Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([CH3:12])[N:5]=1)=[C:2]=S.C(N(CC)CC)C.Cl.Cl.[NH2:22][CH2:23][C:24]1([OH:32])[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1.C(N=C=NC(C)C)(C)C>CN(C)C=O>[N:26]12[CH2:31][CH2:30][CH:29]([CH2:28][CH2:27]1)[C@@:24]1([O:32][C:2]([NH:1][C:4]3[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([CH3:12])[N:5]=3)=[N:22][CH2:23]1)[CH2:25]2
Reactant: NCC1(O)CN2CCC1CC2
Reactant: Cc1nc(N=C=S)ccc1C#N
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(NC2=NC[C@@]3(CN4CCC3CC4)O2)ccc1C#N
Temperature: 70 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
To 6-isothiocyanato-2-methylnicotinonitrile (0.25 g, 1.43 mmol) in N,N-dimethylformamide (20 mL) was added triethylamine (0.5 mL, 3.666 mmol) and 3-(aminomethyl)quinuclidin-3-ol dihydrochloride (0.33 g, 1.46 mmol) at room temperature. The reaction was stirred at 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude urea was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH). The product was then treated with N,N-dimethylformamide (20 mL) and N,N′-diisopropylcarbodiimide (0.67 mL, 4.28 mmol). The reaction was heated to 70° C. for 2 hours. The reaction was cooled to room temperature and concentrated in vacuo to yield the crude product. The crude product was purified by chromatography (Biotage: 85% CHCl3, 14% MeOH, 1% NH4OH) to yield (R)-6-(4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]-2-ylamino)-2-methylnicotinonitrile (0.09 g, 0.3 mmol, 21% yield) as a white powder. 1H NMR (500 MHz, DMSO-D6) δ ppm 9.11 (s, 1 H), 7.87 (d, J=7.93 Hz, 2 H), 6.69 (s, 1 H), 3.89 (d, J=10.38 Hz, 2 H), 3.63 (d, J=10.38 Hz, 3 H), 3.00 (s, 5 H), 2.72-2.80 (m, 4 H), 2.64-2.69 (m, 5 H), 2.60 (s, 7 H), 2.00 (d, J=2.14 Hz, 3 H), 1.91 (s, 1 H), 1.87 (s, 2 H), 1.58 (s, 5 H), 1.42-1.50 (m, 2 H). MS (LC/MS) R.T.=0.48; [M+H]+=298.13.
Reaction SMILES: [OH:1][CH:2]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:3][CH2:4][C@@H:5]1[C@@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8](=[O:21])[CH2:7][CH2:6]1.C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:45](O)[CH2:46][OH:47]>O>[CH2:45]1[CH2:46][O:47][CH:7]2[CH:8]([C@@H:9]([C@@H:5]([CH2:4][CH2:3][CH:2]([OH:1])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:6]2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:21]1
Reactant: OCCO
Reactant: CCCCCC(O)CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCC(O)CC[C@H]1CC2OCCOC2[C@@H]1CCCCCCC(=O)OCC

Procedure:
A solution of 3.4 g. of ethyl 15-hydroxy-9-oxo-prostanoate (Example 50) in 85 ml. of benzene containing 30 mg. of p-toluenesulfonic acid monohydrate and 2 ml. of ethylene glycol is stirred at the reflux temperature for 18 hours. The water formed is removed by means of a Dean-Stark distilling receiver. The cooled solution is washed with 5% aqueous sodium carbonate solution, saturated sodium chloride solution, dried with anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give 3.78 g. (99%) of oil; λ max. 2.93 (hydroxy group) and 5.77 μ (ester carbonyl group).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:9])=[C:6]([CH3:8])[CH:7]=1.O[CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].S(=O)(=O)(O)O.O>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([I:9])=[CH:4][C:3]=1[CH2:11][N:12]1[C:16](=[O:17])[C:15]2[C:14](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]1=[O:22]
Reactant: O=C1c2ccccc2C(=O)N1CO
Reactant: Cc1cc(Br)ccc1I
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1cc(Br)c(CN2C(=O)c3ccccc3C2=O)cc1I
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 5-bromo-2-iodo toluene (512 mg, 1.72 mmol) in trifluoroacetic acid (5 mL) was added N-(hydroxymethy) phthalimide (305 mg, 1.72 mmol). The mixture developed a pink color. The solution was stirred at room temperature for 22 hours then concentrated sulfuric acid (1 mL) was added. The homogeneous solution was stirred for 18 hours at room temperature. Water was added and the precipitated solid collected by filtration and dried in a current of air (0.776 gm). This material, which by proton NMR analysis contained approximately 15% of an isomeric product, was carried forward to the following procedure without further purification. 1H NMR (400 MHz, CDCl3) δ7.85 (m, 2H) 7.76(m, 2H) 7.5 (s, 1H) 7.38(s, 1H) 4.84(s, 2H) 2.31(s, 3H).
