Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:48])[CH2:38][C:39]1[CH:40]=[N:41][C:42]([O:46][CH3:47])=[C:43](Br)[CH:44]=1)[CH3:35]>>[CH2:34]([O:36][C:37](=[O:48])[CH2:38][C:39]1[CH:40]=[N:41][C:42]([O:46][CH3:47])=[C:43]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:12]=2[CH2:11][N:10]([CH2:31][CH3:32])[C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:33])[CH:44]=1)[CH3:35]
Reactant: CCOC(=O)Cc1cnc(OC)c(Br)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)NCc1ccccc1
Product: CCOC(=O)Cc1cnc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)NCc2ccccc2)c1

Procedure:
3-Benzyl-1-ethyl-1-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-urea and (5-bromo-6-methoxy-pyridin-3-yl)-acetic acid ethyl ester were reacted as described in Example 11, Step 4 to provide {5-[2-(3-benzyl-1-ethyl-ureidomethyl)-4-trifluoromethyl-phenyl]-6-methoxy-pyridin-3-yl}-acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:14]=[C:13]([C:15]2[C:20]([O:21][CH2:22][CH:23]([CH3:26])[CH2:24]C)=[CH:19][CH:18]=[CH:17][C:16]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH:12]=[C:11]([C:37]2[CH:42]=[CH:41][C:40]([NH2:43])=[C:39]([OH:44])[CH:38]=2)[C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:45](OC(=O)C)(=[O:47])[CH3:46]>C(OCC)(=O)C>[C:45]([NH:43][C:40]1[CH:41]=[CH:42][C:37]([C:11]2[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5])=[C:2]([NH2:1])[N:14]=[C:13]([C:15]3[C:16]([O:27][CH2:28][C:29]4[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)=[CH:17][CH:18]=[CH:19][C:20]=3[O:21][CH2:22][CH:23]3[CH2:26][CH2:24]3)[CH:12]=2)=[CH:38][C:39]=1[OH:44])(=[O:47])[CH3:46]
Reactant: CCC(C)COc1cccc(OCc2ccc(OC)cc2)c1-c1cc(-c2ccc(N)c(O)c2)c(C(=O)OC(C)(C)C)c(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(COc2cccc(OCC3CC3)c2-c2cc(-c3ccc(NC(C)=O)c(O)c3)c(C(=O)OC(C)(C)C)c(N)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 2-amino-4-(4-amino-3-hydroxyphenyl)-6-[2-[(4-methoxybenzyl)oxy]-6-(2-methylbutoxy)phenyl]nicotinate (2.46 g, 4.21 mmol) was added acetic anhydride (0.44 mL, 4.63 mmol). The mixture was stirred at room temperature for overnight. The mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl 4-[4-(acetylamino)-3-hydroxyphenyl]-2-amino-6-{2-(cyclopropylmethoxy)-6-[(4-methoxybenzyl)oxy]phenyl}nicotinate. (2.65 g, 100%); LC-MS (M/z=626, M+1)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=3)[C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:16])[CH:8]=[CH:7][C:5]=2[N:6]=1.C([O:34][CH2:35][C:36](Cl)=[O:37])(=O)C.O>CN(C)C=O>[C:35]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([CH:28]=[CH:29][CH:30]=3)[C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:25])[F:26])[CH:19]=3)=[O:16])[CH:8]=[CH:7][C:5]=2[N:6]=1)(=[O:34])[CH2:36][OH:37]
Reactant: Nc1nc2ccc(Oc3cccc(C(=O)Nc4cccc(C(F)(F)F)c4)c3)cc2s1
Reactant: CC(=O)OCC(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CO)Nc1nc2ccc(Oc3cccc(C(=O)Nc4cccc(C(F)(F)F)c4)c3)cc2s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.5 %

Procedure:
A solution of 3-[(2-amino-1,3-benzothiazol-6-yl)oxy]-N-[3-(trifluoromethyl)phenyl]benzamide (429 mg, 1.0 mmol) produced in Example A29(v) and 2-chloro-2-oxoethyl acetate (546 mg, 4.0 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 6 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (5 mL)/tetrahydrofuran (5 mL), 8N aqueous sodium hydroxide solution (1 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (eluent:hexane/ethyl acetate=1:1), and triturated with diethyl ether to give the title compound (300 mg, 62%) as a pale-yellow solid.
Reaction SMILES: C([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]([NH:20][N:21]([CH3:23])[CH3:22])=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH: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]([NH:20][N:21]([CH3:23])[CH3:22])=[O:19]
Reactant: CN(C)NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CN(C)NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O
Reaction time: 1 h
Yield: 95.5 %

