Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([C:11](=[O:20])[CH2:12][O:13][C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:8][C:7](=[O:21])[N:6]1[CH2:22][C:23]1[CH:28]=C[C:26](C#N)=[C:25](N)[CH:24]=1)=[O:4].[N:32]1[CH:37]=[N:36][CH:35]=[N:34][CH:33]=1.CC(O)=O>CCO>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([C:11](=[O:20])[CH2:12][O:13][C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:8][C:7](=[O:21])[N:6]1[CH2:22][C:23]1[CH:28]=[C:33]2[C:26]([C:37]([NH2:32])=[N:36][CH:35]=[N:34]2)=[CH:25][CH:24]=1)=[O:4]
Reactant: c1ncncn1
Reactant: COC(=O)C1CN(C(=O)COc2ccc(Cl)s2)CC(=O)N1Cc1ccc(C#N)c(N)c1
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)C1CN(C(=O)COc2ccc(Cl)s2)CC(=O)N1Cc1ccc2c(N)ncnc2c1
Yield: 40.8 %

Procedure:
A solution containing (±)-1-(3-amino-4-cyano-benzyl)-4-[(5-chloro-thiophen-2-yloxy)-acetyl]-6-oxo-piperazine-2-carboxylic acid methyl ester (110 mg, 0.25 mmol), 1,3,5-triazine (207 mg, 2.55 mmol), and glacial HOAc (157 mg, 2.55 mmol) in absolute EtOH (5 mL) is maintained at reflux for 16 hours. The reaction mixture is concentrated to dryness and then purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 50 mg (32%) of the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) δ3.34-3.89 (m, 2H), 3.60 (s, 3H), 4.14-4.54 (m, 3H), 4.64 (br d, J=14.4 Hz, 1H), 4.78-5.11 (m, 3H), 6.19 (d, J=4.1 Hz, 1H), 6.73 (d, J=4.1 Hz, 1H), 7.64 (s, 1H), 7.65 (d, J=9.0 Hz, 1H), 8.34 (d, J=9.0 Hz, 1H), 8.79 (s, 1H), 9.71 (br s, 2H) ppm; MS (ion spray): m/z 490 (M+H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Cl.[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[O:29][CH2:30][C@@H:31]([NH:33][C:34](=[O:36])[CH3:35])[CH3:32])[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[OH:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[O:29][CH2:30][C@@H:31]([NH:33][C:34](=[O:36])[CH3:35])[CH3:32])[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1
Reactant: ClCc1ccccn1
Reactant: CC(=O)N[C@@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Agent: Cl
Product: CC(=O)N[C@@H](C)COc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 63 %

Procedure:
The procedure described in Example 3 was repeated using picolyl chloride hydrochloride and N-[(1S)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]acetamide to give the title compound in 63% yield; NMR spectrum (DMSO-d6) 1.21 (s, 3H), 1.73 (s, 3H), 4.12-4.30 (m, 2H), 4.33-4.43 (m, 1H), 5.29 (s, 2H), 7.15-7.25 (m, 2H), 7.35 (t, 2H), 7.51-7.59 (m, 2H), 7.72 (t, 1H), 7.87 (t, 1H), 7.99 (s, 1H), 8.14 (d, 1H), 8.48 (s, 1H), 8.59 (d, 1H), 9.80 (s, 1H); Mass spectrum MH+ 478.0.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH3:32])=[CH:26][C:25]=4[F:33])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].ClCCl>>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[CH2:31]([O:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C:22]2[N:21]=[CH:20][N:19]=[C:18]3[N:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[N:15]=[CH:16][C:17]=23)=[C:25]([F:33])[CH:26]=1)[CH3:32]
Reactant: CCOc1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(Oc2ncnc3c2cnn3C2CCNCC2)c(F)c1
Yield: 99 %

Procedure:
A solution of 4-[4-(4-ethoxy-2-fluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 43; 110 mg) in 20% trifluoroacetic acid/dichloromethane (5 mL) was stirred at room temperature for 3 hours. The solvent was removed to afford 4-(4-ethoxy-2-fluoro-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (112 mg, 99%) which was used directly in the next step without further purification.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([CH2:10]O)=[N:5]2.S(Cl)([Cl:14])=O>>[Cl:14][CH2:10][C:6]1[CH:7]=[CH:8][C:9]2[N:4]([CH:3]=[CH:2][N:1]=2)[N:5]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2nccn2n1
Product: ClCc1ccc2nccn2n1
Yield: 69 %