Reaction SMILES: [Si]([O:8][CH:9]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:23]2[CH:36]=[CH:35][C:26]([CH2:27][NH:28][CH2:29][CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])=[C:25]([CH3:37])[CH:24]=2)([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:14][C:13]=1[CH3:38])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[CH2:19]([C:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:10][CH:9]([OH:8])[C:39]([CH3:40])([CH3:42])[CH3:41])=[C:13]([CH3:38])[CH:14]=1)([C:23]1[CH:36]=[CH:35][C:26]([CH2:27][NH:28][CH2:29][CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])=[C:25]([CH3:37])[CH:24]=1)[CH2:21][CH3:22])[CH3:20]
Reactant: CCC(CC)(c1ccc(CNCCS(C)(=O)=O)c(C)c1)c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(CNCCS(C)(=O)=O)c(C)c1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Temperature: 25 °C
Yield: 79.4 %

Procedure:
To a mixture of [4-(1-{4-[2-(t-butyldimethylsilanyloxy)-3,3-dimethylbutoxy]-3-methylphenyl}-1-ethylpropyl)-2-methylbenzyl]-(2-methanesulfonylethyl)amine (1.47 g, 2.43 mmol) in THF (30 mL) is added 1M TBAF (2.7 mL, 2.7 mmol), and refluxed for 2 h. After cooling to RT, the mixture is diluted with H2O (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layers are MgSO4 dried, concentrated, and chromatographed (80% EtOAc/Hex) to give the title compound (0.97 g, 1.93 mmol, 79%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:18])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.CO[C:25](OC)([N:27]([CH3:29])[CH3:28])[CH3:26]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([N:18]=[C:25]([N:27]([CH3:29])[CH3:28])[CH3:26])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: COC(C)(OC)N(C)C
Solvent: CN(C)C=O
Product: CC(=NC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2)N(C)C
Reaction time: 2.5 h

Procedure:
19 g (60 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamide are suspended in 110 ml of N,N-dimethylformamide, whereupon the suspension is treated with 17 ml (116 mmol) of N,N-dimethylacetamide dimethyl acetal and the mixture is stirred at 115° for 2.5 hours. The mixture is then cooled to 0°, the product is filtered off under suction, rinsed with N,N-dimethylformamide and diethyl ether and dried at 80° in a high vacuum. There is obtained (S)-8-chloro-N-[1-(dimethylamino)ethylidene]-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamide of decomposition point 289°-291°.
