Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:25][C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ncccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1ncccn1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 38A, 100 mg, 0.35 mmol) in methylene chloride (1 mL) was treated with 2 drops of dry N,N-dimethylformamide. The reaction mixture was cooled to 0° C. and then treated dropwise with oxalyl chloride (34 mL, 0.39 mmol). The reaction mixture was stirred at 0° C. for 10 min and then stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in a small amount of methylene chloride and was slowly added to a cooled (0° C.) solution of 2-aminopyrimidine (67 mg, 0.70 mmol) in methylene chloride (1 mL). The resulting reaction mixture was stirred at 0° C. for 30 min and then stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo to remove methylene chloride. The resulting residue was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-pyrimidin-2-yl-propionamide (85.4 mg, 67%) as a white solid: mp 103-105° C.; EI-HRMS m/e calcd for C18H19Cl2N3O (M+) 363.0905, found 363.0915.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])=[CH:7][CH:6]=1)=O.[Br:33][C:34]1[C:35]([NH2:40])=[N:36][CH:37]=[CH:38][CH:39]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[Br:33][C:34]1[C:35]2[N:36]([CH:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]([CH2:11][C@H:12]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:13][N:14]4[C:15](=[O:24])[C:16]5[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=5)[C:22]4=[O:23])=[CH:9][CH:10]=3)[N:40]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(=O)CBr)cc1)CN1C(=O)c2ccccc2C1=O
Reactant: Nc1ncccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cn3cccc(Br)c3n2)cc1)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A solution of 1,1-dimethylethyl {(1S)-2-[4-(bromoacetyl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}carbamate (6.9 mmol), 3-bromo-2-pyridinamine (8.4 mmol), and sodium bicarbonate (10.4 mmol) in isopropanol (70 mL) were stirred at 80° C. for 18 h. The reaction was then cooled to RT and a precipitate formed which, was filtered, washed with cold hexanes (3×100 mL), and dried to afford the title compound light gray solid (72%). ESMS [M+H]+: 576.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([CH3:28])=[N:23][NH:24][C:25](=[O:27])[CH:26]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:29]>O1CCOCC1.O>[ClH:29].[CH3:28][C:22]1[C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:20][CH:19]=2)=[CH:26][C:25](=[O:27])[NH:24][N:23]=1
Reactant: Cc1n[nH]c(=O)cc1-c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1n[nH]c(=O)cc1-c1ccc(OC2CCNCC2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of the product from step 2 (4-[4-(3-methyl-6-oxo-1,6-dihydro-pyridazin-4-yl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester) (7.6 g, 20 mmol) in 30 mL of dioxane and 3.0 mL of water was cooled to 0° C. as 24 mL of 4M HCl in dioxane was added dropwise. After stirring at 50° C. for 1 h, the solvent was evaporated. The white solid was triturated with ether to give 6-methyl-5-[4-(piperidin-4-yloxy)-phenyl]-2H-pyridazin-3-one HCl (6.2 g, 92%): Mp 225-7° C.; MS m/z 286 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][N:8]1[C:17]([CH3:18])=[CH:16][C:15]2[C:10](=[C:11]([F:19])[CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:20])([CH3:4])([CH3:3])[CH3:2].[Br:22]N1C(=O)CCC1=O.CCOCC>CN(C)C=O>[C:1]([O:5][C:6](=[O:21])[NH:7][N:8]1[C:17]([CH3:18])=[C:16]([Br:22])[C:15]2[C:10](=[C:11]([F:19])[CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2cccc(F)c2c(=O)n1NC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1c(Br)c2cccc(F)c2c(=O)n1NC(=O)OC(C)(C)C
Yield: 18.5 %

