Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][N:5]1[C:10]2[N:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])O[C:6]1=[O:16].[CH3:18][C:19]1[O:20][C:21]2[CH:38]=[CH:37][C:24]3[NH:25][C:26]([CH2:31]C(OCC)=O)=[N:27][S:28](=[O:30])(=[O:29])[C:23]=3[C:22]=2[N:39]=1.[H-].[Na+].Cl>O1CCCC1.O.C(O)(=O)C>[OH:15][C:8]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:5]([CH2:4][CH2:3][CH:2]([CH3:1])[CH3:17])[C:6](=[O:16])[C:31]=1[C:26]1[NH:25][C:24]2[CH:37]=[CH:38][C:21]3[O:20][C:19]([CH3:18])=[N:39][C:22]=3[C:23]=2[S:28](=[O:30])(=[O:29])[N:27]=1
Reactant: CCOC(=O)CC1=NS(=O)(=O)c2c(ccc3oc(C)nc23)N1
Reactant: CC(C)CCn1c(=O)oc(=O)c2cccnc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc2c3c(ccc2o1)NC(c1c(O)c2cccnc2n(CCC(C)C)c1=O)=NS3(=O)=O
Temperature: 0 °C
Yield: 59.9 %

Procedure:
To a solution of the product of Example 12A (16.7 mg, 0.0714 mmol) and the product of Example 352F (23.1 mg, 0.0714 mmol) in anhydrous tetrahydrofuran (2 mL) at 0° C. was added sodium hydride (60%, 11.4 mg, 0.286 mmol) under a nitrogen atmosphere. The reaction was heated at reflux for 3 hours, cooled to 0° C., and treated with glacial acetic acid (0.165 mL). The resulting yellow solution was heated at reflux for 2 hours, cooled to 0° C., diluted with water (5 mL), and acidified with 1N aqueous hydrochloric acid to pH 3. The resulting precipitate was collected by filtration, washed with water and dried to give the title compound as a yellow solid (20 mg, 60%). MS (ESI−) m/z 466 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 0.99 (d, J=6.25 Hz, 6 H) 1.58 (m, 2 H) 1.71 (m, 1 H) 2.73 (s, 3H) 4.50 (m, 2 H) 7.50 (dd, J=7.72, 4.41 Hz, 1 H) 7.64 (d, J=8.82 Hz, 1 H) 8.10 (d, J=8.82 Hz, 1 H) 8.57 (dd, J=7.91, 2.02 Hz, 1 H) 8.89 (dd, J=4.60, 2.02 Hz, 1 H) 14.18 (s, 1 H). A suspension of the product of Example 352G (14.6 mg, 0.0312 mmol) in anhydrous tetrahydrofuran (3 mL) and distilled water (1 mL) was treated with 0.998 N aqueous sodium hydroxide (0.0313 mL, 0.0312 mmol) and the yellow solution mixed for 15 minutes. The solvent was removed under reduced pressure and the residue dried to afford the sodium salt of Example 352G (15 mg, 98%). 1H NMR (300 MHz, DMSO-d6) δ 0.97 (d, J=6.25 Hz, 6 H) 1.48 (m, 2 H) 1.65 (m, 1 H) 2.67 (s, 3 H) 4.30 (m, J=8.82, 6.25 Hz, 2 H) 7.13 (dd, J=7.91, 4.60 Hz, 1 H) 7.21 (d, J=8.82 Hz, 1 H) 7.86 (d, J=8.82 Hz, 1 H) 8.38 (dd, J=8.09, 1.47 Hz, 1 H) 8.53 (m, J=2.94 Hz, 1 H) 16.09 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[O:5][C:6]1[N:7]=[C:8]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:33][CH2:32][C:27]4(OCC[O:28]4)[CH2:26][CH2:25]3)=[C:20]([CH3:34])[CH:19]=2)[C:9]([C:14]([NH2:16])=[O:15])=[N:10][C:11]=1[CH2:12][CH3:13].Cl.C(O)(=O)C.N>O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][CH:37]=1)[O:5][C:6]1[N:7]=[C:8]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:25][CH2:26][C:27](=[O:28])[CH2:32][CH2:33]3)=[C:20]([CH3:34])[CH:19]=2)[C:9]([C:14]([NH2:16])=[O:15])=[N:10][C:11]=1[CH2:12][CH3:13]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC4(CC3)OCCO4)c(C)c2)nc1Oc1cccc(N)c1
Agent: Cl
Agent: N
Solvent: O
Solvent: CC(=O)O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(=O)CC3)c(C)c2)nc1Oc1cccc(N)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 96.5 %

