:8]([CH3:10])[CH3:9].[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O)=[O:14].C([O-])([O-])=O.[Na+].[Na+].C(Cl)(Cl)Cl.CC(C)=O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][N:8]([CH3:10])[C:7]1[CH:6]=[N:5][N:4]([CH3:11])[C:3](=[O:12])[C:2]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:13]=[O:14]
Reactant: CN(C)c1cnn(C)c(=O)c1Cl
Reactant: O=Cc1ccccc1B(O)O
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: COCCOC
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CN(C)c1cnn(C)c(=O)c1-c1ccccc1C=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-Chloro-5-(dimethylamino)-2-methylpyridazin-3(2H)-one (50.00 mmol) was dissolved in dimethoxyethane (155 ml), and Pd(PPh3)4 (1.60 g, 1.38 mmol) was added under argon. After stirring at room temperature for 10 min, 2-formylbenzeneboronic acid (10.50 g, 70.00 mmol) and 2M Na2CO3 solution (49.5 ml) were added. Subsequently, the reaction mixture was refluxed (oil bath temperature: 110° C.) for 15 h. The reaction was followed by TLC (eluent: chloroform:acetone (9:1)). Upon cooling the reaction mixture was poured onto ice (375 g), filtered over Celite and washed with chloroform (130 ml). The two layers were separated and the aqueous phase was extracted with chloroform (3×380 ml). The combined organic layers were washed with water (1×100 ml), dried over MgSO4, filtered and purified by flash column chromatography with a mixture of diisopropyl ether and acetone (8:1) as the eluent and crystallized from a mixture of ethyl acetate and hexane (2.3:1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][CH2:31][C:32](O)=[O:33])[CH:25]=1>>[OH:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][NH:14][C:10]2[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:32](=[O:33])[CH2:31][CH2:30][C:26]4[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=4)[CH:7]=[CH:6][CH:5]=3)[CH:13]=[CH:12][N:11]=2)=[CH:22][CH:21]=1
Reactant: Nc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Reactant: O=C(O)CCc1cccnc1
Product: O=C(CCc1cccnc1)Nc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 24 was coupled to 3-Pyridin-3-yl-propionic acid following procedure K. LC-MS showed the product had the expected M+H+ of 440. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 9.1 (s, 1H), 8.5 (d, 1H) 8.3 (d, 1H) 7.7 (m, 3H), 7.4 (t, 1H), 7.3 (t, 1H), 7.2 (d, 1H), 7.1 (d, 1H), 7.0 (d, 2H), 6.7 (d, 2H), δ 3.5 (t, 2H), 2.9 (t, 2H), 2.8 (t, 2H), δ 2.7 (t, 2H).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>C(OCC)(=O)C>[C:2](=[O:3])([O:4][CH2:5][CH3:6])[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[CH2:20][CH2:21][CH3:22]
Reactant: CCOC(=O)Cl
Reactant: CCCc1cc(-c2ccccc2)ccc1O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCc1cc(-c2ccccc2)ccc1OC(=O)OCC
Reaction time: 8 h
Yield: 93.1 %

Procedure:
At 5 to 10° C., 18.4 g (0.17 mol) of ethyl chloroformate are added dropwise with cooling to a solution of 36.3 g (0.17 mol) of 4-hydroxy-3-propyl-biphenyl in 160 ml of ethyl acetate and 17.2 g (0.17 mol) of triethylamine. The solution is left standing overnight at 20° C. and washed with water and dilute hydrochloric acid, and the organic phase is dried and concentrated 45 g (yield 93.2% of theory) of (4-phenyl-2-propyl-phenyl) ethyl carbonate are obtained as a pale oil of log p=4.76 (pH=2.3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]=1[O:34][CH3:35]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[O:21][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[O:34][CH3:35])=[CH:6][CH:7]=1
Reactant: COc1c(CBr)ccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(O)C1
Product: COc1c(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(F)cc2)ccc2ccccc12