Procedure:
A mixture of (2S,5R)-6-(benzyloxy)-N′,N′-dimethyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 232 (0.25 g, 0.78 mmol) and Pd/C (0.30 g) in methanol (80 mL) was hydrogenated at 1 atm at room temperature for 1 h. The mixture was filtered through Celite pad and concentrated to provide 233 (0.17 g) as a white foam which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]2[N:10]=[C:9]([C:11]3[N:15]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)[N:14]=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)[O:8][C:7](=[O:27])[C:6]=2[CH:28]=1.[NH2:30][CH2:31][CH:32]1[CH2:35][CH2:34][O:33]1>O1CCCC1>[Cl:1][C:2]1[CH:28]=[C:6]([C:7]([NH:30][CH2:31][CH:32]2[CH2:35][CH2:34][O:33]2)=[O:27])[C:5]([NH:10][C:9]([C:11]2[N:15]([C:16]3[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[N:14]=[C:13]([C:23]([F:25])([F:24])[F:26])[CH:12]=2)=[O:8])=[C:4]([CH3:29])[CH:3]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: NCC1CCO1
Solvent: C1CCOC1
Product: Cc1cc(Cl)cc(C(=O)NCC2CCO2)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 25 °C
Yield: 71 %

Procedure:
To a solution of 6-chloro-2-[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-8-methyl-4H-3,1-benzoxazin-4-one (200 mg, 0.45 mmol) (prepared according to WO 02/48115, example 2D) in tetrahydrofurane (4 ml), is added 2-aminomethyloxetane (the product of step 2) (79 mg, 0.91 mmol), and the mixture is heated to reflux for 30 minutes. The solution is allowed to cool to ambient temperature and the solvent evaporated in vacuo. The residue is purified by prep. HPLC (hexane/ethyl acetate gradient on LiChrospher Si 60, Merck NW25 column) to afford 180 mg (71%) of the title compound as a white solid. [1H-NMR (CDCl3): 10.21 (s, 1H), 8.48 (d, 1H), 7.88 (d, 1H), 7.41 (m, 1H), 7.32 (s, 1H), 7.29 (m, 2H), 6.63 (m, 1H), 4.98 (m, 1H), 4.68 (m, 1H), 4.48 (m, 1H), 3.71 (m, 1H), 3.59 (m, 1H), 2.68 (m, 1H), 2.43 (m, 1H), 2.19 (s, 3H); MS (electrospray ES+): 528, 530 ((M+H)+)].
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH:48]C(OC(C)(C)C)=O)[C:26](=[O:47])[NH:27][C@H:28]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[C:32]([C:44](=[O:46])[NH2:45])[CH:31]=2)[CH3:29])=[CH:20][CH:19]=1)[P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:13]([O:12][P:10]([CH:9]([C:18]1[CH:19]=[CH:20][C:21]([CH2:24][C@H:25]([NH2:48])[C:26](=[O:47])[NH:27][C@H:28]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]3)=[C:32]([C:44](=[O:46])[NH2:45])[CH:31]=2)[CH3:29])=[CH:22][CH:23]=1)[P:4]([O:5][CH2:6][CH3:7])([O:3][CH2:1][CH3:2])=[O:8])(=[O:11])[O:15][CH2:16][CH3:17])[CH3:14]
Reactant: CCOP(=O)(OCC)C(c1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)c2ccc(OCC3CCCCC3)c(C(N)=O)c2)cc1)P(=O)(OCC)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(OCC)C(c1ccc(C[C@H](N)C(=O)N[C@@H](C)c2ccc(OCC3CCCCC3)c(C(N)=O)c2)cc1)P(=O)(OCC)OCC
Reaction time: 0.33 h
Yield: 65.7 %