Reaction SMILES: C(N(CC1C=CC=CC=1)C1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](C)[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)CCOC1)C1C=CC=CC=1.[O:47]1[CH2:50][C:49](CN)([CH2:51][NH2:52])[CH2:48]1>>[NH2:52][CH2:51][C:49]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:38])(=[O:39])[CH2:29][CH2:28]3)[CH:17]=2)[CH2:50][O:47][CH2:48]1
Reactant: NCC1(CN)COC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N(Cc4ccccc4)Cc4ccccc4)CCOC3)c2c1
Product: NCC1(CNc2cc(N3CCS(=O)(=O)c4ccccc4C3)nc3ccccc23)COC1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,4-dichloroquinoline and 2,3,4,5-tetrahydro-1,4-benzothiazepine) and oxetane-3,3-diyldimethanamine. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.32 (d, J=2.1 Hz, 1 H), 8.11 (t, J=2.0 Hz, 1 H), 8.04 (d, J=1.9 Hz, 1 H), 7.93 (d, J=2.0 Hz, 1 H), 7.77 (m, J=8.3 Hz, 2 H), 7.63 (t, J=3.7 Hz, 1 H), 7.53 (d, J=3.8 Hz, 1 H), 6.30 (s, 1 H), 5.45 (s, 2 H), 4.65 (m, J=5.5 Hz, 6 H), 4.01 (s, 2 H), 3.83 (t, J=2.4 Hz, 2 H), 3.51 (s, 2 H).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:31])[NH:9][C:10]2[CH:30]=[CH:29][C:13]([C:14]([N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>ClCCl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[C:1]1([NH:7][C:8]([NH:9][C:10]2[CH:30]=[CH:29][C:13]([C:14]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])=[CH:12][CH:11]=2)=[O:31])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(NC(=O)Nc3ccccc3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccccc1)Nc1ccc(C(=O)N2CCNCC2)cc1
Reaction time: 8 h

Procedure:
tert-Butyl 4-(4-(3-phenylureido)benzoyl)piperazine-1-carboxylate (15.0 g, 35.34 mmol) was stirred with 50% trifluoroacetic acid in dichloromethane (200 ml) at room temperature for 1 hour. The reaction was concentrated under vacuum and then dryed overnight on high vacuum to afford the title compound (15.5 g). MS (ESI) m/z 325.0 [M+H]+
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[Cl-].[Mg+2].[Cl-].S(Cl)(Cl)=O.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28](O)=[O:29])=[CH:22][C:21]=1[O:31][CH3:32]>O.CN(C)C=O>[CH3:32][O:31][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][C:20]=1[O:19][CH3:18])[CH:26]=[CH:27][C:28]([NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:10])=[O:9])=[O:29]
Reactant: Nc1ccccc1C(=O)O
Reactant: COc1ccc(/C=C/C(=O)O)cc1OC
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C=CC(=O)Nc2ccccc2C(=O)O)cc1OC
Temperature: 25 °C
Yield: 75.8 %

Procedure:
Into 15 ml of dimethylformamide were dissolved with heating 2.06 g (0.015 mol) of anthranilic acid and 2.7 g of magnesium chloride (anhydrous), and the resulting solution was cooled to room temperature. To 10 ml of dimethylformamide were added in order 0.78 ml of thionyl chloride and 2.08 g (0.01 mol) of 3',4'-dimethoxycinnamic acid, during which the reaction system was stirred and cooled with ice and water. After being stirred for additional 15 minutes, the resulting mixture was added dropwise to the above solution, with stirring at room temperature. After the completion of the dropping. the reaction mixture was stirred for additional 1.5 hours, and then treated in the same manner as in Example 2. There was obtained 2.48 g (yield: 75.8%) of N-(3',4'-dimethoxycinnamoyl)-anthranilic acid. Melting point: 209°-211° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>O1CCCC1>[Br:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])[CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(Br)cc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)Nc1cc(Br)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Methyl 