Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12](=[S:16])[NH:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:17][CH3:18])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:21]I.O>CN(C=O)C>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([S:16][CH3:21])=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:17][CH3:18])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CI
Reactant: CCc1[nH]n(C2CCCC2)c2nc(=S)[nH]c(=O)c1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(SC)nc(=O)c1-2
Reaction time: 3 h
Yield: 74.2 %

Procedure:
Alternatively, the product can be prepared as follows: To a stirred mixture of 1-cyclopentyl-3-ethyl-6-(thioxo)pyrazolo[3,4-d]pyrimidin-4-one (23.4 g, 0.09 mol) in DMF (250 mL) was added NaH (4.0 g, 0.1 mol., 60% dispersion in mineral oil) over 15 minutes. The resulting mixture was cooled in an ice bath, then methyl iodide (6.3 mL, 0.1 mol) was added over 20 minutes and the resulting mixture was stirred for 3 hours. The reaction mixture was poured into water (400 mL) and the precipitate which formed was collected by filtration, washed with water, then hexane and then was dried at 80°-85° C. in a vacuum oven to afford 18.6 g (74%) of 1-cyclopentyl-3-ethyl-6-(methylthio)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 203°-205° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([CH3:25])([CH3:24])[O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.C[O:34][B:35](OC)[O:36]C>O1CCCC1>[C:20]([SiH2:19][O:18][C:17]([CH3:25])([CH3:24])[C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][CH:9]=[CH:10]2)([CH3:23])([CH3:21])[CH3:22].[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[B:35]([OH:36])[OH:34])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COB(OC)OC
Reactant: CC(C)(C)OC(=O)n1ccc2cc(C(C)(C)O[SiH2]C(C)(C)C)ccc21
Agent: CC(C)[N-]C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(B(O)O)cc2ccccc21
Product: CC(C)(C)[SiH2]OC(C)(C)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a stirred solution of 5-(tert-Butyl-dimethyl-silanyloxymethyl)-indole-1-carboxylic acid tert-butyl ester (3-3, 38.6 g, 106.7 mmol) in tetrahydrofuran (400 mL) was slowly added at −78 deg C. a solution of lithiun diisopropylamide in tetrahydrofuran (2M, 80.1 mL, 160.1 mmol, 1.5 equiv). The reaction mixture was stirred at the same temperature for 1 h, treated with trimethylborate, warmed up to ambient temperature, and partitioned between ethyl acetate and 0.5N-HCl. The organic layer was washed with brine, separated, dried (MgSO4) and concentrated in vacuo to give the crude solid. Trituration of the crude product with hexanes followed by filtration and air-drying afforded the desired boronic acid (3-4, 41.3 g, 95%) as a white powder; 1H NMR (400 MHz, CDCl3) δ 7.96 (d, 1H, J=6.8 Hz), 7.54 (s, 1H), 7.47 (s, 1H), 7.32 (d, 1H, J=6.8 Hz), 7.10 (s, 1H), 4.82 (s, 2H), 1.74 (s, 9H), 0.95 (s, 9H), 0.11 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][NH2:12])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[F:13][C:14]([F:26])([F:25])[C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1F)=[O:16].C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1)[CH2:11][NH:12][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C:15](=[O:16])[C:14]([F:25])([F:26])[F:13]
Reactant: COc1cc(CN)cc(OC)c1
Reactant: O=C(c1ccc(F)cc1F)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CNc2cc(F)ccc2C(=O)C(F)(F)F)cc(OC)c1
Yield: 100.9 %

