Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C:7]1[CH2:8][C:9](O)([CH:17]=[CH:18][CH:19]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=[O:23].[K+].[K+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39].CCOC(C)=O>CC(C)=O.O>[C:1]([O:5][C:6](=[O:21])[C:7]1[CH:19]=[C:18]([O:23][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[CH:17]=[C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CCCCCCCCCBr
Reactant: CC(C)(C)OC(=O)C1=CC=CC(O)(C(=O)OC(C)(C)C)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)CCCCCCCCCOc1cc(C(=O)OC(C)(C)C)cc(C(=O)OC(C)(C)C)c1
Temperature: 50 °C

Procedure:
3-Hydroxy-isophthalic acid di-tert-butyl ester (90 mg, 0.3 mmol) was dissolved in dry acetone (5 ml), K2CO3 (90 mg, 0.65 mmol) and methyl 10-bromodecanoate (0.075 ml, 0.3 mmol) was added. The mixture was heated to reflux. The heating caused dissolution of the K2CO3. After a while, a precipitate was formed. Reflux (50° C.) was continued over night. More K2CO3 (30 mg, 0.2 mmol) and methyl 10-bromodecanoate (0.025 ml, 0.1 mmol) was added. The mixture was refluxed at 50° C. over night. To the dry reaction mixture EtOAc and water was added. After extraction, the organic layer was washed with water and brine, dried (Na2SO4) and concentrated to give the crude title compound as a clear oil.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8]O)=[CH:5][CH:4]=[C:3]([Cl:10])[CH:2]=1.C1(C)C=CC=CC=1.S(Br)([Br:20])=O>N1C=CC=CC=1>[Cl:10][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][Br:20])=[CH:1][CH:2]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: O=S(Br)Br
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Clc1ccc(CCBr)cc1
Reaction time: 1 h
Yield: 65.6 %

Procedure:
A 500 ml. 3 neck round bottomed flask under nitrogen was charged 15.65 g. of 4-chlorophenethanol (1.0 eq., 0.10 moles) in 60 ml. toluene. To the reaction was added dropwise 41.6 g of thionyl bromide (2.0 eq., 0.20 moles) in 15 ml. of toluene maintaining the temp. below 25 C. Finally, 8.7 g. pyridine (1.1 eq., 0.11 moles) in 20 ml. toluene was added dropwise again keeping the temperature below 30° C. with an external ice bath. The reaction was monitored by GLC and after 1 hr. an additional 14.0 g of thionyl bromide (0.67 eq. 0.067 moles) was added followed three hours later by 9.7 gms. (1.1 eq., 0.11 moles). Subsequently 4.3 g. of pyridine was added (0.55 eq., 0.055 moles) after which GLC indicated all the alcohol was consumed. The reaction was quenched by the addition of 300 ml of water while cooling with an ice bath after which 400 ml. of ether was added. The ether was washed water three times with 250 ml.), dried over MgSO4 and concentrated to give 14.4 g of product as an oil (65.2% yield).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([OH:14])[C@@H:11]([C:15]2[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:30][O:31][CH2:32]Cl.O>ClCCl>[CH2:1]([O:8][C@H:9]1[CH2:10][C@H:11]([C:15]2[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=2)[C@@H:12]([O:14][CH2:30][O:31][CH3:32])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: Cn1nccc1[C@H]1C[C@H](OCc2ccccc2)C[C@@H]1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCO[C@H]1C[C@@H](OCc2ccccc2)C[C@@H]1c1ccnn1C
Temperature: 40 °C
Reaction time: 5 h
Yield: 61.3 %