Procedure:
In an analogous manner to that described in Example 3 (c), by alkylating tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-hydroxy-piperidine-1-carboxylate [Example 3 (b)] with 2-bromomethyl-1-methoxy-naphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-[1 -methoxy-naphthalen-2-yl-methoxy]-piperidine-1-carboxylate as a colourless resin; MS: 465 (M)+.
Reaction SMILES: [C:1]12([CH2:11][C:12]([NH:14][C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][N:19]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:20]4=[O:25])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(Cl)Cl.CCOC(C)=O>C(O)C.[Pd]>[C:1]12([CH2:11][C:12]([NH:14][C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH2:17][CH2:18][N:19]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:20]4=[O:25])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1cccc2c(=O)n(Cc3ccccc3)ccc12
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1cccc2c1CCN(Cc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.8 %

Procedure:
A 50 mL round-bottom flask was charged with a solution of 2-Adamantan-1-yl-N-(2-benzyl-1-oxo-1,2-dihydro-isoquinolin-5-yl)-acetamide (14 mg, 0.033 mmol) in absolute ethanol (6 mL) and 10% Pd/C (10 mg). The reaction vessel was evacuated and filled with hydrogen via balloon. The reaction suspension was stirred at room temperature under hydrogen (1 atm) for 17 h. The resulting mixture was filtered and the filtrate was concentrated on a rotary evaporator. The crude product was purified by prep. TLC using DCM/EtOAc (3:1) as the elutant affording the title compound (11.8 mg, 0.027 mmol, 84% yield) as a white solid.
Reaction SMILES: C(O)CO.[S:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH:14](C#N)[C:15]([O:17]C(C)(C)C)=[O:16])[C:8]=2[CH:7]=[CH:6]1.[OH-].[K+].O>C1(C)C=CC=CC=1>[S:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([CH2:14][C:15]([OH:17])=[O:16])[C:8]=2[CH:7]=[CH:6]1
Reactant: CC(C)(C)OC(=O)C(C#N)c1cccc2sccc12
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)Cc1cccc2sccc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To ethylene glycol (11.0 mL) solution of 0.25 g of tert-butyl 2-(1-benzothiophen-4-yl)-2-cyanoacetate were added 11.0 mL of aqueous solution of 40% (w/w) potassium hydroxide and 0.3 mL of water, which was then stirred at 95 to 105° C. for 1 hour. To the reaction mixture were added water and toluene, and the aqueous layer was separated. The pH was adjusted to 2 with 6 mol/L hydrochloric acid, to which was added ethyl acetate. The organic layer was separated, and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. To the resultant residue was added cyclohexane. The precipitate was collected by filtration to provide 0.15 g of 2-(1-benzothiophen-4-yl)acetic acid as white solid form.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](O)=O)=[CH:6][C:5]([CH3:18])=[N:4]1)[CH3:2].[NH4+].[OH-].O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:11]1[C:10]2[C:9](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[C:5]([CH3:18])[C:6]=12
Reactant: CCn1nc(C)cc1Nc1ccccc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCn1nc(C)c2c(Cl)c3ccccc3nc21
Temperature: 25 °C
Yield: 95 %

Procedure:
A mixture of N-(1-ethyl-3-methylpyrazol-5-yl) anthranilic acid (7.0 g), 28.57 mmol) and POCl3 (210 ml) is refluxed for 24 hours. The reaction mixture is cooled to room temperature, poured into ice waterl and neutralized with concentrated NH4OH to a pH of 8.0. The product which slowly crystallized from the solution is collected by filtration, washed with water and dried to afford 6.7 g (95%) of 4-chloro-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: [Mg].II.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9]Cl.CN(C)[C:16]([CH:18]1[CH2:20][CH2:19]1)=[O:17]>O1CCCC1.C(OCC)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][C:16]([CH:18]1[CH2:20][CH2:19]1)=[O:17]
Reactant: CN(C)C(=O)C1CC1
Reactant: COc1cccc(CCl)c1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cccc(CC(=O)C2CC2)c1
Reaction time: 1 h