Procedure:
A solution of (3,5-dimethoxyphenyl)methanamine (0.88 g, 5.20 mmol), 2,2,2-trifluoro-1-(2,4-difluorophenyl)ethanone (1.0 g, 4.80 mmol) and diisopropylethylamine (1.6 mL, 9.6 mmol) in acetonitrile was stirred at 40° C. for 48 h. The solvent was concentrated in vacuo, the residue was taken up in dichloromethane and washed with water and brine, dried, and concentrated under reduced pressure to yield 1.73 g of a yellow oil. The residue was purified by PTLC (20% ethyl acetate in hexanes) to give 527 mg (35%) of the desired aniline: 1H NMR (400 MHz, CDCl3) δ 9.27 (br t, 1H), 7.83 (br s, 1H), 6.47-6.40 (m, 5H), 4.42 (d, 2H), 3.79 (s, 6H).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]([NH:8][C:9]1[C:10]([OH:19])=N[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)=O)[CH3:2].[CH3:24]OCCOC(/N=N/C(OCCOC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[NH4+]>C1COCC1>[CH2:1]([S:3][C:4]1[C:5]([C:6]2[O:19][C:10]3[CH:24]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[CH:14][C:9]=3[N:8]=2)=[CH:20][CH:21]=[CH:22][N:23]=1)[CH3:2]
Reactant: COCCOC(=O)/N=N/C(=O)OCCOC
Reactant: CCSc1ncccc1C(=O)Nc1cc(C(F)(F)F)cnc1O
Agent: [Cl-]
Agent: [NH4+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCSc1ncccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 50 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
A mixture of 0.69 g of 2-ethylsulfanyl-N-(2-hydroxy-5-trifluoromethylpyridin-3-yl) nicotinamide, 0.75 g of DMEAD, 0.79 g of triphenylphosphine and 7 ml of THF was stirred at 50° C. for 4 hours. A saturated aqueous ammonium chloride solution was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.45 g of 2-(2-ethylsulfanylpyridin-3-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as Compound of Present Invention 34).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[N:17]=[C:16]3[C:12]([N:13]=[CH:14][N:15]3[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[C:11]([NH2:24])[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:25]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl>[Br:25][C:14]1[N:15]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:16]2[C:12]([N:13]=1)=[C:11]([NH2:24])[N:10]=[C:9]([O:8][CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[N:17]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc(OCC2CCCCC2)nc2c1ncn2C1CCCCO1
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1nc(OCC2CCCCC2)nc2c1nc(Br)n2C1CCCCO1
Temperature: 2 °C
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
2-[(Cyclohexylmethyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.0364 g) was dissolved in chloroform (20 mL) and cooled to 0° C. before N-bromosuccinimide (0.5852 g) was added gradually (the reaction temperature not exceeding 1.9° C. during the addition of N-bromosuccinimide). The reaction mixture was stirred at ˜2° C. for 15 minutes before being warmed to room temperature at which it was stirred for 6 hours (under nitrogen). Water (100 mL) was added to the reaction mixture and stirred rapidly before the organic layer was separated using a hydrophobic frit. The organic phase was evaporated under reduced pressure to give dark brown oil. This material was purified by silica chromatography eluting with 0-50% ethyl acetate; cyclohexane to give the title compound as a pale yellow solid (0.8200 g).
Reaction SMILES: CC[O:3][CH2:4][CH3:5].[Na].[Cl:7][C:8]1[C:13]([OH:14])=[C:12]([Cl:15])[C:11]([Cl:16])=[C:10]([Cl:17])[C:9]=1[Cl:18].[Cl:19][C:20]1[C:25](CCl)=[C:24]([Cl:28])[C:23]([Cl:29])=[C:22]([Cl:30])[C:21]=1[Cl:31]>COCCO>[Cl:7][C:8]1[C:5]([CH2:4][OH:3])=[C:12]([Cl:15])[C:11]([Cl:16])=[C:10]([Cl:17])[C:9]=1[Cl:18].[Cl:7][C:8]1[C:13]([O:14][C:25]2[C:24]([Cl:28])=[C:23]([Cl:29])[C:22]([Cl:30])=[C:21]([Cl:31])[C:20]=2[Cl:19])=[C:12]([Cl:15])[C:11]([Cl:16])=[C:10]([Cl:17])[C:9]=1[Cl:18]
Reactant: CCOCC
Reactant: ClCc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: [Na]
Solvent: COCCO
Product: Clc1c(Cl)c(Cl)c(Oc2c(Cl)c(Cl)c(Cl)c(Cl)c2Cl)c(Cl)c1Cl
Product: OCc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl

Procedure:
This ether was prepared by reacting, by the procedure of Example 1, 60 g (about 0.2 mole) of pentachlorophenol sodium, 400 ml of methyl glycol and 60 g (about 0.2 mole) of pentachlorobenzyl chloride. In this case, the ether precipitated between 45° and 60° C. After the reaction mixture has cooled, the product that had separated in a sago-like form was removed by suction filtering and worked up as described above. 88 g (83%) having a melting point of 264° to 266° C. was obtained.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].O>ClCCl>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1)=[O:18]
Reactant: COc1ccccc1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C(=O)CCCCl)cc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
Anisole (6.75 g, 62.4 mmol) was dissolved in dichloromethane (80 ml). The mixture was cooled to −5° C. and aluminum chloride (8.32 g, 62.4 mmol) was added. 4-Chlorobutyryl chloride (8.8 g, 62.4 mmol) was added dropwise to the mixture at −10° C. and stirred at −10° C. for 1 hour. The reaction mixture was poured into iced water (100 ml). After separation, the organic layer was washed with 1N hydrochloric acid (50 ml), saturated aqueous sodium hydrogen carbonate (50 ml) and water (50 ml), and was concentrated under reduced pressure to give 4-chloro-1-(4-methoxyphenyl)-1-butanone (12.7 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[CH2:18](Cl)[Cl:19]>O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([O:12][CH2:18][Cl:19])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)NCC(=O)OCCl

