Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH:15]([CH:18]3[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH:26]=[O:27])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1>C(O)C>[F:1][C:2]([F:28])([F:29])[O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH:12]2[CH2:13][CH2:14][CH:15]([CH:18]3[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26][OH:27])[CH2:20][CH2:19]3)[CH2:16][CH2:17]2)=[CH:8][CH:9]=1
Reactant: O=CCCC1CCC(C2CCC(CCc3ccc(OC(F)(F)F)cc3)CC2)CC1
Solvent: CCO
Product: OCCCC1CCC(C2CCC(CCc3ccc(OC(F)(F)F)cc3)CC2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
Ethanol (20 ml) was added to the above 3-(4-(4-(2-(4-trifluoromethoxyphenyl)ethyl)cyclohexyl)cyclohexyl) propanal (2.70 g, 6.58 mmol), followed by cooling the mixture down to 0° C. in a nitrogen gas atmosphere, adding thereto, sodiumboronhydride (0.13 g, 3,43 mmol) so that the liquid temperature could not exceed 10° C., stirring the mixture at 0° C. for 2 hours, extracting the resulting product with ethyl acetate, washing the organic layer successively with a saturated aqueous solution of sodium bicarbonate and water, drying over magnesium sulfate, distilling off the solvent, and recrystallizing the residue from heptane, to obtain 3-(4-(4-(2-(4-trifluoromethoxyphenyl)ethyl)cyclohexyl)cyclohexyl)propanol (2.10 g, 5.09 mmol). Yield: 77.4%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18]CC)=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([S:38]([CH3:41])(=[O:40])=[O:39])[CH:33]=2)[N:3]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:21][CH2:22]2)[CH:5]=[C:4]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([S:38]([CH3:41])(=[O:39])=[O:40])[CH:33]=2)[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(OCc4ccc(Cl)cc4-c4cccc(S(C)(=O)=O)c4)nc(N)n3)CC2)CN1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1cccc(-c2cc(Cl)ccc2COc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution (S)-ethyl 8-(2-amino-6-((5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)methoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (100 mg, 0.13 mmol) in MeOH (3 mL) was added 4 N NaOH (3 mL), and the mixture was stirred at RT for 4 h. The reaction mixture was then concentrated in vacuo. The residue was diluted with water (5 mL) and the pH adjusted to 6-7. The precipitated solid was collected by filtration, the filter cake was washed with cold water, then dried to afford the title compound as an off-white solid isolated as the zwitterionic form.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[C:11](Cl)=[N:10][C:9]=12)=[O:4].C([O-])([O-])=O.[Na+].[Na+].[CH:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30]>C(COC)OC.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]>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[F:21])[C:11]([C:34]3[CH:35]=[CH:36][C:31]([CH:29]=[O:30])=[CH:32][CH:33]=3)=[N:10][C:9]=12)=[O:4]
Reactant: COC(=O)c1cnn2cc(-c3ccc(F)cc3F)c(Cl)nc12
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COC(=O)c1cnn2cc(-c3ccc(F)cc3F)c(-c3ccc(C=O)cc3)nc12
Temperature: 90 °C
Yield: 44.1 %