2-amino-4-bromobenzoate (1 g) was dissolve in tetrahydrofuran (15 mL), triethylamine (4.2 mL) and methanesulfonyl chloride (0.74 mL) were added, and the mixture was stirred at room temperature for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform. After evaporation of the solvent, to the residue were added methanol (20 mL) and 1N aqueous sodium hydroxide solution (13 mL), and the mixture was stirred at 50-60° C. The mixture was acidified with 1N hydrochloric acid, and the precipitated solid was collected by filtration to give the title compound (0.964 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([C:9]#[C:10][Si](C)(C)C)=[CH:5][N:4]=1.FC(F)(F)S(O[C:21]1[CH2:22][CH2:23][N:24]([S:27]([CH2:30][C:31]2([CH3:38])[C:35](=[O:36])[NH:34][C:33](=[O:37])[NH:32]2)(=[O:29])=[O:28])[CH2:25][CH:26]=1)(=O)=O>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:38][C@:31]1([CH2:30][S:27]([N:24]2[CH2:23][CH:22]=[C:21]([C:10]#[C:9][C:6]3[CH:5]=[N:4][C:3]([S:2][CH3:1])=[N:8][CH:7]=3)[CH2:26][CH2:25]2)(=[O:29])=[O:28])[NH:32][C:33](=[O:37])[NH:34][C:35]1=[O:36]
Reactant: CC1(CS(=O)(=O)N2CC=C(OS(=O)(=O)C(F)(F)F)CC2)NC(=O)NC1=O
Reactant: CSc1ncc(C#C[Si](C)(C)C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CSc1ncc(C#CC2=CCN(S(=O)(=O)C[C@@]3(C)NC(=O)NC3=O)CC2)cn1
Temperature: 85 °C

Procedure:
The title compound was prepared by the general method described by Nishihara et al., J. Org. Chem., 2000, 65, 1780-1787. To a solution of 2-(methylthio)-5-[(trimethylsilyl)ethynyl]pyrimidine (0.55 g, 2.47 mmol) and 1-{[(4-methyl-2,5-dioxoimidazolidin-4-yl)methyl]sulfonyl}-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate (0.94 g, 2.22 mmol) in DMF (5 mL) was added CuI (10 mol %) and PdCl2(PPh3)2 (5 mol %) and the mixture was heated at 85° C. for 6 hours. The mixture was partitioned between EtOAc (20 mL) and water (10 mL), and the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, water and concentrated to a brown oil (1.6 g). The title compound was obtained as a solid (10 mg) following purification by preparative HPLC (using a Xterra-Prep-MS-C18 (50×19) column with a 12 minutes gradient 5-35% of acetonitrile in water with 0.06% NH3).
Reaction SMILES: [N:1]1([C:8]([C@H:10]2[CH2:14][C@H:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:12][N:11]2[C:23](=[O:25])[CH3:24])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:26][C:27]([CH3:29])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C@@H:13]1[CH2:12][N:11]([C:23](=[O:25])[CH3:24])[C@@H:10]([C:8]([N:1]2[CH2:7][CH2:6][CH2:5][N:4]([CH:27]([CH3:29])[CH3:26])[CH2:3][CH2:2]2)=[O:9])[CH2:14]1
Reactant: CC(=O)N1C[C@@H](Oc2cccc(F)c2)C[C@@H]1C(=O)N1CCCNCC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(=O)N1C[C@@H](Oc2cccc(F)c2)C[C@@H]1C(=O)N1CCCN(C(C)C)CC1
Reaction time: 48 h
Yield: 83.1 %

Procedure:
To a solution of (2R,4S)-1-[2-([1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone (220 mg, 0.63 mmol) in dichloroethane (3 mL) was added acetone (324 μL, 4.41 mmol) and sodium triacetoxyborohydride (199 mg, 0.945 mmol). After 2 days, the reaction mixture was diluted with satd. aq. NaHCO3 and extracted with CH2Cl2 (4×). The combined organic layers were dried and concentrated. Purification of the residue by FCC provided the desired product (205 mg, 83%). MS (ESI): mass calcd. for C21H30FN3O3, 391.23; m/z found, 392.3 [M+H]+. 1H NMR (CDCl3): 7.22 (ddd, J=8.3, 8.3, 6.9 Hz, 1H), 6.69-6.64 (m, 1H), 6.63 (dd, J=8.3, 2.3 Hz, 1H), 6.57 (ddd, J=10.6, 2.2, 2.2 Hz, 1H), 5.09-5.03 (m, 1H), 5.00-4.95 (m, 1H), 4.03 (dd, J=11.1, 4.9 Hz, 1H), 3.74-3.59 (m, 4H), 3.55-3.45 (m, 1H), 2.92-2.78 (m, 1H), 2.75-2.51 (m, 4H), 2.40-2.23 (m, 2H), 2.04 (s, 3H), 2.01-1.92 (m, 1H), 1.85-1.67 (m, 1H), 1.00-0.94 (m, 6H).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[Cl:15][C:16]1[C:24]2[S:23][C:22]([SH:25])=[N:21][C:20]=2[CH:19]=[CH:18][CH:17]=1>>[Cl:15][C:16]1[C:24]2[S:23][C:22]([S:25][CH2:2][C:3]([N:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:8][CH2:7][CH2:6]3)=[O:4])=[N:21][C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: Sc1nc2cccc(Cl)c2s1