Procedure:
A mixture of 5-(3-aminophenoxy)-3-{[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-methylphenyl]amino}-6-ethylpyrazine-2-carboxamide (840 mg) and 3 M hydrochloric acid (6 mL) was stirred at 80° C. for 5 hours, and then acetic acid (1.5 mL) was added thereto, followed by stirring at 80° C. overnight. The reaction mixture was left to be cooled, and then water (30 mL) was added thereto, followed by ice-cooling. The pH was adjusted to 9 by the addition of concentrated ammonia. The precipitated solid was collected by filtration and then dried under reduced pressure to obtain 5-(3-aminophenoxy)-6-ethyl-3-{[3-methyl-4-(4-oxopiperidin-1-yl)phenyl]amino}pyrazine-2-carboxamide (0.74 g) as a pale yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][C:17]([NH2:19])=O)=[CH:10][CH:9]=1>C(OCC)C.O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH2:19])=[CH:12][CH:13]=1
Reactant: NC(=O)CCCc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NCCCCc1ccc(Cl)cc1
Reaction time: 0.13 h
Yield: 61 %

Procedure:
To a stirred suspension of lithium aluminum hydride (1.84 g, 48.6 mmol) in diethyl ether (50 mL) at ambient temperature was added a solution of 4-(4-chlorophenyl)butanamide in tetrahydrofuran (25 mL), dropwise over 8 minutes. Stirring was continued at ambient temperature for a further 4 hours. The reaction mixture was carefully quenched by sequential slow addition of water (2 mL), 10M sodium hydroxide (0.75 mL), and water (7 mL). After stirring the mixture for 20 minutes, it was extracted with diethyl ether (50 mL). The organic layer was dried over sodium sulfate and concentrated to afford 4-(4-chlorophenyl)butan-1-amine as a light yellow oil (1.36 g, 61%).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1([CH2:22][CH2:23]OS(C)(=O)=O)[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]1)(=O)=O.[NH3:29]>CO>[CH2:7]1[C:8]2([CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]2)[CH2:22][CH2:23][NH:29][CH2:6]1
Reactant: N
Reactant: CC(C)(C)OC(=O)N1CCCC(CCOS(C)(=O)=O)(CCOS(C)(=O)=O)CC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC2(CCNCC2)CC1
Temperature: 50 °C

Procedure:
A mixture of tert-butyl 4,4-bis(2-(methylsulfonyloxy)ethyl)azepane-1-carboxylate (500 mg, 1.12 mmol), MeOH (2 ml) and NH3 solution (1.5 ml) was heated at 50° C. in a sealed tube for 16 h. The reaction mixture was concentrated under reduced pressure and the crude material was washed with hexanes and dried to afford the desired compound as a yellowish semi-solid which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[CH2:18](Br)[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>>[CH3:1][C:2]1[C:10]2[C:5]([N:6]([CH2:18][C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])[CH:7]=[CH:8][CH:9]=2)=[N:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1
Reactant: Cc1ccc(-c2[nH]c3ncccc3c2C)cc1
Reactant: O=C(CBr)c1ccccc1
Product: Cc1ccc(-c2nc3n(CC(=O)c4ccccc4)cccc-3c2C)cc1