Procedure:
130 mg (0.4 mmol) 5-Chloro-6-(2,4-difluorophenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid methyl ester are given in 1.4 mL dimethoxyethane (no complete dissolution). 0.8 mL Na2CO3 solution (10%) and 66 mg (0.44 mmol) 4-formylphenylboronic acid are added. After addition of 15 mg (0.02 mmol) 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) the reaction mixture is purged 3× with argon and heated at 90° C. for 18 hours (complete dissolution). The reaction mixture is cooled down, treated with water and diluted with dichloromethane. The water phase is extracted once more with dichloromethane and the combined organic phases are washed with brine and dried (Na2SO4). The solvent is removed and the crude product purified via chromatography (silicagel, dichloromethane/methanol). 69.4 mg (41.7%) of the desired aldehyde are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([NH2:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:16]([SnH:20]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>O1CCCC1>[CH2:25]([Sn:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:21][CH2:22][CH2:23][CH3:24])/[C:12](=[CH:11]/[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)/[C:13]([NH2:15])=[O:14])[CH2:26][CH2:27][CH3:28]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: COc1ccc(CCC(N)=O)cc1OC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)/C(=C/c1ccc(OC)c(OC)c1)C(N)=O
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
3-(3,4-dimethoxyphenyl)propionic acid amide (20.5 mg, 0.1 mmol) prepared in the same manner as in Reference Synthetic Example 8 was dissolved in tetrahydrofuran (2 ml) in nitrogen atmosphere, and under cooling with ice, tetrakistriphenylphosphine palladium(0) (5 mg, 0.004 mmol) was added, and then a tetrahydrofuran solution (0.5 ml) of tri-n-butyltin hydride (35 μl, 0.13 mmol) was dropwise added. After stirring for 30 minutes, the solution was concentrated under reduced pressure, and the residue was purified by tin-layer silica gel column chromatography (hexane:ethyl acetate=1:1) to give (E)-2-(tributylstannyl)-3-(3,4-dimethoxyphenyl)acrylamide (14.8 mg, 30%) as a pale yellow oily substance.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=[O:12].[Na+].[Na+].CN[C@@H]1CCCC[C@H]1NC.Cl>CN[C@@H]1CCCC[C@H]1NC.O>[OH:12][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccccc1Cl
Reactant: O=C([O-])[O-]
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
Under nitrogen, 7.82 g (50 mmol) of 2-chlorobenzoic acid was combined with 31 g of H2O. 6.62 g (62.5 mmol) of Na2CO3 was then added. The mixture was heated to reflux with stirring for 30 min, remaining under a nitrogen atmosphere. Separately, 36 mg of CuBr and 79 mg of rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (Ligand F) were combined with 1 mL H2O under nitrogen. The resulting mixture was stirred under an air atmosphere until the CuBr was dissolved to give a deep purple solution. This solution was added to the stirred reaction mixture via syringe at 80° C. under nitrogen and stirred for about 3 h at 100° C. and the reaction was monitored by 1H NMR. Table 3 shows the distribution of starting material and product at different reaction times. A product selectivity of more than 99% was observed. After reaction completion, the mixture was allowed to cool to 25° C. and the reaction mixture was acidified with 15% HCl, producing a white precipitate. The white precipitate was filtered, washed with water and dried yielding 6.00 g 2-hydroxybenzoic acid (85% yield). The filtrate was extracted with ethyl acetate and evaporated to dryness to receive another 0.65 g of 2-hydroxybenzoic acid resulting in a total yield of 6.65 g (48.2 mmol, 96% yield).
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[CH2:16]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH2:28][NH2:29])(=[O:20])=[O:19])[CH3:17].C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:29]([CH2:28][C:22]2[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:21]=2[S:18]([CH2:16][CH3:17])(=[O:20])=[O:19])[CH:10]=1
Reactant: CCS(=O)(=O)c1ccc(C)cc1CN
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCS(=O)(=O)c1ccc(C)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Yield: 27.2 %

Procedure:
(Step 4) 2-Cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (2.35 g), 1-[2-(ethylsulfonyl)-5-methylphenyl]methanamine hydrochloride obtained in Step 3 (3.0 g) and potassium carbonate (4.15 g) were stirred in ethanol (30 ml) at 85° C. for 20 hr. The reaction mixture was treated with 1N sodium hydroxide solution, and extracted with a mixed solvent of ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3). The obtained residue was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (4 ml) was added. The mixture was crystallized from methanol-ethyl acetate, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (0.55 g).
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25].C(N(CC)CC)C.Br[C:37]1[CH:38]=[C:39]([C:43]2[O:44][C:45]3[CH:51]=[CH:50][C:49]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[CH:48][C:46]=3[N:47]=2)[CH:40]=[CH:41][CH:42]=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:28][O:27][C:23](=[O:26])[CH:24]=[CH:25][C:41]1[CH:42]=[CH:37][CH:38]=[C:39]([C:43]2[O:44][C:45]3[CH:51]=[CH:50][C:49]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[CH:48][C:46]=3[N:47]=2)[CH:40]=1
Reactant: C=CC(=O)OC
Reactant: Brc1cccc(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C=Cc1cccc(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Reaction time: 0.03 h

