Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=O)[CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29])(=O)[CH3:8].Cl.O=P(Cl)(Cl)[Cl:34]>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:34][C:17]1[C:18]([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])=[C:7]([CH3:8])[C:10]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)c1ccccc1NC(=O)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1c(N2C(=O)c3ccccc3C2=O)c(Cl)nc2ccccc12
Temperature: 60 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
1.4 g (10.4 mmol) of K2CO3 were added to a solution of 2.7 g (6.9 mmol) of N-(2-acetylphenyl)-2-(1,3-dioxoisoindolin-2-yl)-acetamide in DMF (27 ml), and the mixture was heated for 16 h at 60° C. After cooling to RT, the pH was adjusted to 2-3 with 2N hydrochloric acid. The resulting precipitate was filtered off with suction and dried in vacuo at 70° C. 9 ml (97 mmol) of POCl3 were added to the residue. This solution was heated for 2 h at 100° C. and then stirred for 16 h at RT. Toluene was then added and concentration was carried out in vacuo. This procedure was repeated, there being obtained as residue 2.13 g (5.5 mmol, 79%) of 2-(2-chloro-4-methylquinolin-3-yl)isoindoline-1,3-dione, which was reacted further without additional purification.
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=[O:18])[CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CCO.O>[O:1]([CH2:8][CH2:9][N:10]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])[CH:12]=[N:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1cnn(CCOc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)/C=C/c1cnn(CCOc2ccccc2)c1
Temperature: 60 °C
Yield: 90.6 %

Procedure:
To a solution of (E)-ethyl 3-(1-(2-phenoxyethyl)-1H-pyrazol-4-yl)acrylate (0.143 g, 0.5 mmol) in EtOH (6 mL) was added KOH (0.168 g, 3 mmol) in water (2 mL) and the solution was heated at 60° C. for 6 h. The reaction mixture was then evaporated under vacuum and water (10 mL) was added to the residue. This solution was acidified to pH 4 with aqueous 3N HCl and extracted with EtOAc. The organic extracts were washed with water and brine, dried over Na2SO4 and evaporated in vacuo to get the acid (0.117 g, 91%) as a white solid. ES+(M+H)+259
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:29]([O-])([N+]([O-])=O)=[O:30]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:29]=[O:30])[C:5]([N:7]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CC(C)CN(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)CN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 75.9 %

Procedure:
3.4 g of 1-(2-chloroethyl)-3-isobutyl-3-D-glucopyranosylurea are dissoved in a mixture of 70 ml of tetrahydrofuran and 70 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under stirring and ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.8 g of 1-(2-chloroethyl)-1-nitroso-3-isobutyl-3-D-glucopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[C:9]1[N:13]2[CH:14]=[C:15]([O:18][C@H:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:22]([NH2:29])[CH2:21][CH2:20]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.ClC(Cl)(Cl)C[O:33][C:34](=O)[NH:35][C:36]1[N:40]([C:41]2[CH:42]=[N:43][N:44]([CH2:46][CH2:47][O:48][CH:49]3[CH2:54][CH2:53][CH2:52][CH2:51][O:50]3)[CH:45]=2)[N:39]=[C:38]([C:55]([CH3:58])([CH3:57])[CH3:56])[CH:37]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:55]([C:38]1[CH:37]=[C:36]([NH:35][C:34]([NH:29][C@@H:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([N:3]5[C@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][C@@H:4]5[CH3:8])=[N:10][N:11]=4)[CH:14]=3)[CH2:20][CH2:21]2)=[O:33])[N:40]([C:41]2[CH:42]=[N:43][N:44]([CH2:46][CH2:47][O:48][CH:49]3[CH2:54][CH2:53][CH2:52][CH2:51][O:50]3)[CH:45]=2)[N:39]=1)([CH3:58])([CH3:56])[CH3:57]
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cnn(CCOC3CCCCO3)c2)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCOC5CCCCO5)c4)c4ccccc43)cn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A mixture of Intermediate 96c (200 mg, 0.51 mmol), Intermediate 108b (261 mg, 0.51 mmol) and DIPEA (178 μL, 1.02 mmol) in dioxane (5 mL) was stirred at 80° C. overnight. After cooling, the reaction mixture was partitioned between water and DCM. The aqueous phase 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 1-10% MeOH in DCM to afford the title compound (364 mg, 95%) as a glassy white solid %). LCMS (Method 4): Rt 3.69 min, m/z 751 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.C=O.F[C:17](F)(F)C([O-])=O.C[NH2+]C1C=CC=CC=1.CCOCC>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8](=[CH2:17])[CH2:7][CH2:6]2
Reactant: O=C([O-])C(F)(F)F
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: C=O
Agent: C[NH2+]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C1CCc2cc(OC)ccc2C1=O