Procedure:
To a solution of the (1S*,2R*,4S*)-4-benzyloxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (350 mg, 1.29 mmol) prepared in Example 98a and diisopropylethylamine (1.3 mL, 7.64 mmol) in dichloromethane (5.0 mL), chloromethyl methyl ether (0.48 mL, 6.32 mmol) was added, and the reaction solution was stirred at 40° C. for 5 hours. After allowing to cool, water (10 mL) was added to the reaction solution, and an organic layer was extracted. The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=1:2) to yield the title compound (250 mg, 62%) as a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH:4]([C:14]([OH:16])=O)[CH2:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:29]([NH2:32])([CH3:31])[CH3:30]>C(#N)C>[O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:5][CH:4]([C:14]([NH:32][CH:29]([CH3:31])[CH3:30])=[O:16])[CH2:3]1
Reactant: O=C(O)C1CC(=O)N(Cc2ccccc2)C1
Reactant: CC(C)N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(C)NC(=O)C1CC(=O)N(Cc2ccccc2)C1
Temperature: 60 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
To a solution of 16.4 g (75.0 mmole) of 5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylic acid in 150 ml of acetonitrile was added 13.8 g (85.0 mmole) of 1,1'-carbonyldiimidazole. The reaction was heated to 60° C. for one hour, cooled to room temperature and treated with 5.0 g (85 mmole) of isopropylamine. The reaction was stirred at room temperature for 18 hours, the solvent removed in vacuo and the residue partitioned between chloroform and water. The organic layer was washed with water, 1N hydrochloric acid, dried over magnesium sulfate and evaporated in vacuo to give 18.6 g to give 18.6 g of 5-oxo-1-(phenylmethyl)-N-(2-propyl)-3-pyrrolidinecarboxamide, mp 122°-124° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH3:25][N:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1.C(N(CC)CC)C>O1CCCC1>[Cl:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)=[CH:3][C:2]=1[NH:1][C:31]([C:30]1[N:26]([CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=1)=[O:32]
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2Cl)n(C)n1
Yield: 44.3 %

Procedure:
Using N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (128 mg, 0.373 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (77.2 mg, 0.485 mmol), triethylamine (113 mg, 1.12 mmol) and tetrahydrofuran (5.0 mL) as starting materials and in the same manner as in Example 96, the title compound (77 mg, 44%) was obtained as a white powder. melting point 255° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][O:13][C:14]2[CH:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[CH:16][C:15]=2[Cl:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.O.C(O)(=O)C.[Zn]>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][O:13][C:14]2[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=2[Cl:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(COc2cc([N+](=O)[O-])ccc2Cl)C1
Agent: [Zn]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(COc2cc(N)ccc2Cl)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(2-chloro-5-nitro-phenoxymethyl)-azetidine-1-carboxylic acid tert-butyl ester (2.5 g, 7.29 mmol) in 60 mL of MeOH/H2O (1:1) and 3 mL of acetic acid (J. T. Baker) was added Zn powder (2.3 g, 36.47 mmol, Aldrich) at 0° C. The reaction mixture was stirred at 0° C. for 2 h then stirred at 10° C. for 2 h. The resulting mixture was filtered through a Celite® pad and the filtrate was concentrated in vacuo. The residue was treated with 60 mL of saturated aqueous NaHCO3 and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and dried with MgSO4. The resulting solution was concentrated in vacuo and the title compound was obtained by column chromatography (silica gel, EtOAc) as a yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([O:23][CH3:24])=[C:8]([O:21][CH3:22])[CH:9]=2)[N:4]=1.O.[SH:26][C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[NH:29][CH:30]=[N:31]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:11](=[O:20])[C:10]2[C:5](=[CH:6][C:7]([O:23][CH3:24])=[C:8]([O:21][CH3:22])[CH:9]=2)[N:4]=[C:3]1[CH2:2][S:26][C:27]1[N:35]=[CH:34][N:33]=[C:32]2[C:28]=1[N:29]=[CH:30][NH:31]2
Reactant: COc1cc2nc(CCl)n(-c3ccccc3Cl)c(=O)c2cc1OC
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nc(CSc3ncnc4[nH]cnc34)n(-c3ccccc3Cl)c(=O)c2cc1OC
Yield: 65.5 %

Procedure:
Prepared according to Procedure C using Intermediate 2a (200 mg, 0.546 mmol), 6-mercaptopurine monohydrate (102 mg, 0.601 mmol), K2CO3 (83 mg, 0.601 mmol), and DMF (5 mL). The crude product was recrystallized from EtOH to provide 172 mg of an off-white solid (65%), mp 160-180° C. (gradually decomposes). 1H NMR (DMSO-d6) δ: 13.55 (br s, 1H); 8.49 (s, 1H); 8.44 (s, 1H); 7.72 (d, J=6.9 Hz, 1H); 7.66 (d, J=6.9 Hz, 1H) 7.38-7.54 (m, 3H); 7.22 (s, 1H); 4.36-4.52 (m, 2H); 3.94 (s, 3H); 3.89 (s, 3H). 13C NMR (DMSO-d6) ppm: 160.1, 155.4, 151.5, 151.1, 149.4, 143.2, 134.5, 132.3, 131.6, 131.5, 130.4, 128.7, 113.6, 108.4, 105.8, 56.5, 56.1, 32.0. MS (ES): m/z 481.1 (M+). Anal. calcd. for C22H37ClN6O3S.0.5C2H6O.0.05KCl: C, 54.41; H, 3.97; Cl, 7.33; N, 16.55; S, 6.32. Found: C, 54.43; H, 3.94; Cl, 7.69; N, 16.69; S, 6.52.
Reaction SMILES: [Br:1][C:2]([Br:6])([Br:5])[CH:3]=[O:4].[CH2:7]=[C:8]([CH3:10])[CH3:9].[Cl-].[Al+3].[Cl-].[Cl-]>O>[Br:1][C:2]([Br:6])([Br:5])[CH:3]([OH:4])[CH2:9][C:8]([CH3:10])=[CH2:7]
Reactant: O=CC(Br)(Br)Br
Reactant: C=C(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: C=C(C)CC(O)C(Br)(Br)Br
Reaction time: 5 h
Yield: 85 %