Procedure:
Tri(o-toly)phosphine (9 mg, 0.030 mmol), palladium(II) acetate (6 mg, 0.027 mmol), methyl acrylate (31 mg, 0.34 mmol), triethylamine (116 mg, 1.14 mmol) and aryl bromide (32) (100 mg, 0.29 mmol) in acetonitrile (3 mL) were heated in a CEM Discover microwave for 90 minutes at 90° C. The solvent was removed under a stream of nitrogen gas, water was added and the organics extracted with EtOAc. The organic layer was dried (Na2SO4) and the solvent concentrated in vacuo. The crude product was purified by column chromatography eluting with 20% EtOAc in heptane. Yield: 41 mg, 40%; LC-MS tr 1.86 min; HPLC Purity: 67%; MS (ES+) m/z 356 (M+H)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[Cl:15][C:16]1[CH:17]=[C:18](N(C2CC2)CC2C=CC(OC)=CC=2)[C:19]2[N:20]([C:22]([C:25]#[N:26])=[CH:23][N:24]=2)[N:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([N:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[CH2:4][CH2:3][O:2][CH3:1])[C:19]2[N:20]([C:22]([C:25]#[N:26])=[CH:23][N:24]=2)[N:21]=1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: COCCNCc1ccc(OC)cc1
Product: COCCN(Cc1ccc(OC)cc1)c1cc(Cl)nn2c(C#N)cnc12

Procedure:
15A was prepared from 2-methoxy-N-(4-methoxybenzyl)ethanamine and 1F following the procedure employed in the preparation of 1G. HPLC: Rt=3.20 min. (CHROMOLITH® column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min., monitoring at 220 nm). MS (ES): m/z=372.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH3:24][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Reactant: 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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2C)c([N+](=O)[O-])c1
Temperature: 120 °C
Reaction time: 14 h
Yield: 79.9 %

Procedure:
A suspension of methyl 4-bromo-3-nitrobenzoate (Chess 1687; 3 g; 11.53 mmol; 1 eq.), o-tolylboronic acid (Aldrich 393606; 1.88 g; 13.84 mmol; 1.2 eq.), potassium carbonate (7.97 g, 57.68 mmol, 5 eq.) and tetrakis(triphenylphosphine)palladium(0) (668.2 mg, 0.577 mmol, 0.05 eq.) in toluene (15 mL) and water (15 mL) was stirred at 120° C. for 14 hours. The resulting mixture was allowed to return to room temperature and the two phases were separated. The organic layer was concentrated in vacuo and purified by column chromatography (c-hexane) to afford the title compound (2.5 g, 79%) as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.[C:18](Cl)(=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.Cl>O.C1COCC1>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([N:8]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=2)[CH3:7])=[O:27])=[CH:20][CH:21]=1
Reactant: CNc1ccc(C(=O)O)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)N(C)c2ccc(C(=O)O)cc2)cc1
Reaction time: 0.25 h
Yield: 51.3 %

Procedure:
Aqueous solution (50 ml) of sodium carbonate (23 g) was added to THF solution (50 ml) of 4-(methylamino)benzoic acid (5.0 g), and p-anisoyl chloride (5.6 g) was added dropwise to the solution under ice-cooling, which was stirred for 15 minutes, and then stirred at room temperature for 30 minutes. Concentrated hydrochloric acid was added to the reaction mixture under ice-cooling to make the water layer acidic, and extraction was conducted using ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried, and then concentrated. The residue was purified using silica gel column chromatography (development solvent; hexane˜hexane:ethyl acetate=1:2), and recrystallized (ethyl acetate-hexane) to give the titled compound (4.8 g).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23](O)[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[CH3:29][CH:10]1[CH:11]=[C:12]2[CH:13]([CH:14]([CH2:19][CH2:20][CH:21]3[CH2:22][CH:23]=[CH:24][C:25](=[O:26])[O:27]3)[CH:15]([CH3:18])[CH:16]=[CH:17]2)[CH:8]([O:7][C:5](=[O:6])[CH:3]([CH3:4])[CH2:2][CH3:1])[CH2:9]1
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC3CC=CC(=O)O3)C21