Procedure:
A 250 ml round-bottomed flask is filled with magnesium (4.9 g, 0.20 mol) and iodine (0.1 g) is sublimated to the magnesium, then diethyl ether (100 ml) is added and under boiling a solution of 3-methoxybenzyl chloride (11.9 ml, 0.1 mol) and diethyl ether (40 ml) are added to the reaction mixture. The mixture is boiled for one hour and at this temperature a solution of cyclopropanecarboxylic acid dimethylamide (16.6 g, 0.15 mol) and tetrahydrofuran (70 ml) are added. The reaction mixture is stirred for half an hour and under cooling aqueous hydrogen chloride (80 ml, 1:1) is added dropwise to the mixture. The organic layer is dried and the residue (32 g) is fractionated in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Te:14][C:13]([CH:15]=O)=[CH:12][CH:11]=2)=[C:6]([F:17])[C:5]=1[F:18])[CH3:2].[CH3:19][C:20](C)([O-])C.[K+]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1.CC(OC)(C)C.O.Cl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Te:14][C:13]([CH:15]=[CH:19][CH3:20])=[CH:12][CH:11]=2)=[C:6]([F:17])[C:5]=1[F:18])[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CCOc1ccc(-c2ccc(C=O)[te]2)c(F)c1F
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CC=Cc1ccc(-c2ccc(OCC)c(F)c2F)[te]1
Reaction time: 2 h

Procedure:
6.0 g (16.0 mmol) of ethyltriphenylphosphonium bromide are initially introduced together with 5.2 g (14.3 mmol) of 5-(4-ethoxy-2,3-difluorophenyl)-tellurophene-2-carbaldehyde in 150 ml of THF at 0° C., and 0.89 g (7.9 mmol) of potassium tert-butoxide dissolved in 7 ml of THF is added. After 2 h at room temperature, the mixture is diluted with MTBE, and water and 2 N hydrochloric acid are added. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:toluene=3:2). Further purification is carried out by recrystallisation from ethanol; 2-(4-ethoxy-2,3-difluorophenyl)-5-propenyltellurophene is obtained as a yellowish solid.
Reaction SMILES: [I:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]([CH3:12])([CH3:11])[C:8]([NH2:10])=O)[N:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl.N1C=CC=CC=1.CCOC(C)=O.O>[I:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]([CH3:12])([CH3:11])[C:8]#[N:10])[N:3]=1
Reactant: CC(C)(C(N)=O)n1ccc(I)n1
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C#N)n1ccc(I)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-(3-iodo-1H-pyrazol-1-yl)-2-methylpropanamide 7.05 (100 mg, 0.36 mmol) was dissolved in DCM (3 mL) and pyridine (1 mL). Trifluoroacetic anhydride (70 μL, 0.50 mmol) was added and the resulting mixture was stirred at r.t. for 24 h. The reaction mixture was diluted with EtOAc and water, and the phases were separated. The organic phase was washed twice with aqueous HCl (second wash remained acidic) followed by water and was dried over Na2SO4, filtered and concentrated to afford 2-(3-iodo-1H-pyrazol-1-yl)-2-methylpropanenitrile 7.07 that was used without further purification. LCMS-ESI+ (m/z): [M+H]+ calcd for C7H9IN3: 262.0; found: 261.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([O:19][CH3:20])[C@@H:14]([CH3:18])[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])(C)C.Cl.[CH:22]1[C:34]2C(COC(ON3C(=O)CCC3=O)=O)[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1.CO>O1CCOCC1.COCCOC>[CH:31]1[C:32]2[CH:4]([CH2:1][O:5][C:6]([N:8]3[CH2:12][CH2:11][CH2:10][C@H:9]3[C@H:13]([O:19][CH3:20])[C@@H:14]([CH3:18])[C:15]([OH:17])=[O:16])=[O:7])[C:34]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]=2[CH:28]=[CH:29][CH:30]=1
Reactant: CO[C@H]([C@@H](C)C(=O)O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Solvent: COCCOC
Solvent: C1COCCO1
Solvent: CO
Product: CO[C@H]([C@@H](C)C(=O)O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring solution of #11 (2.4 g, 8.4 mmol, 1.0 eq.) in 10 mL of dioxane under nitrogen, 4M HCl in dioxane (20 mL, 80 mM, 10 eq.) was added. The reaction was allowed to stir at room temperature for 3 hours before being concentrated in vacuo and placed underneath high vacuum. Crude material was then dissolved with 30 mL of 10% Na2CO3. This solution was then added to a stirring solution of 1-{[(9H-fluoren-9-ylmethoxy)carbonyl]oxy}pyrrolidine-2,5-dione (2.96 g, 8.77 mmol, 1.05 eq.) in 30 mL of DME. Reaction was allowed to stir at room temperature until TLC (20% methanol/40% ethyl acetate/40% heptanes) indicated the consumption of Boc de-protected starting material. The reaction was concentrated in vacuo to a smaller volume, washed twice with ether, acidified to pH 2 using concentrated HCl and then extracted three times with a solution of 90% dichloromethane 10% methanol. The organics where washed with saturated sodium bicarbonate and brine before being dried over sodium sulfate, filtered, and concentrated in vacuo to a brown solid #119 (3.4 g, quant.). LC-MS (Protocol Q): m/z 410.0 [M+H+], retention time=1.81 minutes.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Br[CH2:36][C:37]1[C:42]2[N:43]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[C:44](=[O:49])[O:45][C:46]([CH3:48])([CH3:47])[C:41]=2[CH:40]=[CH:39][CH:38]=1>>[CH3:47][C:46]1([CH3:48])[O:45][C:44](=[O:49])[N:43]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:55])[CH3:56])[C:42]2[C:37]([CH2:36][O:1][CH:2]3[CH:7]([C:8]4[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[O:26][CH3:27])=[CH:10][CH:9]=4)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]3)=[CH:38][CH:39]=[CH:40][C:41]1=2
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: CC1(C)OC(=O)N(COCC[Si](C)(C)C)c2c(CBr)cccc21
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc3c2N(COCC[Si](C)(C)C)C(=O)OC3(C)C)cc1