Procedure:
The title compound was prepared from 3-methyl-2-(p-methylphenyl)-pyrrolo[2,3-b]pyridine and phenacyl bromide on a 3 mmol scale according to the procedure described in example 8 yielding 1.21 g (96%).
Reaction SMILES: C([NH:3][CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([CH:22]3[CH2:32][CH:23]3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])C.COC([N:37]([C:52]1[C:61](C(OC)=O)=[C:60]2[C:55](C3CC3C[O:59]2)=CC=1)S(C1C=CC(F)=CC=1/C=C\CO)(=O)=O)=O.O[C@H]1CCNC1>>[OH:59][C@H:60]1[CH2:61][CH2:52][N:37]([NH:3][CH2:4]/[CH:5]=[CH:6]\[C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[S:14]([NH:17][C:18]2[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]3[C:21]([CH:22]4[CH2:32][CH:23]4[CH2:24][O:25]3)=[CH:20][CH:19]=2)(=[O:15])=[O:16])[CH2:55]1
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCC1CC21
Reactant: CCNC/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Agent: O[C@H]1CCNC1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CNN2CC[C@H](O)C2)ccc2c1OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Intermediate 63, starting from methyl (1aRS,7bSR)-5-{N-[methoxycarbonyl]-N-[2-((Z)-3-hydroxyprop-1-enyl)-4-fluorobenzene-sulfonyl]amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 64) and (S)-3-hydroxypyrrolidine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[CH:21][C:22]([NH:24][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[NH:26])=[CH:23][C:15]1=2)C(=O)OC(C)(C)C.Cl.O>CO.C(=O)([O-])[O-].[Na+].[Na+]>[OH:1][CH2:2][CH2:3][NH:4][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][S:17][C:16]2[CH:20]=[CH:21][C:22]([NH:24][C:25]([C:27]3[S:28][CH:29]=[CH:30][CH:31]=3)=[NH:26])=[CH:23][C:15]1=2
Reactant: CC(C)(C)OC(=O)N(CCO)CCN1CCSc2ccc(NC(=N)c3cccs3)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N=C(Nc1ccc2c(c1)N(CCNCCO)CCS2)c1cccs1
Temperature: 90 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
To a stirred solution of tert-butyl 2-hydroxyethyl(2-(6-(thiophene-2-carboximidamido)-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)carbamate (334 mg, 0.722 mmol) in methanol (5 mL) was added HCl, 3M in water (2.407 mL, 7.22 mmol). The resulting solution was stirred at 90° C. for 1 hour. The mixture was then cooled to room temperature, diluted with saturated sodium carbonate and extracted with dichloromethane (6×). The combined organics were dried, filtered, concentrated, and then chromatographed in 1:9 (2M NH3 in methanol):ethyl acetate, giving the desired product 26 (175 mg, 66.9%). 1H NMR (DMSO-d6) δ 7.71 (d, J=3.3 Hz, 1H), 7.58 (d, J=5.1 Hz, 1H), 7.10-7.06 (m, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.34 (brs, 2H), 6.22 (s, 1H), 6.07 (d, J=7.5 Hz, 1H), 4.49-4.43 (m, 1H), 3.63-3.55 (m, 2H), 3.46-3.38 (m, 2H), 3.37-3.28 (m, 2H), 3.01-2.95 (m, 2H), 2.71 (t, J=6.4 Hz, 2H), 2.59 (t, J=5.7 Hz, 2H), 1.91-1.75 (m, 1H); ESI-MS (m/z, %): 363 (MH+, 100), 276 (99), 268 (62); HRMS calculated for C17H23N4OS2 (MH+), calculated: 363.1307, observed: 363.1290; HPLC purity: 97% by area.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].N1CCCCC1>CCO>[CH2:15]([O:14][C:12](=[O:13])/[C:11](/[C:9]#[N:10])=[CH:1]/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:16]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)CC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)/C(C#N)=C/c1ccccc1
Reaction time: 8 h
Yield: 48.3 %

