Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[CH2:16]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
4-Hydroxybenzaldehyde of the formula (7) (100 g), potassium carbonate (226 g) and acetone (500 ml) were taken in a reaction flask and stirred for 15 minutes. Benzylbromide (154 g) was then added at room temperature and the reaction mass was stirred at the same temperature for a period of 8–10, h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was dumped into ice water and extracted with toluene. The combined organic extracts were washed with 10% aq. sodium hydroxide solution followed by water. The solvent was removed under reduced pressure and the resulting residue Visas triturated with pet. ether to afford 4-benzyloxybenzaldehyde of the formula (8) (160–165 g, 93–95%).
Reaction SMILES: [CH:1]1([CH2:4][NH2:5])[CH2:3][CH2:2]1.[CH2:6]=[C:7]1[O:11][C:9](=[O:10])[CH2:8]1>O1CCCC1>[CH:1]1([CH2:4][NH:5][C:9](=[O:10])[CH2:8][C:7](=[O:11])[CH3:6])[CH2:3][CH2:2]1
Reactant: C=C1CC(=O)O1
Reactant: NCC1CC1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)NCC1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A solution of 15.1 g (0.22 mol) cyclopropylmethylamine in 50 ml tetrahydrofuran was added dropwise to a solution of 17 grams of diketene (0.20 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue is recrystallized from 100 ml of ethyl acetate. This gave 19.7 g (0.13 mol, 63% yield) of a white solid.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[Mg].[F:6][CH2:7][C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH3:12]>CCOCC>[F:6][CH2:7][C:8]([OH:13])([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][C:2]#[CH:1]
Reactant: C#CCBr
Reactant: CCCCC(=O)CF
Agent: [Mg]
Solvent: CCOCC
Product: C#CCC(O)(CF)CCCC
Temperature: 25 °C

Procedure:
A 0.25 ml. of portion of propargyl bromide is added to a stirred suspension of 0.73 g. of magnesium and 6 mg. of mercuric chloride in 7.5 ml. of ether. The reaction is initiated after a few minutes of vigorous stirring at room temperature. A mixture of 3 g. of 80% 1-fluoro-2-hexanone and 3.63 g. of propargyl bromine in 7.5 ml. of ether is added dropwise through a dropping funnel so that the reaction remains gently refluxing (25° C. to 32° C.). Cooling in a water bath is required. The reaction mixture is cooled in an ice bath, quenched with 8 ml. of cold saturated aqueous ammonium chloride, filtered through Celite and washed with ether. The mother liquid is evaporated to dryness giving a reddish oily residue, which is Kugelrohr-distilled at 45° C./-4 mm giving the product as a colorless liquid.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.C([N:23]=[C:24]=[S:25])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH3:1][C:2]1[O:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:24]([NH2:23])=[S:25])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(-c2ccc(N)cc2)o1
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(C)c(-c2ccc(NC(N)=S)cc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
To a solution of 4-(2,4-dimethyl-oxazol-5-yl)-phenylamine (470 mg, 2.5 mmol, CAS 100060-02-41) in tetrahydrofurane (20 mL) was added benzoyl isothiocyanate (449 mg, 2.8 mmol). The reaction was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was suspended in methanol (30 mL). Potassium carbonate (1036 mg, 7.5 mmol) dissolved in water (15 mL) was added drop wise to the suspension. The reaction was stirred at room temperature over night. The resulting solution was evaporated and the residue was stirred with water. The precipitate was filtered off, washed twice with water and twice with diethyl ether. The residue was dissolved in tetrahydrofurane and the solvent was removed under reduced pressure to yield the title compound as an off-white solid (420 mg, 68%). MS ISP (m/e): 248.1 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.80 (s, 1H, NH), 7.55 (d, 2H), 7.50 (d, 2H), 2.41 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: ClC1C=CC(OCC(O)=O)=C(CC2C=C(Cl)C=CC=2OC(C)C(=O)N2CCCC2)C=1.C[O:32][C:33](=[O:61])[CH2:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=1[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[O:50][CH:51]([CH3:60])[C:52](=[O:59])[N:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1>>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([O:35][CH2:34][C:33]([OH:61])=[O:32])=[C:37]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=2[O:50][CH:51]([CH3:60])[C:52](=[O:59])[N:53]2[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]2)[CH:38]=1
Reactant: COC(=O)COc1ccc(Cl)cc1Cc1ccccc1OC(C)C(=O)N1CCCCC1
Agent: CC(Oc1ccc(Cl)cc1Cc1cc(Cl)ccc1OCC(=O)O)C(=O)N1CCCC1
Product: CC(Oc1ccccc1Cc1cc(Cl)ccc1OCC(=O)O)C(=O)N1CCCCC1