Procedure:
Analogously to Method D, 0.30 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.28 g of 8-bromomethyl-4,4-dimethyl-1-(2-trimethylsilanylethoxymethyl)-1,4-dihydrobenzo[d][1,3]oxazin-2-one are reacted. The title compound is obtained as a yellow oil. Rf=0.60 (1:1 EtOAc-heptane); Rt=6.68.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15]O)=[CH:8][C:7]=1[O:21][CH3:22].N1C=CC=CC=1>O>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[CH2:15][Cl:3])=[CH:8][C:7]=1[O:21][CH3:22]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(Sc2ccccc2CO)ccc1Cl
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(Sc2ccccc2CCl)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
Thionyl chloride (6.5 g) is added dropwise to a stirred mixture of the alcohol from the preceding preparation (11.2 g) and pyridine (4.0 g) at 10°-20° C. The mixture is stirred at room temperature for 3 hours and, after standing overnight, for one additional hour at 30°-40° C. The cooled mixture is decomposed by dropwise addition of water (20 ml) and the product extracted with benzene. The work-up of the extract, followed by crystallization of the crude residue from a small volume of hexane, yields 10.2 g (85%) of 2-(4-chloro-3-methoxyphenylthio)benzyl chloride which in the pure state melts at 57°-59° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([BH3-])#N.[Na+]>C(O)(=O)C.O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH2:11]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)N1CCC(C2CNc3ccccc32)CC1
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of 3-(1-acetyl-4-piperidyl)indole (48.2 g) in acetic acid (1 l) was added sodium cyanoborohydride (95 g) at 15° to 20° C. slowly over a period of 1.5 hours with stirring. The mixture was further stirred at ambient temperature for 3 hours, after which a further amount (10 g) of sodium cyanoborohydride was added. The mixture was stirred for 1 hour and the reaction mixture was diluted with water (500 ml), concentrated under reduced pressure, and allowed to stand overnight. To this reaction mixture was added 2N aqueous sodium hydroxide solution (1.5 l), and the mixture was extracted with ethyl acetate (1 l) 3 times. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was dissolved in a mixture of tetrahydrofuran (200 ml) and 2N aqueous sodium hydroxide solution (300 ml). The solution was stirred at ambient temperature for 2 hours, after which it was concentrated under reduced pressure. The residue was extracted with ethyl acetate (600 ml) and the extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel, elution being carried out with a mixture of chloroform and methanol (50:1 V/V) to give 3-(1-acetyl-4-piperidyl)indoline (41.1 g).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)[CH:11]=[CH:10][C:5]=2[C:6]=1[C:7](Cl)=[O:8].[NH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[CH:28]2>>[NH:30]1[C:31]2[C:27](=[CH:26][C:25]([NH:24][C:7]([C:6]3[C:5]4[CH:10]=[CH:11][C:12]([O:14][C:15]5[CH:20]=[CH:19][N:18]=[C:17]6[CH:21]=[CH:22][S:23][C:16]=56)=[CH:13][C:4]=4[O:3][C:2]=3[CH3:1])=[O:8])=[CH:33][CH:32]=2)[CH:28]=[CH:29]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)Cl
Product: Cc1oc2cc(Oc3ccnc4ccsc34)ccc2c1C(=O)Nc1ccc2[nH]ccc2c1