Procedure:
A mixture of 6-methoxytetralone (29.24 g, 165.9 mmol), paraformaldehyde (22.4 g, 746.6 mmol) and N-methylanilinium trifluoroactate (55 g, 248.9 mmol) in 250 mL THF was refluxed for 4 hours and allowed to come to room temperature. To this was added ether (250 mL) with stirring and the mixture was decanted to remove the gummy precipitate. The supernatant was washed with sat. NaHCO3, the oganic layer was dried (MgSO4) and concentrated. The residue was redissolved in ether, filtered through celite and concentrated to afford the title compound as a thick yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([OH:18])[CH:5]=[CH:6][C:7]=1[C:8](=[O:17])[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10].C(O[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=2)=[CH:30][CH:29]=1)CCCCCCC>C(Cl)(Cl)Cl.CCCCCC>[CH2:4]([C:28]1[CH:29]=[CH:30][C:31]([C:34]2[CH:35]=[CH:36][C:37]([C:38]([O:18][C:4]3[CH:5]=[CH:6][C:7]([C:8](=[O:17])[CH:9]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH3:10])=[C:2]([OH:1])[CH:3]=3)=[O:39])=[CH:41][CH:42]=2)=[CH:32][CH:33]=1)[CH2:3][CH2:2][CH2:7][CH2:8][CH2:9][CH2:11][CH3:12]
Reactant: CC(C(=O)c1ccc(O)cc1O)c1ccccc1
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)C(C)c4ccccc4)c(O)c3)cc2)cc1