Procedure:
To [(4-{(S)-2-tert-Butoxycarbonylamino-2-[(S)-1-(3-carbamoyl-4-cyclohexylmethoxy-phenyl)-ethylcarbamoyl]-ethyl}-phenyl)-(diethoxy-phosphoryl)-methyl]-phosphonic acid diethyl ester (2.8 g, 3.5 mmol) in methylene chloride (20 mL) was added TFA (6 mL). The mixture was stirred for 20 min., evaporated to dryness, and dissolved in DMSO (30 mL). Purification by RP HPLC (CH3CN/H2O) and lyophylization yielded a white solid (1.9 g, 2.3 mmol, 66%). MS [M+H]+ 710.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2([N:18]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17][O:16][CH2:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:33])[CH:8]=2)[N:3]=1.[S:34]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[CH2:38][NH:37][CH2:36][CH2:35]1.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH2:19]([N:18]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1([CH2:13][NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:33])[CH:8]=3)[N:3]=[C:2]([N:37]3[CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[S:34][CH2:35][CH2:36]3)[N:11]=2)[CH2:17][O:16][CH2:15]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc2nc(Cl)nc(NCC3(N(Cc4ccccc4)Cc4ccccc4)COC3)c2c1
Reactant: c1ccc2c(c1)CNCCS2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc2nc(N3CCSc4ccccc4C3)nc(NCC3(N(Cc4ccccc4)Cc4ccccc4)COC3)c2c1
Temperature: 150 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
A mixture of (2-chloro-6-methylquinazolin-4-yl)-[3-(dibenzylamino)oxetan-3-ylmethyl]-amine (2 g, 4.4 mmol, prepared in analogy to N-(3-aminooxetan-3-ylmethyl)-2-chloro-6-methylquinazolin-4-amine in Example 55-1), 2,3,4,5-tetrahydro-1,4-benzothiazepine (720 mg, 4.4 mmol), triethylamine (1.2 mL, 8.6 mmol) in N,N-dimethylformamide (20 mL) was heated with stirring in a 30 mL of microwave process vial for 2 hours at 150° C. The reaction mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 1.7 g of the product as a white solid.
Reaction SMILES: [Si]([O:8][C:9]1[CH:29]=[CH:28][C:12]([CH2:13][CH2:14][N:15]2[C:20](=[O:21])[CH:19]=[CH:18][C:17]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16]2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.C1C=CN=CC=1.F>C(#N)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH2:14][N:15]2[C:20](=[O:21])[CH:19]=[CH:18][C:17]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:16]2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CCn2nc(-c3ccccc3)ccc2=O)cc1
Agent: F
Solvent: CC#N
Solvent: c1ccncc1
Product: O=c1ccc(-c2ccccc2)nn1CCc1ccc(O)cc1
Reaction time: 18 h