Procedure:
A mixture of benzaldehyde (0.6 mol, 63.7 g), ethyl cyanoacetate (0.6 mol, 67.8 g) and piperidine (1 mL) in EtOH (60 mL) was stirred overnight. The clear solution was then placed in an ice-water bath to initiate the crystallization. The crystalline material was filtered, washed with EtOH and dried in a vacuum oven at 50° C. to give 58.27 g of (E)-2-cyano-3-phenyl-acrylic acid ethyl ester. The mother liquors and the washings were concentrated under reduced pressure; the residue was cooled in an ice-water bath to produce more crystalline product. This material was collected by filtration and washed with hexane, and a mixture EtOH/hexane (1/4), it was then dried in a vacuum oven at 63° C. to give 38.01 g of (E)-2-cyano-3-phenyl-acrylic acid ethyl ester (80% combined yield).
Reaction SMILES: I[C:2]1[C:3](=[O:13])[N:4]([CH2:10][O:11][CH3:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[CH2:34]([OH:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Cu](I)I>[CH2:34]([O:41][C:2]1[C:3](=[O:13])[N:4]([CH2:10][O:11][CH3:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COCn1c(C)nc(C)c(I)c1=O
Reactant: OCc1ccccc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCn1c(C)nc(C)c(OCc2ccccc2)c1=O
Reaction time: 0.08 h

Procedure:
The compound 326-3 (4.78 g) was dissolved in toluene (130 ml). Cesium carbonate (10.6 g), 1,10-phenanthroline (4.41 g) and copper iodide (3.1 g) were added to the solution, and the obtained mixture was stirred for 5 minutes. Thereafter, benzyl alcohol (5.28 ml) was added to the reaction mixture. The obtained mixture was stirred at 110° C. for 5 days. The reaction mixture was diluted with ethyl acetate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=19:1 to 1:2), so as to obtain the title compound (1.42 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>ClCCl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[NH:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[N:21]=[CH:22][CH:23]=[CH:24][N:25]=3)=[CH:18][CH:19]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(-c3ncccn3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1=C(c2ccc(-c3ncccn3)cc2)CCNC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
4-(4-pyrimidin-2-yl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (crude from step 3) was dissolved in dichloromethane (200 ml) and trifluoroacetic acid (22 ml, 0.29 mol) was added at r.t. The mixture was stirred at r.t. for 5 hr and solvents were removed in vacuum. Diethyl ether was added and off-white solid was formed. The solid was filtered and washed with diethyl ether to give a salt (14.4 g, 71%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([OH:17])[C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:24]([O:17][C:6]1[CH:7]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:9]=[C:2]([Br:1])[C:3]=1[CH:4]=[O:5])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1c(O)cc(OC2CCCCO2)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1c(Br)cc(OC2CCCCO2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
To a solution of 2-bromo-6-hydroxy-4-(tetrahydro-pyran-2-yloxy)-benzaldehyde (3.00 g, 10.0 mmol) in DMF (20 mL) was added K2CO3 (2.76 g, 20.0 mmol) followed by benzyl bromide (1.43 mL, 12.0 mmol) at 0° C. The suspension was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography (silica, hexanes/ethyl acetate=6:1) to give the title compound (3.79 g, 97%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 10.39 (s, 1H), 7.47-7.33 (m, 5H), 6.98 (d, J=2.1 Hz, 1H), 6.70 (d, J=2.1 Hz, 1H), 5.47-5.45 (m, 1H), 5.16 (s, 2H), 3.80-3.78 (m, 1H), 3.66-3.62 (m, 1H), 1.88-1.55 (m, 6H).
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)[CH:5]=1.[C:16]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[CH3:17].[Li]>>[C:20]([O:19][C:16](=[O:18])[CH2:17][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)[CH:5]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1cccc(-n2cccn2)c1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cccn2)c1

Procedure:
The title compound was prepared from 3-pyrazol-1-yl-benzoic acid methyl ester [CAS-No. 168618-35-7] by treatment with lithium tert.-butyl acetate according to general procedure K (method b). Obtained as a yellow oil (5.00 g).
Reaction SMILES: Cl.[OH2:2].[O:3]([C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[CH:13]=NCC(C)C)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1(C)C=CC=CC=1>[O:3]([C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[CH:13]=[O:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)CN=Cc1cccc(Oc2ccccc2)c1
Reactant: O
Agent: Cl
Solvent: Cc1ccccc1
Product: O=Cc1cccc(Oc2ccccc2)c1
Yield: 94.9 %