Procedure:
The title compound was prepared according to the procedure as described in Example 17 Step 1 using 2-((tert-butoxycarbonyl)amino)acetic acid (1 g, 5.7 mmol) in DCM (25 mL) and H2O (25 mL), NaHCO3 (1.92 g, 22.8 mmol), TBAHSO4 (194 mg, 0.57 mmol) and a solution of chloromethyl sulfochloridate (693 mL, 6.8 mmol) in DCM (5 mL). The title compound was obtained as colorless oil (911 mg, 71.3%).
Reaction SMILES: [OH-:1].[K+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]([CH2:10][CH2:11]CC#N)[CH:9]=1.[CH2:24]([OH:26])[CH3:25]>>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:8]([CH2:10][CH2:11][CH2:25][C:24]([OH:1])=[O:26])[CH:9]=1
Reactant: CCO
Reactant: N#CCCCc1cc(Cl)ccc1OCCc1ccccc1
Reactant: [OH-]
Agent: [K+]
Product: O=C(O)CCCc1cc(Cl)ccc1OCCc1ccccc1

Procedure:
15 ml of a 20% (w/v) aqueous solution of potassium hydroxide was added to a solution of 1.53 g of the crude 4-[5-chloro-2-(2-phenylethoxy)phenyl]butyronitrile in 15 ml of ethanol and the resulting mixture was heated under reflux for 17 hours. After evaporation of the ethanol under reduced pressure, conc. hydrochloric acid was added dropwise to the reaction mixture until it became acidic. Then the reaction mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, 1.41 g of crude 4-[5-chloro-2-(2-phenylethoxy)phenyl]butyric acid was obtained. This compound was not purified any more but used in the subsequent reaction.
Reaction SMILES: [NH2:1][OH:2].[CH2:3]([O:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9])[CH3:4]>CCO>[CH2:3]([O:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8](=[N:1][OH:2])[NH2:9])[CH3:4]
Reactant: CCOc1ccccc1C#N
Reactant: NO
Solvent: CCO
Product: CCOc1ccccc1C(N)=NO
Temperature: 50 °C
Reaction time: 12 h
Yield: 97.2 %

Procedure:
Hydroxylamine (Fluka 55458; 50% in water; 4.08 mL; 67.95 mmol; 5 eq.) was added to a solution of 2-ethoxybenzonitrile (Fluorochem 18661; 2 g; 13.59 mmol; 1 eq.) in EtOH (30 mL) and the reaction mixture was stirred at 50° C. for 12 hours. Evaporation in vacuo gave a white solid, which was further dried under high vacuum to afford the title compound (2.38 g, 97%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:8]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:7][C:6]=1[NH:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Cl)[CH:24]=1)[CH3:2].C(N(CC)CC)C.[SH:40][CH2:41][CH:42]([OH:45])[CH2:43][OH:44].ClCC1C=C(C=CC=1)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[C:8]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:7][C:6]=1[NH:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][S:40][CH2:41][CH:42]([OH:45])[CH2:43][OH:44])[CH:24]=1)[CH3:2]
Reactant: OCC(O)CS
Reactant: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1NC(=O)c1cccc(CCl)c1
Agent: O=C(O)c1cccc(CCl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1NC(=O)c1cccc(CSCC(O)CO)c1
Reaction time: 36 h
Yield: 77 %

Procedure:
Subsequently, 2-(3-chloromethyl-benzoylamino)-4,5-bis-(2-methoxy-ethoxy)-benzoic acid ethyl ester (1.1 g) was dissolved in anhydrous methylene chloride (20 ml). Triethylamine (800 μl) and 3-mercapto-1,2-propanediol (compound B′) (600 μl) were added dropwise to the solution at room temperature, and the mixture was stirred at that temperature for 36 hr. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was then subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 2-[3-(2,3-dihydroxy-propylsulfanylmethyl)-benzoylamino]-4,5-bis-(2-methoxy-ethoxy)-benzoic acid ethyl ester (970 mg, yield 77%).
Reaction SMILES: [C:1]([N:11]1[CH2:18][C:17](=[O:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH2:20](O)[CH2:21][OH:22].C1C=CC=CC=1>O>[C:1]([N:11]1[CH2:18][C:17]2([O:22][CH2:21][CH2:20][O:19]2)[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Reactant: OCCO
Solvent: O
Solvent: c1ccccc1
Product: O=C(O)[C@@H]1CC2(CN1C(=O)OCc1ccccc1)OCCO2
Reaction time: 8 h
Yield: 97 %