Procedure:
A mixture of 281 parts of tribromoacetaldehyde, 168 parts of isobutene and 150 parts of petroleum ether was cooled to - 20° to - 5° C., and 13 parts of anhydrous aluminum chloride was added to the mixture dividedly in several times. The mixture was agitated at the above temperature for 5 hours. As the reaction advanced, crystals were precipitated from the reaction mixture. At the point of termination of the reaction, diethyl ether was added to the reaction mixture to form a homogeneous solution. The solution was then agitated at room temperature for 30 minutes, and 200 parts of water was added to the reaction mixture. The organic layer was recovered, low-boiling-point substances were removed by distillation, and the residue was subjected to distillation under reduced pressure to obtain 287 parts of 1,1,1-tribromo-4-methyl-4-penten-2-ol. The yield was 85%.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]([CH3:13])([CH3:12])[C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:12])([CH3:13])[C:8]([NH:10][CH3:11])=[O:9])=[CH:14][CH:15]=1
Reactant: CNC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CNC(=O)C(C)(C)Oc1ccc(OCc2cccc(F)c2)cc1

Procedure:
In analogy to the procedure described in Example 3b), the alkylation of 2-(4-hydroxy-phenoxy)-2,N-dimethyl-propionamide with 3-fluoro-benzylbromide in 2-butanone using potassium carbonate as the base yielded the 2-[4-(3-fluoro-benzyloxy)-phenoxy]-2,N-dimethyl-propionamide as an brown oil; MS: m/e=318 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[NH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].O.C(OCC)(=O)C>CN(C)C=O>[F:13][C:12]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][OH:23])[CH2:18][CH2:17]1
Reactant: Fc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: OCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: OCC1CCN(c2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of 1-fluoro-2,4-bis(trifluoromethyl)benzene (1.5 g) in N,N-dimethylformamide (10 mL) were added 4-piperidinemethanol (1.49 g) and potassium carbonate (1.79 g), and the mixture was stirred at 80° C. overnight. Water/ethyl acetate were added to the reaction mixture, and the organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.84 g).
Reaction SMILES: [Br-:1].[C:2]([CH2:5][CH2:6][N+:7]1[C:11]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=2[S:9][C:8]=1[CH3:17])([OH:4])=[O:3].[Br-].N([CH:26]=[CH:27][CH:28]=[CH:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N+:33]([CH2:40][CH3:41])=[CH:32][CH:31]=1)C1C=CC=CC=1.C(O)C>C(N(CC)CC)C>[Br-:1].[CH2:40]([N+:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:30]([CH:29]=[CH:28][CH:27]=[CH:26][CH:17]=[C:8]2[N:7]([CH2:6][CH2:5][C:2]([OH:4])=[O:3])[C:11]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=3[S:9]2)=[CH:31][CH:32]=1)[CH3:41]
Reactant: Cc1ccc2c(c1)sc(C)[n+]2CCC(=O)O
Reactant: CC[n+]1ccc(C=CC=CNc2ccccc2)c2ccccc21
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC[n+]1ccc(C=CC=CC=C2Sc3cc(C)ccc3N2CCC(=O)O)c2ccccc21
Yield: 15.2 %

Procedure:
To reaction were subjected 3.7 g of 3-(2-carboxyethyl)-2,6-dimethylbenzothiazolium bromide, 4.3 g of 4-(4-anilino-1,3-butadien-1-yl)-1-ethylquinolinium bromide, 150 ml of ethanol and 5 ml of triethylamine under reflux for one hour. After completion of the reaction, the reaction product was cooled, and the crude crystals thus obtained were purified by means of methanol to obtain 0.9 g of the objective compound (melting point 190° C.) which was glittering green. Its maximum absorption wavelength as measured in triethylamine-containing methanol was 740 nm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[N:10]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:9]=2)=[CH:4][C:3]=1[O:23][CH3:24].Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].N1C=CC=CC=1.ClCCl>O>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:26](=[O:27])[O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:3]([O:23][CH3:24])[CH:4]=3)=[CH:9][N:10]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COc1cc(-c2cn(C3CCCC3)c3ncnc(N)c23)ccc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 5 %