Procedure:
20 g of 37% hydrochloric acid (about 0.2 mol) and 20 ml of water are added, with stirring, to a solution of 40 g (0.158 mol) of 3-phenoxybenzylidene-isobutylamine in 40 ml of toluene, and the whole is refluxed for 15 minutes. The organic phase is separated; it is then washed neutral with 10% sodium hydrogen carbonate solution, and the toluene is removed by rotation in a slight water-jet vacuum. Distillation of the residue yields 29.7 g (0.15 mol) of 3-phenoxybenzaldehyde, corresponding to a yield of 94.9% of theory; b.p. 94° C./6 Pa; nD20 =1.5976.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li])CCC.Cl.Cl[CH2:17][C:18]1[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=1.Cl>O1CCCC1>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:17][C:18]2[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=2)=[CH:2]1
Reactant: Cn1ccnc1CCl
Reactant: C1=Cc2ccccc2C1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1ccnc1CC1=CCc2ccccc21
Temperature: 25 °C
Yield: 76.7 %

Procedure:
A solution of 17.4 ml of indene (0.1497 mol) in 150 ml of tetrahydrofuran (THF) was cooled to −60° C. and 61.8 ml of n-butyllithium (2M in hexane, 0.136 mol) were subsequently added while stirring. The mixture was allowed to warm to room temperature while stirring for 3 h and 5 g (0.0299 mol) of 2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride was then added while stirring. The mixture was then stirred for a further 12 hours and hydrolyzed with 400 ml of dilute hydrochloric acid, the organic phase was separated off and the aqueous phase was extracted once with ethyl acetate. The aqueous phase was then neutralized with aqueous ammonia solution and extracted 3 times with 80 ml each time of dichloromethane. The organic phases were combined and dried over magnesium sulfate. After the magnesium sulfate had been filtered off, the solvent was distilled off. The crude product was purified by column chromatography using a mixture of hexane:ethyl acetate=1:1 and then the percentage of ethyl acetate slowly increased. Thus 4.82 g of 2-(1H-inden-3-ylmethyl)-1-methyl-1H-imidazole were obtained (77%).
Reaction SMILES: C(OCC)C.C[Si]([CH2:10][C:11](=[C:24]=[CH2:25])[CH2:12][CH:13]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15](O)[O:14]1)(C)C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.O>CCOC(C)=O>[CH2:10]=[C:11]1[C:24](=[CH2:25])[CH:15]2[O:14][CH:13]([CH2:22][C:21]3[C:16]2=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:12]1
Reactant: C=C=C(CC1Cc2ccccc2C(O)O1)C[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C=C1CC2Cc3ccccc3C(O2)C1=C
Temperature: -78 °C
Yield: 78.5 %

Procedure:
1.20 mL of diethyl ether was added to 3-(2-trimethylsilanylmethyl-buta-2,3-dienyl)-isochroman-1-ol (78 mg, 0.27 mmol) under nitrogen atmosphere. While stirring at −78° C., TMSOTf (49 μL, 0.27 mmol) was added. While stirring the reaction mixture, the reaction temperature was slowly increased to room temperature for 3 hours. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed, H2O was added. After stirring for about 5 minutes, the reaction mixture was diluted with EtOAc and washed with water and saturated brine. The organic layer was separated from the reaction mixture and dried with anhydrous MgSO4. The solvent was removed under reduced pressure and the remaining material was purified with column chromatography (EtOAc/n-hexane=⅙) to obtain 42 mg of the product (78%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:15]=[C:16]([F:22])[C:17]([F:21])=[C:18]([F:20])[CH:19]=1)#[CH:13].N>>[F:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:15]=[C:16]([F:22])[C:17]([F:21])=[C:18]([F:20])[CH:19]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: C#Cc1cc(F)c(F)c(F)c1
Reactant: ON=C(Cl)c1cncc(F)c1
Agent: N
Product: Fc1cncc(-c2cc(-c3cc(F)c(F)c(F)c3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and 5-ethynyl-1,2,3-trifluorobenzene (Apollo, 78 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.49 (s, 1H), 7.76 (dd, J=8.3, 6.6 Hz, 2H), 0.16 (ddd, J=9.2, 2.7, 1.7 Hz, 1H), 8.62 (d, J=2.7 Hz, 1H), 8.95 (t, J=1.5 Hz, 1H) ppm; MS (DCI/NH3) m/z 295 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:25]=[C:24]3[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]4[S:23][CH2:22][C:16]5([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]5)[O:15][C:14]=43)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:28]([C:32]1[CH:42]=[CH:41][C:35]([O:36][CH2:37][C@@H:38]2[CH2:40][O:39]2)=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([C:32]1[CH:42]=[CH:41][C:35]([O:36][CH2:37][C@@H:38]([OH:39])[CH2:40][N:19]2[CH2:18][CH2:17][C:16]3([O:15][C:14]4[C:24]5[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]=4[S:23][CH2:22]3)=[CH:9][CH:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:25]=5)[CH2:21][CH2:20]2)=[CH:34][CH:33]=1)([CH3:29])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccc(N3CCOCC3)cc2C2=C1SCC1(CCNCC1)O2
Product: CC(C)(C)c1ccc(OC[C@@H](O)CN2CCC3(CC2)CSC2=C(O3)c3cc(N4CCOCC4)ccc3C(=O)C2=O)cc1