Procedure:
600 mg (2.5 millimols) of the thus obtained 3-hydroxy-4-(1-oxo-2-phenylpropyl)phenol was reacted with 830 mg (2.4 millimols) of 4-(4'-octyloxyphenyl)benzoic acid chloride, similar to the procedure as described in Preparation Example 2, to obtain 960 mg of a crude product. The crude product was refined through silica gel column chromatography while using a mixed solvent of chloroform/hexane (50/50) as the eluent. The refined product was recrystallized from a mixed solvent of chloroform/ethanol (20/80) to obtain 153 mg of 3-hydroxy-4-(1-oxo-2-phenylpropyl)phenyl 4-(4'-octylphenyl)benzoate.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([CH2:39][CH2:40][C:41]([OH:43])=[O:42])[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].O[C:45]1[CH:46]=[N:47][C:48]2[C:53]([C:54]=1[CH:55]=O)=[CH:52][C:51]([O:57][CH3:58])=[CH:50][CH:49]=2.N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>CN(C)C=O.C(OCC)(=O)C>[C:25]([O:29][C:30](=[O:31])[NH:32][C@H:33]1[CH2:34][CH2:35][C@H:36]([CH2:39][C:40]2[C:41](=[O:43])[O:42][C:45]3[CH:46]=[N:47][C:48]4[C:53]([C:54]=3[CH:55]=2)=[CH:52][C:51]([O:57][CH3:58])=[CH:50][CH:49]=4)[CH2:37][CH2:38]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCC(=O)O)CC1
Reactant: COc1ccc2ncc(O)c(C=O)c2c1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2ncc3oc(=O)c(C[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)cc3c2c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.04 g, 2.73 mmol, 1.5 eq) is added at room temperature to a stirred solution of 3-(trans-4-tert-butoxycarbonylamino-cyclohexyl)-propionic acid (494 mg, 1.82 mmol, 1.0 eq) and 3-hydroxy-6-methoxy-quinoline-4-carbaldehyde (370 mg, 1.82 mmol, 1.0 eq) in N,N-dimethylformamide (20 mL), followed by 1,8-diazabicycloundec-7-ene (817 μL, 5.46 mmol, 3.0 eq). After 4 hours stirring at 50° C., solvent is evaporated and the residue is extracted with ethyl acetate (3×30 mL) and water (30 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1 to 2:1, v/v) to afford [trans-4-(6-methoxy-2-oxo-2H-1-oxa-9-aza-phenanthren-3-ylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester as a yellow solid (270 mg, 34% yield).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([NH2:15])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C(Cl)Cl.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(Cl)c1ccncc1
Reactant: COc1ccc(N)cc1OC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(NC(=O)c2ccncc2)cc1OC1CCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
7.0 g (33.8 mmol) of 3-cyclopentyloxy-4-methoxy-phenylamine (Garcia et al., JOC, 2005, 70, p 1050) were dissolved in 150 ml of DCM. The solution was cooled to 0° C. and 5.74 g (40.5 mmol) isonicotinoyl chloride in 50 ml DCM were added to the solution. A precipitate was formed. The reaction mixture was subsequently stirred at room temperature during two hours. A solution of 2.7 g NaOH in 100 ml water was added to the reddish reaction mixture. The organic layer was separated, dried over Na2SO4 and evaporated. The crude product was purified by flash chromatography on silica gel (ethyl acetate/n-hexane 2:1) to afford 7.2 g (62%) of the desired product. MS (ESI): 313.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.[CH2:13]([S:29](Cl)(=[O:31])=[O:30])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>N1C=CC=CC=1>[CH2:13]([S:29]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2)(=[O:31])=[O:30])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Cl
Reactant: Nc1cccc2ccc(O)cc12
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1cccc2ccc(O)cc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
A solution of 51.4 g (0.33 mole) 8-amino-2-naphthol in 500 ml pyridine was cooled to 0° and treated with 108.0 g (0.33 mole) hexadecanesulfonyl chloride. The mixture was stirred briefly at 0° C. and overnight at room temperature, then poured into ice water containing 500 ml concentrated hydrochloric acid. The solid was collected, washed, dried, and recrystallized from benzene to give 100 g of product, m.p. 103.5°-107° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)=[C:14]([O:28][CH3:29])[CH:13]=3)[C:5]2=[N:6][CH:7]=1.Cl.[C:31]([C:33]1([OH:39])[CH2:38][CH2:37][CH2:36][NH:35][CH2:34]1)#[CH:32]>>[CH3:29][O:28][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[O:18][CH2:19][C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH2:11][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:32]3[N:35]4[CH2:34][C:33]([OH:39])([CH2:38][CH2:37][CH2:36]4)[CH:31]=3)[CH:3]=[C:4]2[N:10]=[CH:9]1
Reactant: C#CC1(O)CCCNC1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)cnc43)cc2OC)cn1
Agent: Cl
Product: COc1ccc(COc2ccc(Cn3cnc4cc(C5=CC6(O)CCCN5C6)cnc43)cc2OC)cn1