Reactant: O=C(CCl)N1CCCc2ccccc21
Product: O=C(CSc1nc2cccc(Cl)c2s1)N1CCCc2ccccc21
Yield: 46 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 7-chlorobenzo[d]thiazole-2-thiol as the nucleophile to yield 26 as a white solid (46%): MS m/z: 375 (M+H)+. Anal. Calcd. For, C18H15ClN2OS2: C, 57.67; H, 4.03; N, 7.47; S, 17.11; Cl, 9.46. Found: C, 57.50; H, 3.99; N, 7.47; S, 17.36; Cl, 9.52.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=O)[NH:3][C:2]1=O.C[Si](C)(C)N[Si](C)(C)C.S(=O)(=O)(O)O.Br[CH2:28][C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33]>C1(C)C=CC=CC=1.O1CCOCC1.CO>[CH3:35][O:34][C:32]([C:31]1[CH:30]=[C:29]([CH:38]=[CH:37][CH:36]=1)[CH2:28][N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[N:3][CH2:2]1)=[O:33]
Reactant: O=c1[nH]c2c(c(=O)[nH]1)CCCC2
Reactant: COC(=O)c1cccc(CBr)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cccc(CN2CN=CC3=C2CCCC3)c1
Temperature: 122.5 °C
Reaction time: 4 h
Yield: 13 %

Procedure:
To a mixture of 5,6,7,8-tetrahydroquinazoline-2,4(1H, 3H)-dione (10.4 g, 62 mmol) and hexamethyldisilazane (HMDS, 33 mL, 158 mmol) in toluene (100 mL) was added concentrated sulfuric acid (0.34 mL, 6.2 mmol) at r.t. The mixture was heated to reflux overnight until a clear solution was obtained. After the removal of toluene and excess HMDS with vacuum evaporation, methyl 3-bromomethylbenzoate (16 g, 70 mmol) was added to the residue. The reaction mixture was heated to 115-130° C. and was stirred at this temperature for 4 h. The reaction mixture was diluted with 1,4-dioxane (6 mL) and methanol (100 mL) at 100° C., and was stirred for 30 min. The reaction mixture was evaporated to remove the solvent. The residue was dissolved in ethyl acetate (EA, 300 mL) and washed by 1N hydrochloric acid (100 mL×1) and water (100 mL×3). The organic layer was dried with anhydrous sodium sulfate and evaporated to give the crude product, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=2:1) to give the title compound (2.3 g, 12% yield) as yellow powder. 1H NMR (DMSO-d6): 11.40 (s, 1H), 7.87 (d, J=7.5 Hz, 1 H), 7.79 (s, 1H), 7.55-7.44 (m, 2H), 5.12 (s, 2H), 3.85 (s, 3H), 2.45-2.35 (m, 2H ), 2.25-2.20 (m, 2H), 1.65-1.40 (m, 4H). MS: m/z 315.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][NH:16][C:15]3=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:21]([NH:29][NH2:30])(=O)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][N:16]4[C:21]([C:22]5[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=5)=[N:29][N:30]=[C:15]34)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCCCC1Cc1noc(-c2cccc(Cl)c2)n1
Reactant: NNC(=O)c1ccncc1
Solvent: ClCCl
Product: Clc1cccc(-c2nc(CC3CCCn4c(-c5ccncc5)nnc43)no2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