Procedure:
Compound 214 was synthesized using 9-morpholin-4-ylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-tert-butylphenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=107-109° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.74 (d, J=8.0 Hz, 1H), 7.25 (d, J=8.8 Hz, 2H), 7.18 (brs, 1H), 7.0 (d, J=8.8 Hz, 1H), 6.83 (d, J=8.4 Hz, 2H), 4.85 (brs, 1H), 3.91 (m, 2H), 3.82 (m, 1H), 3.74 (m, 4H), 3.43 (m, 4H), 3.05 (s, 2H), 2.76 (m, 2H), 2.43 (m, 4H), 1.97 (m, 2H), 1.78 (m, 2H), 1.22 (s, 9H); LCMS: 593 [M+H].
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][C:14]2[C:10](=[CH:11][N:12]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][C:18]=3[F:25])[N:13]=2)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>ClCCl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH2:1]([C:8]1[CH:16]=[CH:15][C:14]2[C:10](=[CH:11][N:12]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][C:18]=3[F:25])[N:13]=2)[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(-n2cc3cc(Cc4ccccc4)ccc3n2)c(F)c1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=Cc1ccc(-n2cc3cc(Cc4ccccc4)ccc3n2)c(F)c1
Reaction time: 8 h

Procedure:
To a mixture of (4-(5-benzyl-2H-indazol-2-yl)-3-fluorophenyl)methanol (100 mg, 0.30 mmol), 4-methylmorpholine N-oxide (43 mg, 0.36 mmol) and activated molecular sieves (200 mg) in dichloromethane (10 mL) was added TPAP (10.6 mg, 0.03 mmol) at room temperature. After stirred overnight, the reaction mixture was filtered, concentrated and purified by silica gel column chromatography (hexane/ethyl acetate) to give 4-(5-benzyl-2H-indazol-2-yl)-3-fluorobenzaldehyde as white solid: 1H NMR (400 MHz, CD3OD) δ 10.0 (d, J=1.6 Hz, 1H), 8.55 (m, 1H), 8.41 (t, J=7.4 Hz, 1H), 7.84 (m, 2H), 7.68 (d, J=9.0 Hz, 1H), 7.46 (s, 1H), 7.34-7.30 (m, 2H), 7.27-7.19 (m, 4H), 4.06 (s, 2H); 19F NMR (376 MHz, CD3OD) δ −122.3. MS (ESI) m/z: Calculated: 330.36; Observed: 331.2 (M++1).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19]>>[CH2:1]([S:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:18](=[O:19])[N:17]([CH3:16])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCSc1ccc(O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CCCCCCCSc1ccc(OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title compound was prepared from 4-heptylsulfanyl-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (74%, colourless oil, HPLC-MS m/z=358.2 (M+1), Rt: 6.21 min.