Procedure:
Thionyl chloride (10 ml) was added to imidazo[1,2-b]pyridazin-6-ylmethanol (1.5 g, 9.0 mmol) at 20° C. under an atmosphere of nitrogen at RT. The reaction mixture was stirred at reflux for 3 h (the reaction was monitored by TLC) upon which the volatiles were removed under reduced pressure. The reaction mixture was diluted with water and extracted with EtOAc. The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 15% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 6-(chloromethyl)imidazo[1,2-b]pyridazine (1.2 g, 69%,) as an off-white solid. 1H NMR, 200 MHz, DMSO-d6: δ 8.35 (s, 1H), 8.3 (d, 1H), 7.85 (s, 1H), 7.35 (d, 1H), 4.95 (s, 2H). MS: [M+H]+: m/z=149.9.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:18])[CH3:17])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24]>>[CH2:21]([N:22]([CH2:25][CH3:26])[CH2:23][CH2:24][N:15]([C@@H:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11]1)[C:16](=[O:18])[CH3:17])[CH3:20]
Reactant: CCN(CC)CCCl
Reactant: CC(=O)N[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1
Product: CCN(CC)CCN(C(C)=O)[C@@H]1CCN(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
(R)-N-[1-(4-nitrophenyl)pyrrolidin-3-yl]acetamide was reacted with 2-chloroethyldiethylamine by method F. This resulted in the product with the molecular weight of 348.45 (C18H28N4O3); MS (ESI): 349 (M+H+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:24])[N:8]([C:10]2[N:11]=[CH:12][N:13]([CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH:14]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl[C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29]>O.CCOC(C)=O>[Cl:33][C:32]([Cl:35])([Cl:34])[CH2:31][O:30][C:28](=[O:29])[NH:24][C:7]1[N:8]([C:10]2[N:11]=[CH:12][N:13]([CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[CH:14]=2)[N:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2cn(CCOC3CCCCO3)cn2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cn(CCOC3CCCCO3)cn2)n1
Reaction time: 0.17 h
Yield: 20.9 %

Procedure:
To a mixture of Intermediate 119b (550 mg) in water (3 mL) and EtOAc (6 mL) was added NaOH (132 mg, 3.30 mmol). After 10 min stirring, 2,2,2-trichloroethyl chloroformate (273 μL, 1.98 mmol) was added and the reaction mixture was stirred at RT for 2 h. The aqueous layer was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-80% EtOAc in cyclohexane, to afford the title compound (175 mg). LCMS (Method 4): Rt 4.54 min, m/z 508, 510 [MH+].
Reaction SMILES: [OH-].[Na+:2].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.C(O)(=O)C>CO>[Na+:2].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]([O-:14])=[O:13])=[CH:6][CH:5]=1
Reactant: O=C(O)CNc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=C([O-])CNc1ccc(O)cc1
Temperature: 0 °C