Procedure:
A stirred mixture of 12.8 g (0.049 mole) of N-carbobenzyloxy-4-keto-L-proline, 53 ml (0.095 mole) of ethylene glycol, and 0.35 g of p-toluenesulfonic acid H2O in 1.31 l. of benzene is heated and the resulting solution is refluxed for 7 hours (water formed is collected in a Dean-Stark apparatus). After standing overnight at room temperature, the lower glycol layer is separated and the benzene solution is washed with 150 ml of saturated sodium chloride, dried (MgSO4), and the solvent evaporated to give 14.6 g of N-carbobenzyloxy-4,4-ethylenedioxy-L-proline as a syrupy residue. The latter is dissolved in 60 ml of ethanol, filtered, treated with 5 g of cyclohexylamine, and diluted with ether. On seeding and rubbing, the crystalline cyclohexylamine salt separates; weight after cooling overnight, 9.0 g., m.p. 179°-180° (s. 173°). The material is recrystallized from acetonitrile, m.p. 182°-184° (s. 179°), [α]D26 -21° (c, 1 % in EtOh).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:29][N:30]1[C:34]([CH3:35])=[CH:33][C:32]([CH2:36]OS(C)(=O)=O)=[N:31]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:21]=5[C:20](=[O:28])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:36][C:32]2[CH:33]=[C:34]([CH3:35])[N:30]([CH3:29])[N:31]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(COS(C)(=O)=O)nn1C
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccc(F)cc21
Product: Cc1cc(Cn2cc(C(=O)N3CCC4(CC3)OC(=O)c3cc(F)ccc34)c3ccc(Cl)cc32)nn1C

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-5-fluoro-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 19) with methanesulfonic acid 1,5-dimethyl-1H-pyrazol-3-ylmethyl ester (prepared by mesylation of commercially available methanesulfonic acid 1,5-dimethyl-1H-pyrazol-3-ylmethyl ester) gave the title compound. ES-MS m/e (%): 507.2(M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.[BH3-]C#N.[Na+].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][NH:7]2
Reactant: COc1c(C)ccc2[nH]ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(C)ccc2c1CCN2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a solution of 4-methoxy-5-methylindole 27 (0.48 g, 2.98 mmol) in acetic acid (20 ml) was added NaBH3CN (0.75 g, 9 mmol) portionwise over 10 min (exothermic reaction) and the mixture was then stirred at rt for 0.5 h. Water (2-3 ml) was added and the solvent removed in vacuo. The residue was dissolved in EtOAc and washed with saturated aq. NaHCO3 and brine, dried and evaporated to give 28 as a viscous oil (449 mg, 92%) which was immediately used in the next step; δH (90 MHZ) 6.80 (1 H, d, J 9, 7-H), 6.31 (1 H, d, 6-H), 3.76 (3 H, s, OMe), 3.56 (2 H, t, J 8, 2-H), 3.12 (3 H, t, 3-H) and 2.14 (3 H, s, Me).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:14]4[NH:15][C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=5[C:22](=[O:23])[C:13]=4[CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.Cl[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1.CO>CN(C=O)C>[N:26]1[CH:27]=[CH:28][CH:29]=[N:30][C:25]=1[N:11]1[CH2:12][C:13]2[C:22](=[O:23])[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[NH:15][C:14]=2[CH:10]1[C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1
Reactant: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)NC2
Reactant: Clc1ncccn1
Solvent: CO
Solvent: CN(C)C=O
Product: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)N(c1ncccn1)C2

Procedure:
1,2,3,4-Tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one (100 mg, 0.3265 mmol) (prepared as in Example 5) and 2-chloropyrimidine (38 mg, 0.3265 mmol) were stirred in DMF (2.5 mL) at 100° C. for 16 h. The solvent was removed under vacuum and the residue purified by column chromatography (silica gel, 5% CH3OH/CH3Cl) to yield a yellow oil. Trituration of the oil with MeOH afforded the product as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:21])=[CH:13]\[CH:14]=[CH:15]\[C:16](\[CH3:20])=[CH:17]\[CH:18]=[O:19].C[OH:23]>>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:21])=[CH:13]\[CH:14]=[CH:15]\[C:16](\[CH3:20])=[CH:17]\[C:18]([OH:23])=[O:19]
Reactant: CC1=C(/C=C/C(C)=C\C=C\C(C)=C\C=O)C(C)(C)CCC1
Reactant: CO
Product: CC1=C(/C=C/C(C)=C\C=C\C(C)=C\C(=O)O)C(C)(C)CCC1
Reaction time: 2.5 h
Yield: 80 %