Procedure:
7-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1-azabicyclo[3.2.1]oct-6-en-5-ol was prepared from 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine and 3-ethynylpiperidin-3-ol hydrochloride using the procedure outlined for the synthesis of Example 3-30: 1H NMR (500 MHz, CDCl3) δ 8.76 (d, J=2.0 Hz, 1H), 8.29 (d, J=1.5 Hz, 1H), 8.20 (d, J=2.7 Hz, 1H), 8.04 (s, 1H), 7.68 (dd, J=8.5, 2.7 Hz, 1H), 6.93 (d, J=2.0 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.85 (dd, J=8.0, 1.5 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.19 (s, 1H), 5.41 (s, 2H), 5.05 (s, 2H), 3.95 (s, 3H), 3.83 (s, 3H), 3.43-3.41 (m, 1H), 2.94-2.91 (m, 1H), 2.85-2.81 (m, 2H), 1.91-1.84 (m, 2H), 1.74-1.71 (m, 2H) ppm; (M+1)=500.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([Br:15])=[C:10]([CH:16]([CH3:18])[CH3:17])[N:9]=2)[CH:7]=1.[O:23]=[CH:24][C@@H:25]([C@H:27]([C@@H:29]([C@@H:31]([CH2:33][OH:34])[OH:32])[OH:30])[OH:28])O>C(O)CCC.C(O)(=O)C>[Br:15][C:11]1[C:12](=[O:14])[NH:13][C:8]([C:6]2[CH:7]=[C:2]([NH:1][CH:33]3[CH:31]([OH:32])[CH:29]([OH:30])[CH:27]([OH:28])[CH:25]([CH2:24][OH:23])[O:34]3)[CH:3]=[CH:4][C:5]=2[O:19][CH2:20][CH2:21][CH3:22])=[N:9][C:10]=1[CH:16]([CH3:18])[CH3:17]
Reactant: CCCOc1ccc(N)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CC(=O)O
Solvent: CCCCO
Product: CCCOc1ccc(NC2OC(CO)C(O)C(O)C2O)cc1-c1nc(C(C)C)c(Br)c(=O)[nH]1
Yield: 20.6 %

Procedure:
The compound of example 34 (200 mg, 0.55 mmol) was dissolved in n-butanol (10 ml), and added with glucose (200 mg, 1 mmol) and one drop of glacial acetic acid. The reaction mixture was heated under nitrogen protection to reflux for 12 h. The cooled reaction mixture was concentrated to dryness, and added with dichloromethane. The organic layer was washed with saturated saline (20 ml×3), dried with anhydrous Na2SO4, and concentrated under reduced pressure. The residue was passed through a silica gel column to give the title compound (60 mg, yield: 21%). 1H NMR (DMSO-d6) δ: 7.47 (1H, d), 7.21 (1H, dd), 7.09 (1H, d), 4.31 (1H, d), 4.01 (3H, t), 3.63 (1H, d), 3.46 (1H, d), 3.09-3.29 (4H, m), 2.57 (2H, q), 2.46 (2H, q), 1.72 (2H, m), 1.18 (6H, d), 0.95 (3H, t).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:24]>>[C:25]1([CH:23]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)[CH3:24])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: CC(Br)c1ccccc1
Product: CC(c1ccccc1)N1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 137 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (1-bromoethyl)benzene and conditions outlined in procedure V. LCMS: 406 [M+H]; Rt=0.96 min.
Reaction SMILES: C([C:5]1C=CC=[C:7]2[C:8]([NH:10]C(=O)[C:6]=12)=O)CCC.[O:16]=[C:17]1[N:21]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[NH:18]1.NN>CO>[O:16]=[C:17]1[N:21]([CH:22]2[CH2:23][CH2:24][N:25]([CH2:5][CH2:6][CH2:7][CH2:8][NH2:10])[CH2:26][CH2:27]2)[C:20]2[CH:28]=[CH:29][CH:30]=[CH:31][C:19]=2[NH:18]1
Reactant: CCCCc1cccc2c1C(=O)NC2=O
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: NN
Solvent: CO
Product: NCCCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(2-keto-1-benzimidazolinyl)piperidine butylphthalimide (1.42 g, 3.39 mmol) was dissolved in 30 mL of methanol. To this solution was added anhydrous hydrazine (426 mL, 13.57 mmol) and the reaction mixture was stirred at ambient temperature for 18 hours. The resulting precipitate was filtered and discarded. The filtrate was evaporated to dryness, and the residue was dissolved in dichloromethane and filtered again. The filtrate was evaporated to dryness to give the title compound as a solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[CH:9]([CH:22]1[NH:27][C@@H:26]([CH2:28][OH:29])[CH2:25][N:24]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH3:38])[CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.ClCCl.Cl[CH2:43][C:44](Cl)=[O:45]>O>[CH:9]([CH:22]1[N:27]2[C@@H:26]([CH2:28][O:29][CH2:43][C:44]2=[O:45])[CH2:25][N:24]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH3:38])[CH2:23]1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)CCl
Reactant: COc1ccccc1CN1CC(C(c2ccccc2)c2ccccc2)N[C@@H](CO)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1CN1CC(C(c2ccccc2)c2ccccc2)N2C(=O)COC[C@H]2C1
Reaction time: 1 h