Procedure:
A solution of (8-fluoro-3-methyl-1-oxo-1H-isoquinolin-2-yl)-carbamic acid tert-butyl ester (501.9 mg, 1.717 mmol) and N-bromosuccinimide (366.0 mg, 2.056 mmol) in N,N-dimethylformamide (5 mL) was stirred at r.t. for 60 min. It was poured into 50 ml ether, washed with 5% aq. NaHCO3 two times, then with water 3 times, white precipitate formed, which was filtered and washed with ether to give 118 mg of the pure title product. Supernatant gave 490 mg more of the title product as a colourless solid; total yield 95.4%. LC-MS (m/z) 271.5 and 273.3 (major fragment, M-Boc), tR=1.39. 1H NMR (500 MHz, CDCl3) 1.51 (br. s, 9H, tBu), 2.64 (s, 3H, Me), 7.11 (dd, J=8.2 Hz, J=10.6 Hz, 1H, C7H), 3.67 (br. s, 1H, NH), 7.63 (dt, J (d)=4.95 Hz, J (t)=8.1 Hz, 1H, C6H), 7.68 (d, J=8.1 Hz, 1H, C5H). 19F NMR (470.59 MHz, CFCl3=0 ppm), 4:96 mixture of rotamers, −108.9 (br. s, 0.04F), −109.98 (br. s, 0.96F). 13C APT NMR (CDCl3=77.43 ppm): 20.15 (Me), 28.47 (tBu), 83.47 (C of tBu), 113.44 (C), 114.24 (d, J=21.4 Hz, C7H), 122.57 (d, J=4 Hz, C5H), 134.68 (d, J=10.3 Hz, C6H), 138.31 (s, C), 142.69 (s, C), 155.91 (C), 158.42 (C), 161.63 (s, C), 163.74 (s, C).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.O.[Se](=O)=[O:22]>O1CCOCC1>[OH2:2].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17](=[O:19])[CH:18]=[O:22])=[CH:15][CH:16]=2)=[CH:7][CH:8]=1
Reactant: O=[Se]=O
Reactant: COc1ccc(COc2ccc(C(C)=O)cc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(COc2ccc(C(=O)C=O)cc2)cc1

Procedure:
A 10.0 g portion of 1-[4-[(4-methoxyphenyl)-methoxy]phenyl]ethanone was dissolved in 50 ml of hot p-dioxane. A 2.0 ml portion of water and 4.4 g of selenium dioxide were added and the mixture was stirred at reflux for 67 hours, then cooled and filtered through diatomaceous earth. The filtrate was poured into 300 ml of water and the solid collected. This solid was extracted with eight 100 ml portions of ethyl acetate. The extracts were combined, washed with water, dried and evaporated. The residue was dissolved in 100 ml of boiling toluene, treated with charcoal and filtered through diatomaceous earth. The filtrate was treated with 200 ml. of hexane, giving the desired product as a pale yellow solid, m.p. 127°-138° C.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[C:21]3[CH:20]=[C:19]([C:22]([O:24]C)=[O:23])[NH:18][C:17]=3[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].CO>C1COCC1>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[C:21]3[CH:20]=[C:19]([C:22]([OH:24])=[O:23])[NH:18][C:17]=3[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2c1ccc(Cc2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cc2c([nH]1)CCC2c1ccc(Cc2ccccc2)cc1

Procedure:
The title compound was synthesized from methyl 4-(4-benzylphenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (150 mg, 0.45 mmol) and lithium hydroxide monohydrate (108 mg, 4.5 mmol), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (10 mL) was used. The resulting product was purified by chromatography over silica gel (gradient 0 to 100% EtOAc in heptane over 20 min) to give a pure product (50 mg). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.14-2.25 (m, 1H), 2.66-2.94 (m, 3H), 3.91 (s, 2H), 4.14 (t, J=7.30 Hz, 1H), 6.51 (s, 1H), 7.09 (s, 5H), 7.12-7.19 (m, 3H), 7.21-7.28 (m, 2H). LCMS m/e 316 (M−H) and 100% pure by HPLC.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][C:3]=1[CH:4]=O.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[C:26]=2[NH2:32])[CH2:21][CH2:20]1>CC(N(C)C)=O>[CH3:17][O:16][C:11]1[C:10]([C:7]2[CH:8]=[CH:9][C:2]([OH:1])=[C:3]([C:4]3[NH:32][C:26]4[C:25]([N:22]5[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]5)=[CH:30][CH:29]=[CH:28][C:27]=4[N:31]=3)[CH:6]=2)=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1ncccc1-c1ccc(O)c(C=O)c1
Reactant: CN1CCN(c2cccc(N)c2N)CC1
Solvent: CC(=O)N(C)C
Product: COc1ncccc1-c1ccc(O)c(-c2nc3cccc(N4CCN(C)CC4)c3[nH]2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 10.4 %