Procedure:
The titled compound is prepared analogously to {4-chloro-2-[5-chloro-2-(1-methyl-2-oxo-2-pyrrolidin-1-yl-ethoxy)-benzyl]-phenoxy}-acetic acid (Example 1) by replacing {4-chloro-2-[5-chloro-2-(1-methyl-2-oxo-2-pyrrolidin-1-yl-ethoxy)-benzyl]-phenoxy}-acetic acid benzyl ester with {4-chloro-2-[2-(1-methyl-2-oxo-2-piperidin-1-yl-ethoxy)-benzyl]-phenoxy}-acetic acid methyl ester; MH+=432.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:8]=[CH:7][N:6]=[C:5]2[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Br:30])[CH:25]=1.C(N(CC)CC)C.[C:38](Cl)(=[O:41])[CH:39]=[CH2:40]>ClCCl.O1CCCC1>[Br:30][C:26]1[CH:25]=[C:24]([NH:23][C:5]2[C:4]3[C:9](=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[C:2]([NH:1][C:38]([CH:39]=[CH2:40])=[O:41])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: C=CC(=O)Cl
Reactant: CN1CCC(CCCOc2cc3ncnc(Nc4cccc(Br)c4)c3cc2N)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CC(=O)Nc1cc2c(Nc3cccc(Br)c3)ncnc2cc1OCCCC1CCN(C)CC1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of 300 mg of 6-amino-4-[(3-bromophenyl)amino]-7-[3-(1-methylpiperidin-4-yl)propyloxy]quinazoline in 7 ml of dichloromethane are added 0.28 ml of triethylamine. The reaction mixture is cooled to about −10° C. in an ice/sodium chloride cooling bath. Then a solution of 59 μl of acrylic acid chloride in 1 ml of tetrahydrofuran is added dropwise within 10 minutes. The cooling bath is removed and the mixture is stirred for a further 15 minutes at ambient temperature. For working up, the reaction mixture is poured on to 20 ml of ice water and mixed with 2-3 ml of 2 N sodium hydroxide solution, whereupon a light-colored precipitate is formed. The precipitate is suction filtered, washed with cold water and dissolved in dichloromethane. The solution is dried over sodium sulfate and concentrated by evaporation. The resin-like crude product is purified by chromatography over a silica gel column with methylene chloride/methanol/concentrated ammonia solution (90:10:0.5). Yield: 118 mg (35% of theory); Rf value: 0.35 (silica gel, methylene chloride/methanol/concentrated aqueous ammonia solution=90:10:0.1); mass spectrum (ESI+): m/z=524, 526 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[CH:13]([CH2:33][O:34]C(=O)C)[CH:14]([NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH2:15][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[CH:13]([CH2:33][OH:34])[CH:14]([NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH2:15][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)OCC1C(NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CC2CN(C(=O)OC(C)(C)C)CC21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C(CO)C2C1
Temperature: 25 °C

Procedure:
A solution of 4-acetoxymethyl-5-[2-(3-trifluoromethylbenzoylamino)acetylamino]octahydrocyclopenta[c]-pyrrole-2-carboxylic acid tert-butyl ester in tetrahydrofuran is treated with aqueous lithium hydroxide and the mixture is stirred at room temperature until the reaction is complete. The reaction mixture is concentrated under vacuum yielding an aqueous residue. The aqueous residue is extracted with ethyl acetate, and the organic phases are dried over sodium sulfate and concentrated under vacuum yielding a residue. The residue is purified by flash column chromatography providing the title product.
Reaction SMILES: [H-].[Na+].[Br-].[CH:4]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:6][CH2:5]1.[CH3:26][O:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][CH2:33][C:34]2=O)=[CH:30][CH:29]=1.COCCOCCN(CCOCCOC)CCOCCOC>C1COCC1>[C:4]1(=[C:34]2[C:35]3[C:31](=[CH:30][CH:29]=[C:28]([O:27][CH3:26])[CH:36]=3)[CH2:32][CH2:33]2)[CH2:6][CH2:5]1
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CC2)cc1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [Br-]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=C1CC1)CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.5 %