Procedure:
A mixture of 5-(4-amino-3-methoxyphenyl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.025 g, 0.08 mmol), benzyl chloroformate (0.016 g, 0.09 mmol), pyridine (0.50 ml) and dichloromethane (0.50 ml) was stirred at room temperature over the weekend and poured into water. The resulting precipitate was collected by filteration and purified by flash column chromatography on silica using ethyl acetate/n-heptane (9:1) as the mobile phase to give benzyl N-[4-(4-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methoxyphenyl]carbamate as a white solid (0.002 g, 0.004 mmol): 1H NMR (DMSO-d6, 400 MHz) δ 8.64 (s, 1H), 8.13 (s, 1H), 7.74 (d, 1H), 7.34-7.45 (m, 6H), 7.10 (d, 1H), 7.02 (dd, 1H), 6.08 (broad, 2H), 5.16 (s, 2H), 5.08 (m, 1H), 3.86 (s, 3H), 2.11 (m, 2H), 1.91 (m, 4H), 1.69 (m, 2H); MH+458; TLC (ethyl acetate) Rf 0.32; RP-HPLC (Hypersil C18, 5 μm, 200 A, 25 cm; 25%-100% acetonitrile-0.1M ammonium acetate over 25 min 1 ml/min) Rt 19.00 min.
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:26][OH:27])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>N1C=CC=CC=1.O>[N+:1]([C:4]1[CH:29]=[CH:28][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15]([O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][C@H:13]2[CH2:26][O:27][S:36]([C:33]2[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=2)(=[O:38])=[O:37])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OC(=O)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(2S,4R)-1-(p-Nitrobenzyloxycarbonyl)-2-hydroxymethyl-4-benzoyloxypyrrolidine (32.6 g) was dissolved in 64 ml of dry pyridine, and 28.02 g of p-toluenesulfonyl chloride was added thereto, followed by stirring at room temperature for 12 hours. The reaction mixture was diluted with water and extracted with a mixture of diethyl ether and dichloromethane (4:1). The extract was washed successively with brine, dilute hydrochloric acid, brine, a saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and distilled to remove the solvent. Recrystallization of the residue from diethyl ether gave (2S,4R)-1-(p-nitrobenzyloxycarbonyl)-2-p-toluenesulfonyloxymethyl-4-benzoyloxypyrrolidine.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]([CH2:28][C:29](Cl)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:29](=[O:30])[CH2:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CC(=O)N1c2ccc(O)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(OC(=O)CC(C)(C)C)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-hydroxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with tert-butylacetyl chloride (9.0 l) and N,N-diisopropylethylamine (28 l) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:22](=[CH:23][CH:24]=1)[O:21][C:8]1([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[CH2:7][CH:6]2[OH:25])#[N:2].N1C=CN=C1.[CH3:31][C:32]([Si:35](Cl)([CH3:37])[CH3:36])([CH3:34])[CH3:33]>CN(C=O)C>[Si:35]([O:25][CH:6]1[C:5]2[C:22](=[CH:23][CH:24]=[C:3]([C:1]#[N:2])[CH:4]=2)[O:21][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH2:7]1)([C:32]([CH3:34])([CH3:33])[CH3:31])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O)c1cc(C#N)ccc1O2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O[Si](C)(C)C(C)(C)C)c1cc(C#N)ccc1O2

Procedure:
To a solution of 15.1 g of tert-butyl 6-cyano-4-hydroxy-spiro[chroman-2,4′-piperidine]-1′-carboxylate in DMF were added 3.6 g of imidazole and 7.95 g of TBSCl at rt, and the reaction mixture was stirred at rt for 1d. To this reaction mixture was added 598 mg of imidazole and 1.3 g of TBSCl at rt, and the reaction mixture was stirred at rt for 1d. The reaction mixture was poured into ice-cold brine, and the aqueous mixture was extracted with AcOEt twice. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of hexane and AcOEt (100/0-80/20) as eluent to give the intended compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[CH2:22]([N:29]1[C:33]([CH2:34]O)=[CH:32][C:31]([CH3:36])=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl>[CH2:22]([N:29]1[C:33]([CH2:34][Br:20])=[CH:32][C:31]([CH3:36])=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrBr
Reactant: Cc1cc(CO)n(Cc2ccccc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(CBr)n(Cc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 61.9 %