Procedure:
To a stirred solution of 4.0 g (10 mmol) mevinolin in 20 ml pyridine at room temperature are added 20 ml acetic acid anhydride. After 1 h the reaction mixture is concentrated in-vacuo. The residue is dissolved with 10 ml methyl-t-butyl ether and washed successively with water, 0.1 N HCl and brine. The organic phase is then dried over sodium sulfate and the solvent removed in vacuo. The crude product is purified by silica gel chromatography (methyl-t-butyl ether 1/3) to afford 2-methyl-butyric acid 3,7-dimethyl-8-[2-(6-oxo-3,6-dihydro-2H-pyran-2-yl)-ethyl]-1,2,3,7,8,8a-hexahydro-naphthalen-1-yl ester) as a white powder.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:7]=[C:8]([S:10]([F:15])([F:14])([F:13])([F:12])[F:11])[CH:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:30][CH3:31].IC.Cl>C(COC)OC.C(OCC)(=O)C.O>[C:1]([C:4]1[CH:5]=[C:6]([N:16]([CH2:30][CH3:31])[C:17](=[O:22])[C:18]([F:21])([F:19])[F:20])[CH:7]=[C:8]([S:10]([F:14])([F:15])([F:13])([F:12])[F:11])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(NC(=O)C(F)(F)F)cc(S(F)(F)(F)(F)F)c1
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: COCCOC
Solvent: O
Product: CCN(C(=O)C(F)(F)F)c1cc(C(C)=O)cc(S(F)(F)(F)(F)F)c1
Temperature: 100 °C

Procedure:
N-(3-Acetyl-5-pentafluorosulfanylphenyl)-2,2,2-trifluoroacetamide (100 mg, example 4d) was dissolved in absolute dimethoxyethane (5 ml) in a microwave insert and admixed with powdered potassium carbonate (40 mg). After adding iodoethane (60 μl), the mixture was heated to 100° C. in the microwave for 30 min. Subsequently, further iodomethane (60 μl) was added and the mixture was heated again to 100° C. for 30 min. This operation was repeated once more. Then the mixture was worked up by adding it to a mixture of water, ethyl acetate and 1 N HCl. Removal of the organic phase was followed by extraction three times more with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC. The product-containing fractions were combined, freed of the acetonitrile and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 50 mg of the desired compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH3:26])[CH:19]=3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH:27]1([N:33]=[C:34]=[O:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.CCN(CC)CC>ClCCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH3:26])[CH:19]=3)[C:34]([NH:33][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:35])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C=NC1CCCCC1
Reactant: CCOc1cccc(Nc2c3ccccc3nn2-c2ccc(Cl)cc2)c1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCOc1cccc(N(C(=O)NC2CCCCC2)c2c3ccccc3nn2-c2ccc(Cl)cc2)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-(3-ethoxy-phenyl)-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in 1,2-dichloroethane in the presence of Et3N (3 eq.) for 3 d under reflux conditions to give the title compound as yellow solid. MS; m/e=489.1 [M+H+].
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)(=O)=O.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:24]2[CH:28]=[CH:27][N:26]=[CH:25]2)=[CH:11][CH:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CS(=O)(=O)OCCCCc1ccc(OCc2ccccc2)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc(CCCCn3ccnc3)cc2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
A mixture of 4-(4-benzyloxyphenyl)butyl methane sulfonate (25.0 g), imidazole (11.2 g), potassium carbonate (15.5 g) and N,N-dimethylformamide (200 ml) was stirred for 16 hours at 80° C. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate-methanol (20:1, v/v), 1-[4-(4-benzyloxyphenyl)butyl]imidazole (14.0 g, 61%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 97-98° C.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1.[NH:22]([CH3:47])[C@H:23]([C:27]([N:29]([CH3:46])[C@H:30]([C:43]([NH2:45])=[O:44])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:33]=1)=[O:28])[CH:24]([CH3:26])[CH3:25].O>C1COCC1>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([N:22]([CH3:47])[C@H:23]([C:27]([N:29]([CH3:46])[C@H:30]([C:43]([NH2:45])=[O:44])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([C:39]([CH3:42])([CH3:40])[CH3:41])[CH:33]=1)=[O:28])[CH:24]([CH3:26])[CH3:25])=[O:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1
Reactant: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(F)c1)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccc(O)c(F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 27 h
Yield: 9.7 %