Procedure:
18 g of sodium hydroxide are dissolved in 250 ml of methanol and 75 g of p-hydroxy-phenyl-glycine are added. After stirring at 60° C. for 15 minutes 2 ml of acetic acid is added to the reaction mixture which is cooled to 0° C. and the suspension is filtered. The wet p-hydroxy-phenyl-glycine sodium salt obtained is suspended in 500 ml of ethanol, 75 g of acetoacetic acid methylester and 0.5 ml of acetic acid are added and the mixture is refluxed for 90 minutes. The residue is cooled to -5° C. and the suspension obtained is filtered, the crystals are dried in vacuo at 60° C. 124.1 g of sodium-D-N-(2-methoxy-carbonyl-1-methyl-vinyl)-α-amino-(p-hydroxy-phenyl)-acetate are obtained.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([O:15][CH2:16][O:17][C:18](=[O:46])[N:19]([C:43](=[O:45])[CH3:44])[CH2:20][C@@H:21]1[O:25][C:24](=[O:26])[N:23]([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:40][C:39]4[C:35](=[N:36][N:37]([CH3:41])[CH:38]=4)[CH2:34]3)=[C:29]([F:42])[CH:28]=2)[CH2:22]1)=[O:14])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:43]([N:19]([CH2:20][C@@H:21]1[O:25][C:24](=[O:26])[N:23]([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:40][C:39]4[C:35](=[N:36][N:37]([CH3:41])[CH:38]=4)[CH2:34]3)=[C:29]([F:42])[CH:28]=2)[CH2:22]1)[C:18]([O:17][CH2:16][O:15][C:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)=[O:14])=[O:46])(=[O:45])[CH3:44]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 11 (1 equiv) in dichloromethane at rt under nitrogen is added TFA (5 equiv) dropwise. The reaction mixture is stirred at rt for 2 h, concentrated in vacuo, purified directly by HPLC (C-18 column, 0-100% gradient elution, MeCN:H2O with 0.1% TFA), and fractions containing product are lyophilized to give the title compound. Theoretical MS 545 (M+1)+
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH3:10][O-:11].[Na+]>CN(C=O)C>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([O:11][CH3:10])[N:3]=1
Reactant: Oc1ccc(Cl)nc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(O)c(Br)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 0° C. solution of 2-bromo-6-chloropyridin-3-ol (1 eq.) and DMF (0.2 M) is added NaOMe (2.2 eq.). The solution is allowed to warm to room temperature as the cooling bath expires and allowed to stir at room temperature for 24 h. The reaction is quenched with saturated NH4Cl and diluted with water. The aqueous solution is extracted with EtOAc. The combined EtOAc layers are dried over MgSO4, concentrated in vacuo, and purified by column chromatography to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11](=[O:12])[O:13][CH2:14][CH3:15])=[C:4]([F:9])[CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(Cl)cc1F
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(Cl)cc1F
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
A solution of 6.9 grams (47 mmole) of 4-chloro-2-fluoroaniline in 75 mL of pyridine was stirred and cooled in an ice bath. During 15 minutes, 5.4 grams (50 mmole) of ethyl chloroformate was added dropwise. Upon completion of the addition the reaction mixture was heated at 60°-70° C. for 1.5 hours, then concentrated under reduced pressure to a residue. The residue was stirred with 150 mL of aqueous 3N hydrochloric acid, and the resulting precipitate was collected by filtration. The precipitate was washed with aqueous 3N hydrochloric acid and then with water. The precipitate was dried under ambient conditions for about 18 hours, then dried under vacuum for two hours, yielding 9.6 grams of ethyl N-(4-chloro-2-fluoro-phenyl)carbamate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])=[N:5][CH:4]=1)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([C:3]1[S:7][C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=[N:5][CH:4]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)CNc1ncc(C=O)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1cnc(NCC(=O)O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 181.2 %

Procedure:
To a magnetically stirred solution of material from Example 2 (2.19 g, 9.04 mmol) in CH2Cl2 (50 mL) is added TFA (25 mL, 324 mmol). The resulting solution is allowed to stir at room temperature for 8 h and then evaporated to dryness under a gentle stream of N2 over 18 h. The resulting tan residue is dissolved in CH2Cl2, sonicated briefly and the solvent is removed in vacuo to give 3.05 g (96%) the title compound as a tan solid as a •1.3 TFA salt by weight. LC/MS (Condition A): ret. T=0.82 min, (M+H)+ 187.00. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.67 (1 H, s), 9.11 (1 H, br. s.), 8.05 (1 H, s), 4.12 (2 H, d, J=5.19 Hz).
Reaction SMILES: C1(C([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:60]([OH:61])[CH:41]6[CH:42]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:62]([CH3:64])[CH3:63])=[O:16])C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[CH2:44]([O:43][CH:42]1[CH:37]2[CH:38]3[O:39][C:35]([O:34][CH2:33][C:21]45[CH:20]6[CH2:29][C:28]([CH:30]=[O:31])([C:17]4([C:15]([OH:16])=[O:14])[C:18]([CH:62]([CH3:63])[CH3:64])=[CH:19]6)[CH:27]4[CH:23]([CH:24]([CH3:32])[CH2:25][CH2:26]4)[CH2:22]5)([CH:60]([OH:61])[CH:41]1[O:40]3)[O:36]2)[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]
Reactant: CCCCCCCCCCCCCCCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)O)OC2OC1C3O
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
25.0 mg of compound (52) was dissolved in 2.89 ml of ethyl acetate and allowed to react in the presence of a catalytic amount of 10% palladium-carbon under stirring under a hydrogen atmosphere at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was concentrated in vacuo. The reaction product was charged onto a silica gel column (Kieselgel 60, Merck, 1.0φ×21 cm) and eluted with n-hexane-chloroform (2:1) to give 12.3 mg of compound (53) as a colorless oily substance.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:36]([NH:39][NH2:40])(=[O:38])[CH3:37]>O1CCCC1>[C:36]([NH:39][NH:40][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])(=[O:38])[CH3:37]
Reactant: CC(=O)NN
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 91.6 %