Procedure:
To a stirring solution of 1.10 g (4.21 mmol, 1.2 equiv) of triphenylphosphine in 15 mL of CCl4 at -5° C. is added 200 μL (3.86 mmol, 1.1 equiv) of Br2. The resulting orange-yellow suspension is stirred 10 min at 0° C., then a solution of 710 mg (3.51 mmol) of (2-Benzyl-5-methyl-2H-pyrazol-3yl) methanol, prepared as in Part C, in 5 mL of CCl4 is added over 2 min. The resulting solution is stirred 0.5 h at RT, and then poured into 25 mL NaHCO3 and extracted with Et2O (2×25 mL), dried (MgSO4), and the solvent removed in vacuo. Purification of the residue by silica gel flash column chromatography using hexane/EtOAc 5/1 as eluent afforded 576 mg of the title compound as a clear oil: 1H NMR (CDCl3, 300 MHz) δ7.32 (m, 3H), 7.19 (m, 2H), 6.16 (s, 1H), 5.42 (s, 2H), 4.32 (s, 2H), 2.31 (s, 3H); low resolution MS (FAB)m/e 265 (M+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:13][C:14]([C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][OH:23])[CH2:18][CH2:17]1)=[O:15])[CH3:12].C(N(CC)CC)C>ClCCl>[CH2:11]([O:13][C:14]([C@H:16]1[CH2:21][CH2:20][C@H:19]([CH:22]=[O:23])[CH2:18][CH2:17]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)[C@H]1CC[C@H](CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)[C@H]1CC[C@H](C=O)CC1
Temperature: -50 °C
Reaction time: 0.08 h

Procedure:
To a solution of oxalyl chloride (2.8 ml, 32 mmol) in dichloromethane (150 ml) was added dimethylsulfoxide (5.0 ml, 64 mmol) at −78° C. The mixture was stirred for 5 minutes at −50° C. A solution of cis/trans-4-hydroxymethyl-cyclohexanecarboxylic acid ethyl ester (3:1) (5.0 g, 27 mmol) in dichloromethane (30 ml) was added at −65° C. Stirring for 30 minutes was followed by addition of triethylamine (18.7 ml, 134 mmol). The cooling bath was removed 15 minutes after completed addition, and the reaction mixture was stirred for 2 h. The reaction mixture was concentrated to approximately 20-30 ml by rotating evaporation. The residue was partitioned between ethyl acetate (200 ml) and 0.5 M aqueous hydrochloric acid solution (100 ml). The layers were separated. The aqueous layer was extracted with one 100-portion of ethyl acetate. The combined organic layers were washed with one 100-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (4.9 g, 98%) as light yellow oil, which was used in the next step without further purification. MS m/e: 185 ([M+H]+)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]=O.[CH3:8][C:9]1[CH:13]=[C:12]([CH3:14])[NH:11][C:10]=1[CH:15]=[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][C:17]1=[O:25]>CO>[CH3:8][C:9]1[CH:13]=[C:12]([CH3:14])[NH:11][C:10]=1/[CH:15]=[C:16]1\[C:17](=[O:25])[N:18]([CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:19]2[C:24]\1=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: Cc1cc(C)c(C=C2C(=O)Nc3ccccc32)[nH]1
Reactant: C=O
Reactant: C1CCNC1
Solvent: CO
Product: Cc1cc(C)c(/C=C2\C(=O)N(CN3CCCC3)c3ccccc32)[nH]1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88.4 %

Procedure:
Pyrrolidine (450 mg, 6.3 mmol) was added to a stirred solution of aqueous formaldehyde (500 mg of 38% solution, 6.0 mmol) and 3-(3,5-dimethyl-1H-pyrrol-2-ylmethylidene)-1,3-dihydro-indol-2-one, (900 mg, 3.8 mmol) in methanol (50 mL). After 15 min, the solution was cooled to 0° C. and the precipitate was filtered off, washed with water, and dried to give 1.08 g of the title compound, mp 129–132° C. HPLC Rt 4.87 min. 1H NMR [(CD3)2SO] δ 1.65 (m, 4H), 2.32 9s, 3H), 2.34 (s, 3H), 2.62 (m, 4H), 4.72 (s, 2H) 6.07 (d, 1H), 7.00 (m, 1H), 7.15 (m, 2H), 7.61 (s, 1H), 7.76 (d, 2H) and 13.1 (br s, 1H). Anal. Calcd for C20H23N3O: C, 74.74; H, 7.21; N, 13.07. Found: C, 74.61; H, 7.25; N, 13.03.