Procedure:
To mixture of 2-hydroxy-5-(2-methoxy-pyridin-3-yl)-benzaldehyde (57 mg, 0.25 mmol) and 3-(4-methyl-piperazin-1-yl)-benzene-1,2-diamine (51 mg, 0.25 mol) was added DMA (1 mL) and the resulting solution was stirred at the room temperature for 15 min, heated at 110° C. for 15 h open to the air, concentrated under reduced pressure. The residual crude was purified by chromatography (500:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (10.8 mg, 10.5%). 1H NMR (MeOH-d4) δ 2.41 (s, 3H), 2.78 (m, 4H), 3.49 (m, 4H), 3.97 (s, 3H), 6.72 (m, 1H) 7.05-7.20 (4H), 7.56 (d, J=9 Hz, 1H), 7.78 (d, J=9 Hz, 1H), 8.10-8.13 (2H). ESI-MS m/z 416.5 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[C:11]([OH:17])[CH:10]=2)=[O:5])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:18])[O:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([Cl:16])=[C:11]([OH:17])[C:10]=2[N+:19]([O-:21])=[O:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(Cl)c(O)cc2oc1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc2cc(Cl)c(O)c([N+](=O)[O-])c2oc1=O
Yield: 47.5 %

Procedure:
2.75 g (10.2 mmol) of 3-ethoxycarbonyl-6-chloro-7-hydroxycoumarin was added into 10 ml of concentrated sulfuric acid, 1.74 g (20.4 mmol) of concentrated nitric acid was added in portions under the cooling of ice-salt bath, the reaction was monitored through thin-layer chromatography to confirm the completion, and ice was added to seize the reaction. The reaction mixture was then filtered and washed by water, dried to give 1.52 g of the title compound (241).
Reaction SMILES: [CH2:1]([C:4]1[CH:44]=[C:43]([CH3:45])[CH:42]=[CH:41][C:5]=1[CH2:6][O:7][CH2:8][C:9]1[CH:40]=[C:12]2[N:13]=[C:14]([CH3:39])[C:15]([C@H:28]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:16]([N:17]3[CH2:22][CH2:21][C:20]([O:24][CH2:25][CH:26]=[CH2:27])([CH3:23])[CH2:19][CH2:18]3)[N:11]2[N:10]=1)C=C.[BH4-].[Na+]>Cl[Ru](=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)(Cl)(=CC1C=CC=CC=1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1.C(Cl)Cl.O>[C:35]([O:34][C@@H:28]([C:15]1[C:14]([CH3:39])=[N:13][C:12]2=[CH:40][C:9]3=[N:10][N:11]2[C:16]=1[N:17]1[CH2:18][CH2:19][C:20]([CH3:23])([O:24][CH2:25][CH2:26][CH2:27][CH2:1][C:4]2[CH:44]=[C:43]([CH3:42])[CH:45]=[CH:41][C:5]=2[CH2:6][O:7][CH2:8]3)[CH2:21][CH2:22]1)[C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH3:36])([CH3:38])[CH3:37]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4ccc(C)cc4CC=C)nn23)CC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)(=Cc2ccccc2)[P](C2CCCCC2)(C2CCCCC2)C2CCCCC2)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCCc1cc(C)ccc1COC3
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A mixture of (S)-ethyl 2-(2-(((2-allyl-4-methylbenzyl)oxy)methyl)-7-(4-(allyloxy)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (50 mg, 0.081 mmol) and Grubbs II catalyst (68.6 mg, 0.081 mmol) in DCM (50 mL) was refluxed for 2 h. It was then concentrated and the residue was dissolved in MeOH (2 mL). NaBH4 (3.06 mg, 0.081 mmol) was then added and the reaction was stirred at rt for 1 h. It was then diluted with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 20% EtOAc/hexane to isolate ethyl (2S)-2-(tert-butoxy)-2-{4,16,24-trimethyl-11,23-dioxa-1,5,7,8-tetraazapentacyclo[22.2.2.16,9.02,7.013,18]nonacosa-2,4,6(29),8,13(18),14,16-heptaen-3-yl}acetate (30 mg, 0.051 mmol, 62.6% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.36-7.25 (m, 1H), 7.08-6.97 (m, 2H), 6.50 (s, 1H), 6.16 (s, 1H), 4.88 (s, 2H), 4.76-4.59 (m, 3H), 4.24-4.08 (m, 2H), 3.96 (t, J=11.0 Hz, 1H), 3.57-3.40 (m, 2H), 2.92 (d, J=11.0 Hz, 1H), 2.80-2.72 (m, 2H), 2.69-2.59 (m, 4H), 2.34 (s, 3H), 2.11-2.01 (m, 1H), 1.98-1.86 (m, 3H), 1.86-1.74 (m, 2H), 1.76-1.60 (m, 2H), 1.29-1.22 (m, 12H), 1.19 (t, J=7.2 Hz, 3H). LCMS (M+1)=593.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[C:13](=[C:16]([CH3:18])[CH3:17])[O:12][C:11]1=[O:19].[C:20]1(C)[CH:25]=CC(S(OC(C)C#C)(=O)=O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:21]([CH3:22])[C:20]#[CH:25])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[C:13](=[C:16]([CH3:17])[CH3:18])[O:12][C:11]1=[O:19]
Reactant: CC(C)=C1OC(=O)N(c2cc(O)c(Cl)cc2F)C1=O
Reactant: C#CC(C)OS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CC(C)Oc1cc(N2C(=O)OC(=C(C)C)C2=O)c(F)cc1Cl