Procedure:
A mixture was formed of 2.42 g (27.89 mmol) of MnO2, 0.35 g (7.2 mmol) of NaCN, 0.12 ml (2.1 mmol) glacial acetic acid in 20 ml of CH3OH at 0° C. A separate solution was formed of 600 mg (2.1 mmol) of 9-cis-retinal (I) in 9 ml of CH3OH, also at 0° C. The solution of 9-cis-retinal was added dropwise to the mixture and stirred for 2.5 h at constant temperature and the reaction mixture was filtered through Celite. The filter cake was washed with a 1:1 mixture of CH3OH and water. The filtrates were combined and diluted with additional water and then extracted three times with ether. The combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. Purification by silica gel flash column chromatography using 20:1 hexane:ethyl acetate as eluent gave the pure methyl ester of 9-cis-retinoic acid (II) in the amount of 530 mg, a yield of 80%. The structure was confirmed by NMR. ##STR9##
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([CH3:10])([O-:9])=[O:8].N1([C:20](=[O:33])[CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)C2C=CC=CC=2N=N1.O>CS(C)=O.C(O)(=O)C>[CH3:32][O:31][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[O:29][CH3:30])[O:22][CH2:21][C:20](=[O:33])[CH2:10][N+:7]([O-:9])=[O:8]
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(OCC(=O)n2nnc3ccccc32)cc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(OCC(=O)C[N+](=O)[O-])cc1OC
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
To a suspension of potassium tert-butoxide (3.38 g) in DMSO (60 ml), a solution of nitromethane (0.836 g) in DMSO (5 ml) was added at 10° C. and the mixture was stirred at the same temperature for 30 minutes. A DMSO (65 ml) suspension of the compound (4.30 g) obtained in Example 19-(1) was added dropwise at 10° C. and the mixture was stirred at the same temperature for an hour, then at room temperature for 3 hours. The reaction mixture was poured into water (250 ml), rendered acidic with 10% aqueous acetic acid, and subjected to extraction with AcOEt. The organic layer was washed with water, dried (MgSO4), filtered and concentrated to give a crude product, which was further purified by silica gel chromatography (AcOEt/hexane) and then recrystallized (AcOEt/hexane) to give the titled compound (0.808 g, pale yellow solid.)
Reaction SMILES: [Al](Cl)([CH2:4][CH3:5])[CH2:2]C.[H][H].[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH2:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:4][CH3:5].[CH2:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:2]
Reactant: CCCCCCC
Reactant: [H][H]
Reactant: CC[Al](Cl)CC
Product: C=CCCCCC=C
Product: C=CCCCCCC
Reaction time: 10 h

Procedure:
A solution of 81.5 grams (0.966 mole) 1-octene and 5.61 grams (0.0509 mole) 1,7-octadiene (molar charge ratio 95:5) in 450 grams of heptane was polymerized with Et2AlCl (16 millimoles) and AATiCl3 (4 millimoles) at 50° C. for 10 hours. During the course of the reaction, hydrogen was bubbled through the reaction mixture. The conversion of the polymer was 52 percent, inherent viscosity was 1.9 dl/gram. The composition of monomers in the copolymer was 97:3 mole ratio from NMR analysis.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[C:4](=[O:22])[CH:3]=1.I[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCOCC1.C(O)=O>[O:1]([C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[C:4](=[O:22])[CH:3]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Ic1ccccc1
Reactant: O=c1cc(O)ccn1CCc1ccc(CN2CCCC2)cc1
Solvent: O=CO
Solvent: C1COCCO1
Product: O=c1cc(Oc2ccccc2)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 100 mg (0.34 mmol) 4-hydroxy-1-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 3) in 2.0 mL 1,4-dioxane is added 43 mg (0.39) potassium-tert-butylate and the mixture is stirred 30 min at RT. 77 μL (0.34 mmol) iodo-benzene and 21 mg (0.34 mmol) Cu-powder are added and the reaction mixture is stirred 5 h at 125° C. A few drops formic acid are added and after filtration the mixture is purified via HPLC chromatography (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 5:95)