37 mg (0.25 mmol) Me3OBF4 was added to a solution of 60 mg (0.21 mmol) 3-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-piperidin-2-one in 2 ml CH2Cl2. The mixture was stirred overnight at room temperature. The reaction mixture was diluted with CH2Cl2, washed with NaHCO3 (sat), dried and concentrated. The residue was dissolved in 3 ml EtOH and 22 mg (0.16 mmol) isonicotinic hydrazide was added. The solution was heated with microwaves at 120° C. for 10 min. The reaction mixture was cooled and the volatiles were removed under reduced pressure. The crude product was purified by preparative HPLC to afford 17 mg (20%) of the desired product. 1H NMR (CDCl3): d ppm 1.75 (m, 1 H) 1.99 (m, 1 H) 2.21 (m, 2 H) 3.16 (dd, 1 H) 3.73 (m, 1 H) 3.85 (dd, 1 H) 4.07 (m, 1 H) 4.19 (m, 1 H) 7.47 (t, 1 H) 7.56 (m, 1 H) 7.67 (m, 2 H) 8.01 (m, 1 H) 8.11 m, 1 H) 8.76 (d, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:18])/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.[CH2:20]([NH:27][OH:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH2:20]([N:27]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:10][C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])([OH:18])[O:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(/C=C/c1ccccc1)c1cc(F)ccc1F
Reactant: ONCc1ccccc1
Agent: Cl
Solvent: CCO
Product: OC1(c2cc(F)ccc2F)CC(c2ccccc2)N(Cc2ccccc2)O1

Procedure:
A mixture of (2E)-1-(2,5-difluorophenyl)-3-phenylprop-2-en-1-one (1-1) (500 mg, 2.05 mmol, 1 equiv) and N-benzylhydroxylamine hydrochloride (327 mg, 2.05 mmol, 1.00 equiv) was heated at reflux in ethanol (10 mL) for 4 h. Additional N-benzylhydroxylamine hydrochloride (327 mg, 2.05 mmol, 1.00 equiv) was added and the mixture was heated at reflux for 16 h. The reaction mixture was partitioned between saturated sodium bicarbonate solution (50 mL) and ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (silica, 100% hexanes initially, grading to 100% EtOAc) to give 2-benzyl-5-(2,5-difluorophenyl)-3-phenylisoxazolidin-5-ol (1-2); LRMS m/z (M+H) 368.3 found, 368.1 required. Methanesulfonyl chloride (0.093 uL, 1.20 mmol, 1.11 equiv) was added to a solution of (1-2) (400 mg, 1.09 mmol, 1 equiv) and triethylamine (0.455 mL, 3.27 mmol, 3.00 equiv) in dichloromethane (30 mL) at 0° C. and the resultant mixture was warmed to 23° C. and stirred for 30 min. The reaction mixture was partitioned between saturated sodium bicarbonate solution (50 mL) and dichloromethane (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (silica, 100% hexanes initially, grading to 100% EtOAc) to give 2-benzyl-5-(2,5-difluorophenyl)-3-phenyl-2,3-dihydroisoxazole (1-3) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.46-7.21 (m, 11H), 7.02 (m, 2H), 5.76 (t, 1H, J=3.0 Hz), 5.12 (d, 11H, J=2.8 Hz), 4.41 (d, 1H, J=12.8 Hz), 4.10 (d, 1H, J=12.8 Hz). LRMS m/z (M+H) 350.3 found, 350.1 required.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([N:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)[N:14]=[C:15](Cl)[CH:16]=[C:11]2[C:10]([CH3:28])=[C:9]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH-:30].[Na+].O>CO>[CH2:1]([N:8]1[C:12]2=[C:13]([N:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)[N:14]=[C:15]([SH:30])[CH:16]=[C:11]2[C:10]([CH3:28])=[C:9]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [SH-]
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)nc(Cl)cc12
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(C)n(Cc2ccccc2)c2c(N3CCc4ccccc4C3)nc(S)cc12
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
A solution of 2-(1-benzyl-5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.24 mmol) prepared in Example 658 and sodium hydrosulfide (26.7 mg, 0.48 mmol) in methanol (2 ml) was refluxed for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. Water was added to the resulting solid. The reaction mixture was stirred for 30 minutes and then filtered. The resulting solid washed with water 3 times and then dried to give 68 mg of the titled compound as a pale yellow solid.