Procedure:
Acetonitrile (50 ml) was added to a mixture comprising 3N-(2-fluoro-4-chloro-5-hydroxyphenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (5.0 g, 15.7 mmol), 1-butyn-3-yl p-toluenesulfonate (4.0 g, 17.8 mmol) and potassium carbonate (1.5 g, 10.9 mmol), and the reaction mixture was heated for 4 hours under reflux. After reaction, acetonitrile was removed by distillation under reduced pressure, and 1N hydrochloric acid (100 ml) was added to the residue, which was then extracted with ether (50 ml×2). After dried, ether was removed by distillation under reduced pressure, and an oily product of 3N-{2-fluoro-4-chloro-5-(1-butyn-3-yl)oxyphenyl}-5-isopropylidene-1,3-oxazolidine-2,4-dione was obtained. This was recrystallized from ether/hexane, and a pure product (4.94 g, 14.6 mmol) was obtained. Yield: 83.6%. Spectral and other data of the product are those as shown in Example 30.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[C:25]([F:28])([F:27])[F:26].[F-].[Cs+]>Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@@H:21]([OH:22])[C:25]([F:28])([F:27])[F:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@H:21]([OH:22])[C:25]([F:28])([F:27])[F:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1[C@H](O)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To (2S,3S)-3-(tert-butyldimethylsilanyloxy)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (5B) (1.00 g, 3.04 mmol) was added trimethyl(trifluoromethyl)silane (550 mg, 3.87 mmol) and cesium fluoride (10 mg, dried under high vacuum at 130° C. for 12 h). The mixture was stirred at rt for 24 h, and then was heated to 50° C. for 5 h. After cooling to rt, 4N HCl (ca. 10 mL) was added and the reaction was stirred overnight. The product was extracted with EtOAc (3×30 mL). The organic layer was washed with saturated aqueous NaHCO3 and brine, then dried (MgSO4), filtered and concentrated. The residue was purified via flash chromatography eluting with 0-15% EtOAc/hexane to provide (2R,3S)-3-(tert-butyldimethylsilanyloxy)-2-[(1R)-(2,2,2-trifluoro-1-hydroxy-ethyl)]-pyrrolidine-1-carboxylic acid tert-butyl ester (5C) (357 mg) as a colorless oil and (2R,3S)-3-(tert-butyldimethylsilanyloxy)-2-[(1S)-(2,2,2-trifluoro-1-hydroxy-ethyl)]-pyrrolidine-1-carboxylic acid tert-butyl ester (5D) (380 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:34])[N:4]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:27](O)=[O:28])[C:5]([CH3:23])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH2:17][NH:18][C:19]([O:21][CH3:22])=[O:20].ClC(OCC(C)C)=O.[CH3:43][N:44]1CCOCC1.CN.C1COCC1>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:34])[N:4]([C:24]2[CH:25]=[C:26]([C:27]([NH:44][CH3:43])=[O:28])[CH:30]=[CH:31][C:32]=2[CH3:33])[C:5]([CH3:23])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[CH2:17][NH:18][C:19](=[O:20])[O:21][CH3:22]
Reactant: CN1CCOCC1
Reactant: COC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)O)ccc2C)c(=O)c1Br
Agent: CC(C)COC(=O)Cl
Agent: CN
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3CNC(=O)OC)c(Br)c2=O)c1
Reaction time: 0.25 h