Procedure:
NaH (1.5 g, 62 mmol) was added to a suspension of cyclopropyltriphenyl-phosphonium bromide (24 g, 62 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) in THF (100 mL), and the resulting mixture was stirred at room temperature for 2 hours. Then, 6-methoxy-1-indanone (H10.1) (Oakwood Products, Inc.) (5.00 g, 31 mmol) and tris(2-(2-methoxyethoxy)ethyl)amine (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) (1.1 mL, 3.1 mmol) were added slowly. The resulting mixture was stirred at room temperature for 10 minutes and then at 62° C. for 4 hours. The reaction mixture was concentrated and purified by chromatography (silica gel, eluting with 1:9 EtOAc/hexane) to provide H10.2 (4.53 g, 79% yield) as a solid. MS ESI (pos.) M/E: 187.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>O1CCCC1>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1)[C:19]([CH3:20])=[O:21]
Reactant: Nc1ccc2oc(=O)[nH]c2c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2oc(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 5-amino-2-benzoxazolinone (3.39 g, 22.5 mmol) and triethylamine (3.17 ml, 22.5 mmol) in dry tetrahydrofuran (50 ml) was dropwise added acetylchloride (1.6 ml, 22.6 mmol). The reaction mixture was stirred for additional 2 hours at room temperature, whereafter the precipitate was filtered off The crystals were treated with water (100 ml), filtered off and washed with water. This treatment left the product as white crystals, M.p. 295°-300° C.
Reaction SMILES: C1COCC1.[CH3:6][C:7]([CH3:20])([CH3:19])[CH2:8][O:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.[H][H]>CO>[CH3:6][C:7]([CH3:20])([CH3:19])[CH2:8][O:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH2:16])=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: CC(C)(C)COCc1ccc(C#N)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)COCc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
Add 1M BH3-THF complex in THF (16 mL, 16 mmol) to neat 4-(2,2-dimethyl-propoxymethyl)-benzonitrile (3.043 g, 15 mmol) and stir the mixture overnight at room temperature. Add methanol and stir until hydrogen evolution stops. Concentrate the solution in vacuo. Dissolve the crude mixture in methanol and filter through an SCX column eluting with methanol followed by 3M ammonia in methanol. Concentrate in vacuo to obtain the title compound (3 g, 96%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:13](Br)=[CH:12][CH:11]=[CH:10][N:9]=1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.CC1(C)C(C)(C)OB([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[CH2:47][C:48](OC)=[O:49])O1.S(=O)(=O)(O)O.[OH-].[Na+]>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:12]1[C:13]2[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[CH2:47][C:48](=[O:49])[NH:7][C:8]=2[N:9]=[CH:10][CH:11]=1
Reactant: Nc1ncccc1Br
Reactant: COC(=O)Cc1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: O=C1Cc2ccccc2-c2cccnc2N1
Temperature: 88 °C
Yield: 79 %