Procedure:
To a stirring solution of 2-(4-(tert-butyldimethylsilyloxy)phenethyl)-6-phenylpyridazin-3(2H)-one (180 mg, 443 μmol) in ACN (3 mL) was added 70% HF-pyridine (0.25 mL) at 23° and stirred for 18 h. Solvents removed under reduced pressure and residue partioned between 9:1 CHCl3/iPrOH (30 mL) and 5% NaHCO3 (15 mL). The aqueous was further extracted with 9:1 CH3Cl/iPrOH (3×20 mL). Combined organics dried over MgSO4 then concentrated to a solid under reduced pressure from toluene. The residue was purified on 40 grams of silica eluting with 0-% EtOAc/CH2Cl2. The isolated solid was recrystallized from ACN (1 mL). MS (ESI pos. ion) m/z (MH+): 293. Calc'd exact mass for C18H16N2O2: 292. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.97 (t, J=7.28 Hz, 2 H) 3.17 (s, 1 H) 4.31 (t, J=7.53 Hz, 2 H) 6.66 (d, J=8.53 Hz, 2 H) 7.02 (t, J=8.28 Hz, 3 H) 7.39-7.54 (m, 3 H) 7.82 (d, J=8.03 Hz, 2 H) 8.01 (d, J=9.54 Hz, 1 H) 9.20 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[N:22]1([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][N:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:25]4[CH2:26][CH2:27][N:22]([C:28]5[C:36]6[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=6)[NH:30][N:29]=5)[CH2:23][CH2:24]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: c1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCN(c2n[nH]c3ccccc23)CC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 3-piperazin-1-yl-1H-indazole (Table No.1, SM 3) in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=488.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][O:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:17]([O:20][CH:21]1[NH:24][C:23](=[O:25])[CH2:22]1)(=[O:19])[CH3:18]>O.C(#N)C.O>[N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][O:9][C:10]([O:12][CH:13]([CH:22]2[CH:21]([O:20][C:17](=[O:19])[CH3:18])[NH:24][C:23]2=[O:25])[CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)OC1CC(=O)N1
Reactant: CCOC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: O
Product: CC(=O)OC1NC(=O)C1C(C)OC(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
Ceric ammonium nitrate (12.1 g) was added to the solution of 1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethane-4-acetoxy-2-azetidinone (6.06 g) in 10% H2O-acetonitrile (90 ml) in portions over 1 hour at room temperature, followed by stirring for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to give an oily residue which was then purified by silica gel chromatography to give 3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-acetoxy-2-azetidinone.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[CH:14]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15]1>C(#N)C>[CH:14]1([NH:19][CH2:2][C:3]([N:5]2[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]2[C:12]#[N:13])=[O:4])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: NC1CCCC1
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.04 g, 0.203 mmol, Example 8D) in acetonitrile (3 mL) at ambient temperature under nitrogen was added cyclopentylamine (0.04 ml, 0.406 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was flash chromatographed with 3% MeOH/CH2Cl2 to provide the desired compound as a pale yellow oil. MS (DCI) m/z 246 (M+H)+; 1H NMR (300 MHz, DMSO) δ 1.5-2 (8H, m), 2.11-2.21 (2H, m), 2.45-2.48 (2H, m), 3.78 (1H, d), 3.8-4.5 (2H, m), 4.53-4.55 (1H, t), 5.01 (1H, m), 5.05 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([NH2:14])[NH:11][N:10]=2)=[CH:5][CH:4]=1.[CH:15]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1)=O.[Sn](CCCC)(CCCC)(Cl)Cl.C1([SiH3])C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([NH:14][CH2:15][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(N)[nH]n2)cn1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CNc2cc(-c3ccc(OC)nc3)n[nH]2)cc1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
A solution of amine 383 (720 mg, 3.79 mmol), methyl 4-formylbenzoate (745 mg, 4.54 mmol), and Bu2SnCl2 (230 mg, 0.76 mmol) in dry THF (5 mL) was stirred at room temperature for 2 hours. It was then treated with PhSiH3 (514 μL, 451 mg, 4.17 mmol) and allowed to stir for another hour at room temperature. The reaction mixture was quenched by addition of MeOH and vigorous stirring for 45 min. It was then concentrated in vacuo and the residue was purified by flash chromatography using the gradient 50-100% EtOAc in hexane to afford the title compound (672 mg, 52% yield). LRMS: (calc) 338.1; (found) 339.2 (M+H1)
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:17][C:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)=[N:15][N:14]=1.[C:27](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:27][N:23]1[C:24]2[C:20](=[CH:19][C:18]([C:16]3[O:17][C:13]([C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])=[N:14][N:15]=3)=[CH:26][CH:25]=2)[CH:21]=[CH:22]1
Reactant: O=C([O-])[O-]
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc3[nH]ccc3c2)o1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc3c(ccn3C)c2)o1
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.7 %

Procedure:
To a solution of 5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-1H-indole (150 mg, 0.44 mmol) in DMF (2 mL) was added potassium carbonate (121 mg, 0.88 mmol) and iodomethane (0.04 ml, 0.66 mmol) and the reaction mixture was stirred for 3 d in a closed round bottomed flask at ambient temperature. The mixture was extracted with water (20 ml) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with aqueous sodium carbonate (half saturated, 20 mL) and brine (20 mL). Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20) afforded the title compound (136 mg, 87%) as a white solid. MS: m/e=357.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[S:7]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CCC>O>[S:4]1[CH:5]=[CH:6][C:2]([C:9]2[CH:10]=[CH:11][S:7][CH:8]=2)=[CH:3]1
Reactant: OB(O)c1ccsc1
Reactant: Brc1ccsc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: c1cc(-c2ccsc2)cs1
Temperature: 100 °C
Yield: 98 %