Procedure:
To a solution of the above crude Boc-Tyr(3-F)-OH (1.18 g), N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (1.10 g, 3.03 mmol) and CMPI (1.16 g, 4.55 mmol) in THF (6 ml), TEA (1.27 ml, 12.1 mmol) was added under cooling with ice and stirred at room temperature for 27 hours. The reaction mixture was mixed with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:concentrated aqueous ammonia=30:1:0.05), giving the titled compound (0.19 g, 10%).
Reaction SMILES: C(O[B:5]1[O:9][C:8]([CH3:11])([CH3:10])[C:7]([CH3:13])([CH3:12])[O:6]1)(C)C.C([Li])CCC.[F:19][C:20]1[CH:25]=[C:24]([O:26][CH:27]([CH3:29])[CH3:28])[CH:23]=[C:22]([F:30])[CH:21]=1>>[F:19][C:20]1[CH:25]=[C:24]([O:26][CH:27]([CH3:28])[CH3:29])[CH:23]=[C:22]([F:30])[C:21]=1[B:5]1[O:6][C:7]([CH3:12])([CH3:13])[C:8]([CH3:10])([CH3:11])[O:9]1
Reactant: CC(C)Oc1cc(F)cc(F)c1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]CCCC
Product: CC(C)Oc1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Yield: 99 %

Procedure:
Method 3 was followed using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.2 equiv.), butyllithium (1.2 equiv.) and 1,3-difluoro-5-isopropoxybenzene (1.0 equiv.) to give 2-(2,6-difluoro-4-isopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in 99% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.24 (s, 12 H), 1.31-1.33 (m, 6 H), 4.43-4.56 (m, 1 H), 6.31-6.44 (m, 2 H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]2[C:10]([C:11]=1[CH2:12][C:13]([NH2:15])=[O:14])=[CH:9][C:8]([O:16]C)=[CH:7][CH:6]=2)[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:3]1[N:4]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:5]2[C:10]([C:11]=1[CH2:12][C:13]([NH2:15])=[O:14])=[CH:9][C:8]([OH:16])=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCc1c(CC(N)=O)c2cc(OC)ccc2n1Cc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCc1c(CC(N)=O)c2cc(O)ccc2n1Cc1ccccc1
Yield: 75.2 %

Procedure:
2-Ethyl-5-methoxy-1-(phenylmethyl)-1H-indole-3-acetamide (5.05 g, 15.7 mmol) and 47 mL of 1M BBr3 in 100 mL of methylene chloride was reacted as described in Example 56, Part C to give a product that was chromatographed on silica gel eluting with EtOAc to give 3.64 g (75% yield) of 2-ethyl-5-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide as a yellow foam.
Reaction SMILES: NC1SC2C(=O)CCCC=2N=1.SC1NC2C=CC=CC=2N=1.[C:22]1([C:28]2[N:29]=[C:30]3[N:34]([CH:35]=2)[C:33]2[CH2:36][CH2:37][CH2:38][C:39](=[O:40])[C:32]=2[S:31]3)[CH:27]=[CH:26][CH:25]=CC=1>>[CH2:36]1[C:33]2[N:34]3[C:35]4[CH:25]=[CH:26][CH:27]=[CH:22][C:28]=4[N:29]=[C:30]3[S:31][C:32]=2[C:39](=[O:40])[CH2:38][CH2:37]1
Reactant: O=C1CCCc2c1sc1nc(-c3ccccc3)cn21
Agent: Nc1nc2c(s1)C(=O)CCC2
Agent: Sc1nc2ccccc2[nH]1
Product: O=C1CCCc2c1sc1nc3ccccc3n21

Procedure:
2-Bromo-1,3-cyclohexadione prepared in Example 1, Route 1 (A) was reacted with 2-mercaptobenzimidazole in the same manner as that of Example 1, Route 1 (B) to give 1,2-dihydrobenzimidazo[2,1-b]benzothiazole-4(3H)-one (Compound (IIb) of Reaction Scheme II), which was subjected to bromination in the same manner as that of Example 1, Route 1 (C) to give 3-bromo-1,2-dihydrobenzimidazo[2,1-b] benzothiazole-4(3H)-one hydrobromide. The hydrobromide (1.45 g) and thiourea (0.15 g) were placed into ethanol (50 ml), and the mixture was heated to reflux for 2 hours, cooled, and the filtered to give the titled compound (61%).