Procedure:
To a cooled (−10° C.) solution of 3-[3-bromo-4-[(4-fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (0.07 g, 0.13 mmol) in DMF (2.0 mL) was added isobutyl chloroformate (0.02 mL, 0.16 mmol) and 4-methylmorpholine (0.02 mL, 0.16 mmol). After 15 min, 2.0M methylamine in THF (0.01 mL, 0.20 mmol) was added. Solvent removed by distillation after 30 min. Crude product purified by preparatory HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHCO3 (30 mL) and extracted in DCM (3×25 mL). The organic extracts were dried over Na2SO4, filtered, concentrated, and dried in vacuo to give a white foam, (0.061 g, 86%). 1H NMR (CD3OD/400 MHz) δ 7.85 (m, 1H), 7.54 (m, 3H), 7.14 (m, 1H), 7.05 (m, 1H), 6.68 (s, 1H), 5.40 (s, 2H), 4.43 (s, 2H), 3.64 (s, 3H), 2.89 (s, 3H), 2.08 (s, 3H), 1.99 (s, 3H). ES HRMS m/z 546.0987 and 548.1018 (M+H calculated for C25H26BrFN3O5 requires 546.1034 and 548.1018).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][NH:11][N:10]=[N:9]2)=[C:4]([F:13])[CH:3]=1.[F:14][CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-:20].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:20])[N:11]([CH2:17][CH2:16][CH2:15][F:14])[N:10]=[N:9]2)=[C:4]([F:13])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: FCCCBr
Reactant: Fc1cc(Cl)ccc1N1CNN=N1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1n(CCCF)nnn1-c1ccc(Cl)cc1F

Procedure:
A stirred solution of 4.7 grams (0.22 mole) of 1-(4-chloro-2-fluorophenyl)-1,4-dihydro-5H-tetrazole, 4.0 grams (0.028 mole) of 3-fluoropropyl bromide and 4.0 grams (0.028 mole) of potassium carbonate in 60 ml of dimethylformamide was heated at 60° C. for 16 hours. The reaction mixture was poured into water and the mixture extracted with diethyl ether. The combined ether extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was dissolved in methylene chloride and passed through a pad of silica gel. The eluate was concentrated under reduced pressure to yield 3.5 grams of 1-(4-chloro-2-fluorophenyl-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one; m.p. 62°-63° C. The reaction was repeated several times.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.Cl.[O:10]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:13]2[CH2:14][CH2:15][CH2:16][O:10][CH2:11][CH2:12]2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: C1CNCCOC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Clc1cc(N2CCCOCC2)ncn1
Temperature: 25 °C