Procedure:
To a solution of the carboxylic acid (6b, 2.37 g, 8.57 mmol) of Example 9 or 16 in tetrahydrofuran (50 mL) were added triethylamine (1.39 mL) and isobutyl chloroformate (1.32 mL) under ice-cooling, followed by agitating at 0° C. for 20 minutes. To the reaction solution was added acetohydrazide (807 mg) at 0° C., stirred at room temperature for 40 minutes and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to afford 2.61 g of the title compound (yield 92%).
Reaction SMILES: C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:15]1([C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:22][CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCCCCC=C(c1ccccc1)c1ccccc1
Agent: O=C(c1ccccc1)c1ccccc1
Product: C=CCCCC=C(c1ccccc1)c1ccccc1
Yield: 71 %

Procedure:
In a reaction conducted in an analogous manner to Example 4, the reagent from Example 2 converted benzophenone into 1,1-diphenyl-1-heptene in a 71% yield. This product could easily be separated from reduction products by column chromatography on silica gel using hexane as the eluent, or even by simple distillation. This hydrocarbon was identified by spectral comparison with an authentic sample that was obtained by the partial reduction of known 1,1-diphenyl-1,6-heptadiene (J. J. Eisch et al., J. Am. Chem. Soc., 1979, 101: 1148).
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[CH2:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[Cl-].[CH3:23][C:24]([NH:27][SiH:28]([CH3:30])[CH3:29])([CH3:26])[CH3:25]>>[CH:1]1([CH2:7][C:8]2[CH:16]([Si:28]([CH3:30])([CH3:29])[NH:27][C:24]([CH3:26])([CH3:25])[CH3:23])[C:15]3[C:10]([CH:9]=2)=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[SiH](C)NC(C)(C)C
Reactant: C1=C(CC2CCCCC2)Cc2ccccc21
Agent: [Cl-]
Agent: [Li]CCCC
Product: CC(C)(C)N[Si](C)(C)C1C(CC2CCCCC2)=Cc2ccccc21
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a mixture of 2-(cyclohexylmethyl)indene (2.0 g, 9.4 mmol) in 40 mL of hexanes were added 6.0 mL of butyl lithium (1.6 M hexane; 9.6 mmol). The mixture was stirred overnight, the mother liquor decanted and the solid dissolved in THF. To this was added N-(1,1-dimethylethyl)dimethylsilanamine chloride (1.64 g, 9.9 mmol) and the solution stirred for 1 hour. The volatiles were removed in vacuo, the residue extracted with hexane, filtered and the volatiles removed in vacuo to give 2.85 g (90 percent) of a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:11]3[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=3[O:9][CH2:8]2)[CH2:4][CH2:3]1.ClC1C=CC(O[CH2:25][C:26]#[N:27])=CC=1.CC(C)([O-])C.[K+].Cl>CN(C=O)C.O>[C:26]([CH2:25][C:14]1[C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]2[C:5]3([CH2:8][O:9][C:10]=2[CH:15]=1)[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)#[N:27]
Reactant: CN1CCC2(CC1)COc1ccc([N+](=O)[O-])cc12
Reactant: N#CCOc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCC2(CC1)COc1cc(CC#N)c([N+](=O)[O-])cc12
Reaction time: 6 h
Yield: 43.5 %

Procedure:
2,3-Dihydro-1'-methyl-5-nitrospiro[benzofuran-3,4'-piperidine] (D4, 0.70 g, 2.8 mmol) and 4-chlorophenoxyacetonitrile (0.90 g, 5.4 mmol) were dissolved in dry DMF (15 ml) and added to potassium t-butoxide (1.60 g, 14.3 mmol). The mixture was stirred under Ar for 6 h, diluted with water (150 ml), acidified (5M HCl) and washed with ethyl acetate. It was then basified (saturated K2CO3 solution) and extracted with ethyl acetate. This extract was dried (Na2SO4) and evaporated to give the title compound (0.35 g, 43%) still containing some spirocyclic starting material (ca 30%, NMR).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C(F)=NC(F)=NC=1[F:16].N1C=CC=CC=1>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([C:11]([F:16])=[O:13])[CH3:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Fc1nc(F)nc(F)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)F
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
To an oven-dried, septaed 10 mL round-bottom flask, cooled under an argon atmosphere, and charged with (R)-N-BOC-alanine, 24b, (189.2 mg, 1.00 nmmol) was added 2.5 mL freshly distilled CH2Cl2 under argon. The reaction was cooled to −15 C and to the flask was added cyanuric fluoride (450 μL, 5 mmol). The reaction was stirred at −15° C. for 15 minutes then anhydrous pyridine (81 μL, 1.0 mmol) was added. Stirring was maintained at −15° C. for 90 minutes, with reaction progress indicated by the gradual formation of a precipitate. Without warming, the crude reaction was poured over ice, and immediately extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed once with water, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting colorless oil was dissolved in CH2Cl2, and precipitated with hexane to afford 155.1 mg of a mixture of 24b and 25b as white crystals. FTIR (film) 1842 cm−1.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].Cl.[NH:27]1[CH2:32][CH2:31][O:30][CH:29]([C:33]([OH:35])=[O:34])[CH2:28]1>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH:29]([C:33]([OH:35])=[O:34])[CH2:28]2)=[C:4]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: O=C(O)C1CNCCO1
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Agent: Cl
Product: COC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 36.8 %