Procedure:
Add potassium carbonate (235.7 g, 1.71 mol) to a solution of 2-amino-3-bromopyridine (88.5 g, 511.7 mmol) in 1,4-dioxane (550 mL) and water (550 mL). Degas the mixture with three cycles of vacuum/nitrogen, add palladium (II) acetate (6.4 g, 28.4 mmol) and tri-t-butylphosphonium tetrafluoroborate (16.5 g, 56.9 mmol) and stir under nitrogen at 88° C. Add a solution of methyl 2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (157.0 g, 568.5 mmol) in 1,4-dioxane (550 mL) dropwise over three minutes and stir the mixture at 88° C. for 20 minutes. Cool mixture to 50° C., add water (100 mL), and separate layers. Extract from aqueous with ethyl acetate (2×100 mL), dry combined organics over sodium sulfate and concentrate. Dissolve the concentrated material in N-methylpyrrolidone (314 mL), cool in ice bath and add sulfuric acid (314 mL, 5.9 mol) dropwise to maintain a temperature of approximately 45° C. Stir mixture at 140° C. for 90 minutes. Cool to ambient temperature, add ice (4 kg) and basify with portion wise addition of 50% aqueous NaOH solution until solution is pH 7-8. Cool suspension to 10-15° C., filter out solids and wash with water (2 L), hexanes (1 L) and methyl tertiary butyl ether (1 L). Dry under vacuum at 40° C. Treat material with refluxing mixture of 10% methanol/dichloromethane solution and filter hot (×4). Concentrate combined filtrates to afford the title compound as a light brown solid (85 g, 404.3 mmol, 71%). MS (m/z): 211 (M+1).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[N:10][C:11](Cl)=[N:12][CH:13]=[C:8]2[C:7]([NH:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:23])=[N:6]1)[CH2:2][CH:3]=[CH2:4].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(C(F)(F)F)=O>O1CCOCC1>[CH2:1]([N:5]1[C:9]2=[N:10][C:11]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:12][CH:13]=[C:8]2[C:7]([NH:15][C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:23])=[N:6]1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCn1nc(Nc2c(C)cccc2C)c2cnc(Cl)nc21
Reactant: Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: C=CCCn1nc(Nc2c(C)cccc2C)c2cnc(Nc3ccccc3)nc21

Procedure:
A solution of 815 mg (2.5 mmol) of 1-(but-3-enyl)-6-chloro-N-(2,6-dimethylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-amine 32 (Example 1, Step D) in 17 mL of 1,4-dioxane was treated sequentially with 280 μl (3.1 mmol) of aniline and 415 μl (5.6 mmol) of TFA. The resulting orange solution was heated at reflux for 6 h, and then was concentrated. The residue was purified by chromatography on silica gel (hexanes:EtOAc, 3:1) to give the title compound 33. 1H-NMR (DMSO-d6) δ 2.24 (s, 6H), 2.45-2.52 (m, 2H), 4.08 (t, J=6.8 Hz, 2H), 4.94 (d, J=10.2 Hz, 1.1 Hz, 1H), 5.02 (dd, J=17.2 Hz, 1.6 Hz, 1H), 5.78-5.88 (m, 1H), 6.95 (t, J=7.3 Hz, 1H), 7.06-7.14 (m, 3H), 7.28 (t, J=8.0 Hz, 2H), 7.84 (d, J=8.0 Hz, 2H), 8.10 (s, 1H), 8.39 (s, 1H), 9.66 (s, 1H). Mass Spectrum (ESI) m/e=385.2 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:23](O)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:23]([N:36]1[CH2:37][CH2:38][CH:33]([C:30]2[CH:29]=[CH:28][C:27]([Cl:26])=[CH:32][CH:31]=2)[CH2:34][CH2:35]1)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)O)cnc12
Product: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ccc(Cl)cc4)CC3)cnc12
Yield: 79.9 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.20 g, 0.58 mmol) obtained in Example 21, step 4 and 4-(4-chlorophenyl)piperidine (0.14 g, 0.70 mmol), the title compound (0.24 g, 81%) was obtained.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:28]1[CH:33]=[CH:32][C:31]([C:34]([CH3:38])([CH3:37])[C:35]#[N:36])=[CH:30][CH:29]=1>O1CCCC1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@@H:24]([OH:25])[C:28]3[CH:33]=[CH:32][C:31]([C:34]([CH3:38])([CH3:37])[C:35]#[N:36])=[CH:30][CH:29]=3)=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: CC(C)(C#N)c1ccc(I)cc1
Solvent: C1CCOC1
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(C(C)(C)C#N)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 2-(4-iodophenyl)-2-methylpropanenitrile. A 1.3 M solution of isopropylmagnesium chloride-lithium chloride complex in tetrahydrofurane is used instead of isopropylmagnesium chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([NH:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([S:24][CH3:25])[CH:18]=2)[OH:16])[CH3:12])=[CH:5][CH:4]=1.[OH:26]O>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]([NH:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([S:24]([CH3:25])=[O:26])[CH:18]=2)[OH:16])[CH3:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(CCC(C)NCC(O)c2ccc(C)c(SC)c2)cc1
Reactant: OO
Solvent: CO
Product: COc1ccc(CCC(C)NCC(O)c2ccc(C)c(S(C)=O)c2)cc1
Reaction time: 8 h