Procedure:
A mixture of 3.0 g (20.1 mmol) of 4,6-dichloropyrimidine, 2.8 g (20.1 mmol) of 1,4-oxazepane hydrochloride and 6.4 g (60.4 mmol) of sodium carbonate in 45 ml of water is stirred under reflux for 16 h. After cooling to RT, the reaction mixture is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate and filtered. Under reduced pressure, the filtrate is concentrated to dryness. The product is obtained as an oil. Yield: 3.9 g (86% of theory)
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11]C)[CH:10]=1)[CH:6]=[O:7].C[C:14]1[N:19]=[C:18]([C:20](O)=O)[CH:17]=[CH:16][CH:15]=1>>[CH3:20][C:18]1[N:19]=[C:14]([C:6]([C:5]2[CH:8]=[C:9]([OH:11])[CH:10]=[C:3]([OH:2])[CH:4]=2)=[O:7])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cccc(C(=O)O)n1
Reactant: COc1cc(C=O)cc(OC)c1
Product: Cc1cccc(C(=O)c2cc(O)cc(O)c2)n1

Procedure:
3,5-Dihydroxyphenyl 6-methyl-2-pyridyl ketone is prepared according to example 1 from 3,5-dimethoxybenzaldehyde and 6-methyl picolinic acid. This intermediate is then reacted according to example 2 and purified to yield pure erythro-α-(3,5-dihydroxyphenyl)-α-(6-phenethyl-2-piperidinyl)methanol hydrochloride, m.p. 285°C.
Reaction SMILES: [C:1]1([CH2:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22]1[C:26]([CH2:27][C:28](=[O:40])[N:29]2[CH2:33][CH2:32][CH2:31][C@H:30]2[CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:25]([CH3:41])[NH:24][C:23]=1[CH:42]=O.N1CCCCC1>C(O)C>[CH3:21][C:22]1[C:26]([CH2:27][C:28](=[O:40])[N:29]2[CH2:33][CH2:32][CH2:31][C@H:30]2[CH2:34][N:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)=[C:25]([CH3:41])[NH:24][C:23]=1/[CH:42]=[C:14]1\[C:15](=[O:20])[NH:16][C:17]2[C:13]\1=[CH:12][C:11]([S:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:10])=[O:9])=[CH:19][CH:18]=2
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3ccccc3)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)N1CCC[C@H]1CN1CCCC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4ccccc4)cc32)c(C)c1CC(=O)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-phenylmethanesulfonyl-1,3-dihydro-indol-2-one (100 mg, 0.35 mmol), 3,5-dimethyl-4-[2-oxo-2-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-ethyl]-1H-pyrrole-2-carbaldehyde (110 mg, 1 eq.) and piperidine (0.5 eq.) in ethanol (2 mL) was stirred at rt for 48 hours. The reaction was concentrated, triturated with methanol, filtered and washed wit DCM to give the titled compound as a pale orange solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[NH:6][C:5](=[NH:7])[CH2:4][CH2:3]1.Br[C:10](=[CH:13]OC(C)C)[CH:11]=[O:12].C1(N2C(C=O)=CN=C2C)CC1>>[CH3:1][C:2]1([CH3:8])[N:6]2[C:10]([CH:11]=[O:12])=[CH:13][N:7]=[C:5]2[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=N)N1
Reactant: CC(C)OC=C(Br)C=O
Agent: Cc1ncc(C=O)n1C1CC1
Product: CC1(C)CCc2ncc(C=O)n21

Procedure:
5,5-Dimethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carbaldehyde was prepared from 5,5-dimethyl-pyrrolidin-2-ylideneamine (Buckley, et al. J. Chem. Soc. 1947, 1507.) and 2-bromo-3-isopropoxy-propenal in the same manner as cyclopropyl-2-methyl-3H-imidazole-4-carbaldehyde (Example 45).