Procedure:
This material was prepared from 2-methyl-6-[thieno[3,2-b]pyridin-7-yloxy]benzofuran-3-carbonyl chloride 101 and 5-aminoindole in a similar manner as that described for example 108. 1H NMR (DMSO-d6) δ 11.04(1H, s),9.96(1H, s),8.52(1H, d, J=5.6 Hz), 8.15(1H, d, J=5.3 Hz), 7.97 (1H, s), 7.83 (1H, d, J=8.3 Hz), 7.69 (1H, d, J=2.3 Hz), 7.60 (1H, d, J=5.6 Hz), 7.36 (2H, s), 7.33 (1H, t, J=2.8 Hz), 7.27 (1H, dd, J=8.6, 2.3 Hz), 6.64 (1H, d, J=5.3 Hz), 6.41 (1H, t, J=2.5 Hz), 2.69 (3H, s).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=2[CH3:26])=[O:17])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:46]=[CH:45][C:40]3[NH:41][C:42](=[O:44])[NH:43][C:39]=3[CH:38]=2)O1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[CH3:13][C:12]([N:8]1[C:6]2[N:7]=[C:2]([C:37]3[CH:46]=[CH:45][C:40]4[NH:41][C:42](=[O:44])[NH:43][C:39]=4[CH:38]=3)[CH:3]=[C:4]([C:16]([NH:18][CH2:19][C:20]3[C:21](=[O:28])[NH:22][C:23]([CH3:27])=[CH:24][C:25]=3[CH3:26])=[O:17])[C:5]=2[C:10]([CH3:11])=[N:9]1)([CH3:14])[CH3:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2c(C)nn3C(C)(C)C)c(=O)[nH]1
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc4[nH]c(=O)[nH]c4c3)nc3c2c(C)nn3C(C)(C)C)c(=O)[nH]1
Reaction time: 0.67 h

Procedure:
The title compound was prepared in the same manner as described in example 74 using 6-chloro-1-(1,1-dimethylethyl)-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (70 mg, 0.174 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-benzimidazol-2-one (58.9 mg, 0.226 mmol), DME (3 mL), water (1.00 mL), sodium carbonate (0.261 mL, 0.523 mmol) and PdCl2(dppf)-CH2Cl2 adduct (11.38 mg, 0.014 mmol) wherein the reaction time was 40 min. The crude product was purified by column chromatography (eluent: gradient of 0 to 15% (9:1 MeOH/NH4OH)/DCM). The final product was collected as a solid, 24 mg (27%). LCMS E-S (M+H)=500.2 1H NMR (400 MHz, DMSO-d6) δ ppm 1.77 (m, 9 H), 2.12 (s, 3 H), 2.24 (s, 3 H), 2.40 (s, 3 H), 4.38 (d, J=4.55 Hz, 2 H), 5.89 (s, 1 H), 7.06 (d, J=8.08 Hz, 1 H), 7.59 (s, 1 H), 7.72-7.86 (m, 2 H), 8.73 (br. s., 2 H), 10.74-10.92 (m, 1 H), 11.53 (br. s., 1 H).