Procedure:
In 70 ml of methanol was dissolved 2.5 g of α-{[3-(4-methoxyphenyl)-1-methylpropylamino]-methyl}-4-methyl-3-methylthiobenzenemethanol and then 8 ml of an aqueous 30% hydrogen peroxide solution was added dropwise to the solution under ice-cooling. After allowing the reaction mixture to stand overnight the at room temperature, methanol was distilled off and after adding 50 ml of water to the residue, the product was extracted with ethyl acetate. The ethyl acetate layer formed was dried with anhydrous magnesium sulfate and after distilling off the solvent, the residue was purified by a silica gel column chromatography (eluate: a mixture of benzene, ethyl acetate, and methanol (4:3:1 by volume ratio) to provide 2.0 g of the amorphous caramel-like powder of α-{[3-(4-methoxyphenyl)-1-methylpropylamino]methyl}-4-methyl-3-methylsulfinylbenzenemethanol.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([F:11])[CH:4]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1>CN(C=O)C>[F:11][C:5]1[CH:4]=[C:3]([CH2:2][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: N#Cc1ccc(CBr)cc1F
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2ccnc2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Bromomethyl-2-fluoro-benzonitrile, as described in Step D above, (3.44 g, 16.0 mmol) and imidazole (5.47 g, 80.3 mmol) were dissolved in DMF (40 mL) and stirred at ambient temperature for 2 h. The DMF was removed in vacuo and the residue was partitioned between EtOAc (300 mL) and aqueous saturated NaHCO3 solution. The organic layer was separated, washed with NaHCO3 solution, H2O, brine, and dried (MgSO4). Filtration and concentration to dryness gave the title compound after chromatography (silica gel, 1-2% CH3OH/CH2Cl2).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:26])[CH:24]=[O:25].O.[Li+].[BH4-]>CO.C1COCC1>[OH:25][CH2:24][C:23]([CH3:26])=[CH:22][CH2:21][C:4]1[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:20])[CH3:19])=[C:6]2[C:10]([CH2:9][O:8][C:7]2=[O:13])=[C:11]([CH3:12])[C:3]=1[O:2][CH3:1]
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)C=O)C(=O)OC2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CO)C(=O)OC2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 97.8 %

Procedure:
A solution of 4-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal (103 mg, 0.27 mmol) in methanol (5 mL) was cooled to 0° C. A solution of CeC13 (0.68 mL, MeOH: H2O, 9:1) was added, followed by LiBH4 (0.14 mL, 0.28 mmol of a 2M solution in THF). The ice bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred for an additional 40 minutes whereupon TLC indicated complete consumption of starting aldehyde. The reaction was worked up by addition of aqueous 1N HCl (0.5 mL) and the product was extracted with CH2Cl2. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography to provide 100 mg (97%) of the product as a clear liquid. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 1.20 (dd, 2H, J=7, 8 Hz), 1.81 (s, 3H), 2.13 (s, 3H), 3.38-3.50 (m, 2H), 3.74 (s, 3H), 3.95 (s, 2H), 4.27 (dd, 2H, J=7, 8 Hz), 5.08 (s, 2H), 5.17-5.44 (m, 1H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:12]2[CH2:17][OH:18])=[O:10])=[CH:5][CH:4]=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1>[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([O:18][CH2:17][C@@H:12]2[CH2:13][C@@H:14]([OH:16])[CH2:15][N:11]2[C:9]([O:8][CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=2)=[O:10])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2CO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2COS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.5 %

Procedure:
To a solution of (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-hydroxypyrrolidine-2-methanol (64 g: 227.6 mmole) in pyridine (350 ml), p-toluenesulfonyl chloride (48 g) is added. The mixture is stirred at room temperature for 4 hours. The reaction mixture is poured into ice water and extracted with ethyl acetate. The extract is successively washed with water, dilute hydrochloric acid and aqueous sodium hydrogen carbonate, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-hydroxypyrrolidine-2-methanol p-toluenesulfonate (60 g).