Procedure:
Into a glass reaction vessel equipped with a cooling apparatus were added 0.015 mmol of bis(dicyclopentyl(2-methoxyphenyl)phosphine)dichloropalladium(II), 1.5 mmol of 3-bromothiophene, 2.25 mmol of 3-thiopheneboronic acid, 3.0 mmol of potassium phosphate and 4 mL of n-butanol. The resultant mixture was stirred with heating at 100° C. for 4 hours. The resultant reaction mixture was cooled down to room temperature, 20 mL of water was added, and the mixture was extracted with 20 mL of diethyl ether twice. The resultant organic layers were mixed, and dried over anhydrous magnesium sulfate, then, filtrated, to obtain a solution. This solution was concentrated, and purified by silica gel column chromatography, to obtain 3-(3-thienyl)-thiophene with a yield of 98%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7].Cl.[C:30](OC(=O)C)(=[O:32])[CH3:31].C(=O)(O)[O-].[Na+]>C1COCC1.O.C(N(CC)CC)C>[C:30]([N:21]1[CH2:20][CH2:19][CH:18]([C:17]2[C:11]3[S:10][C:9]([NH:8][C:6](=[O:7])[C:5]4[CH:26]=[CH:27][N:28]=[C:3]([O:2][CH3:1])[CH:4]=4)=[N:13][C:12]=3[C:14]([O:24][CH3:25])=[CH:15][CH:16]=2)[CH2:23][CH2:22]1)(=[O:32])[CH3:31]
Reactant: COc1cc(C(=O)Nc2nc3c(OC)ccc(C4CCNCC4)c3s2)ccn1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(C(=O)Nc2nc3c(OC)ccc(C4CCN(C(C)=O)CC4)c3s2)ccn1
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of 0.07 g (0.16 mMol) 2-methoxy-N-(4-methoxy-7-piperidin-4-yl-benzothiazol-2-yl)-isonicotinamide 1:2 hydrochloride in 4 ml THF were added 0.049 ml triethyl amine. At 0° C. 0.018 ml (0.11 mMol) acetic anhydride was added dropwise and stirred for 1 h. Then a mixture of 5 ml sat. aqueous sodium bicarbonate and 10 ml water were added. This was extracted three times with 15 ml ethyl acetate, the combined organic phases were dried over sodium sulfate and evaporated to dryness in vacuo. One obtained 0.036 g (51%) N-[7-(1-acetyl-piperidin-4-yl)-4-methoxy-benzothiazol-2-yl]-2-methoxy-isonicotinamide as a white solid. F.p.: 242-244° C.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:6]=1[C:7]([OH:9])=[O:8]>C(Cl)(Cl)Cl.O1CCOCC1>[Br:1][C:13]1[C:5]([O:4][CH3:3])=[C:6]([C:10]([O:14][CH3:15])=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: COc1cccc(OC)c1C(=O)O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1ccc(Br)c(OC)c1C(=O)O
Reaction time: 8 h

Procedure:
A solution of 15 ml of bromine (0.3 mol) in 50 ml of chloroform is added dropwise while stirring and cooling in ice to 54.9 g (0.3 mol) of 2,6-dimethoxybenzoic acid in 150 ml of dioxan. The solution is left at room temperature overnight. The solvent is evaporated and the residue recrystallized from aqueous ethanol. Yield: 59.3 g, m.p. 144°-45° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]12[CH2:16][CH:15]1[CH:14]([OH:17])[CH2:13][CH2:12]2.N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]12[CH2:16][CH:15]1[C:14](=[O:17])[CH2:13][CH2:12]2
Reactant: OC1CCC2(c3ccc4ccccc4c3)CC12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: O=C1CCC2(c3ccc4ccccc4c3)CC12
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
A solution of 5-(naphthalen-2-yl)bicyclo[3.1.0]hexan-2-ol (2.35 g, 10.5 mmol) in dichloromethane (110 mL) was treated with pyridine (1.18 mL, 14.6 mmol, 1.4 eq.) followed by Dess-Martin periodinane (5.34 g, 12.6 mmol, 1.2 eq.) and warmed to ambient temperature. After 2 h, 3 drops of water were added. After 0.5 h, the reaction was quenched with saturated sodium hydrogen carbonate (50 mL), saturated sodium sulphite (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic extracts was dried over magnesium sulphate and concentrated in vacuo. Purification by silica gel chromatography using 1:6 ethyl acetate/petrol as the eluting solvent afforded the desired compound (1.44 g, 62%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.56-1.58 (1H, m, CH), 1.71-1.75 (1H, m, CH), 2.22-2.25 (1H, m, CH), 2.30-2.34 (2H, m, CH2), 2.44-2.57 (2H, m CH2), 7.34 (1H, dd, J 1.9, 8.5, ArH), 7.44-7.51 (2H, m, ArH), 7.72-7.73 (1H, m, ArH), 7.80-7.83 (3H, m, ArH).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]=1[C:21]([F:24])([F:23])[F:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][C:11]=2[C:21]([F:22])([F:24])[F:23])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1ccc(CBr)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(CN2CCN(C)CC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-methylpiperazine (600 mg, 1.5 mmol), ethyl 4-(bromomethyl)-3-(trifluoromethyl)benzoate (310 mg, 1.0 mmol), and potassium carbonate (276 mg, 2.0 mmol) in N,N-dimethylformamide (8 mL) were stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried and concentrated to give the product without further purification (600 mg, 72%).