Procedure:
Methyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.15 g, 2.5 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.5 g, 3 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.47 g, 37%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C([N:8]([CH:38]1[CH2:41][N:40]([S:42]([C:45]2[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53][CH2:54][CH3:55])=[CH:47][CH:46]=2)(=[O:44])=[O:43])[CH2:39]1)[CH2:9][C@@H:10]([C:19]1[CH:20]=[CH:21][C:22]([O:30]CC2C=CC=CC=2)=[C:23]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:24]=1)[O:11][Si](CC)(CC)CC)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C([O-])=O.[NH4+]>O1CCCC1.CO.[Pd]>[CH2:52]([O:51][C:48]1[CH:47]=[CH:46][C:45]([S:42]([N:40]2[CH2:39][CH:38]([NH:8][CH2:9][CH:10]([C:19]3[CH:20]=[CH:21][C:22]([OH:30])=[C:23]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH:24]=3)[OH:11])[CH2:41]2)(=[O:43])=[O:44])=[CH:50][CH:49]=1)[CH2:53][CH2:54][CH3:55]
Reactant: CCCCOc1ccc(S(=O)(=O)N2CC(N(Cc3ccccc3)C[C@H](O[Si](CC)(CC)CC)c3ccc(OCc4ccccc4)c(NS(C)(=O)=O)c3)C2)cc1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C[O-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCOc1ccc(S(=O)(=O)N2CC(NCC(O)c3ccc(O)c(NS(C)(=O)=O)c3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
To a solution of N-[5-((1R)-2-{benzyl-[1-(4-butoxy-benzenesulfonyl)-azetidin-3-yl]-amino}-1-triethylsilanyloxy-ethyl)-2-benzyloxy-phenyl]-methanesulfonamide (0.10 g, 0.12 mmol) in tetrahydrofuran (1 ml) was added 0.2 ml of tetrabutylammonium fluoride (1 M in THF). After 2 h at room temperature, the mixture was treated with water and extracted with ethyl acetate. The organic solution was dried over anhydrous sodium sulfate, and evaporated. The residue obtained was dissolved in methanol (3 ml), and treated with ammonium formate (0.12 g, 1.8 mmol) and 10% Pd/C (20 mg) at reflux for 18 h. It was then cooled to room temperature, filtered through Celite, and eluted with more methanol. The filtrate was evaporated, and the residue washed with ether-hexanes to give 55 mg of an off-white solid; m.p. 67-70° C.; MS (ES) m/z 514.0 (MH+); HRMS (FAB) Calcd. for C22H32N3O7S2 (MH+): 514.1682, Found: 514.1693.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[C:7]([O:13][CH3:14])=[CH:6][C:5]=1[O:15][CH3:16].[OH-].[Na+].Cl>C1COCC1.O.CCOC(C)=O>[CH:10]([C:8]1[C:7]([O:13][CH3:14])=[CH:6][C:5]([O:15][CH3:16])=[C:4]([CH:9]=1)[C:3]([OH:17])=[O:2])([CH3:12])[CH3:11]
Reactant: COC(=O)c1cc(C(C)C)c(OC)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(OC)c(C(C)C)cc1C(=O)O

Procedure:
5-Isopropyl-2,4-dimethoxy-benzoic acid methyl ester (5.5 g, 23.1 mmol) and NaOH (1.38 g, 34.6 mmol) in THF (46 ml) and water (46 ml) was warmed to 50° C. overnight. The reaction was cooled and diluted with water and EtOAc. The aqueous layer was neutralised with HCl (1N, aq.). The product was extracted with EtOAc (×3) and the combined organic layers were washed with brine and dried over MgSO4. The product was filtered and evaporated to dryness to yield 5-isopropyl-2,4-dimethoxy-benzoic acid as a pale peach solid (4.7 g). 1H NMR (DMSO-d6) 12.1 (1H, br s), 7.62 (1H, s), 6.71 (1H, s), 3.95 (3H, s), 3.91 (3H, s), 3.19 (1H, sept), 1.18 (6H, d). MS: [M+H]+ 225.