Procedure:
Potassium carbonate (81.3 mg) was added to a mixture of [(2R)-6-benzhydryl-4-(2-methoxybenzyl)piperazin-2-yl]methanol dihydrochloride (48.0 mg) in a mixed solvent of dichloromethane and water. Chloroacetyl chloride was. added to the mixture below 5° C. and the whole was stirred for 1 hour. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure. The resulting residue was dissolved into tert-butanol (4 ml) and potassium tert-butoxide (22.0 mg) was added to the mixture. The reaction mixture was poured into aqueous sodium hydrogen carbonate, and the whole was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by preparative TLC (15 PLC plate 20×20 cm, silica gel 60 F254, 1 mm, Merck) with a mixture of hexane and ethyl acetate as an eluent to give (9aR)-6-benzhydryl-8-(2-methoxybenzyl)hexahydropyrazino[2,1-c][1,4]oxazin-4-one (30 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:23][C:22]2[C:21]3[CH:24]=[C:25]([C:28](O)=[O:29])[CH:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=1.[CH3:31][NH:32][CH2:33][CH2:34][OH:35]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[N:12][N:11]=[C:10]1[C:14]1[S:23][C:22]2[C:21]3[CH:24]=[C:25]([C:28]([N:32]([CH2:33][CH2:34][OH:35])[CH3:31])=[O:29])[CH:26]=[CH:27][C:20]=3[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=1
Reactant: O=C(O)c1ccc2c(c1)-c1sc(-c3nncn3-c3ccc(F)cc3F)cc1CCO2
Reactant: CNCCO
Product: CN(CCO)C(=O)c1ccc2c(c1)-c1sc(-c3nncn3-c3ccc(F)cc3F)cc1CCO2

Procedure:
2-[4-(2,4-Difluoro-phenyl)-4H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid and 2-(methylamino)ethanol were reacted in the general amide coupling procedure to give 376. NMR: (CDCl3): (400 MHz, CDCl3): 3.13 (3H, s, Me), 3.13-3.16 (2H, m), 3.74-3.78 (2H, m), 3.90-3.95 (2H, m), 4.31-4.34 (2H, m), 6.93 (1H, s, Ar), 7.05 (1H, d, J 8.3, Ar), 7.12-7.16 (2H, m, Ar), 7.31-7.33 (1H, m, Ar), 7.43-7.48 (1H, m, Ar), 7.69-7.70 (1H, m, Ar) and 8.24 (1H, s, Ar). MS: (ESI+) MH+=483.08
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:12]=[O:13])=[CH:5][N:6]2[CH3:11].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:14]1([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]([CH:12]=[O:13])=[CH:5][N:6]3[CH3:11])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: Cn1cc(C=O)c2c(Br)cccc21
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C=O)c2c(-c3ccccc3)cccc21
Temperature: 100 °C
Reaction time: 18.5 h

Procedure:
To a cold solution (0° C.) of 4-bromo-indole-3-carboxaldehyde (0.767 g, 3.4 mmol) in dry DMF (2 mL) was added NaH (60% dispersion in mineral oil, 173 mg, 4.37 mmol). The resulting mixture was stirred at 0° C. for 20 min. Iodomethane (0.8 mL, excess) was added to the reaction mixture in a drop wise fashion. The cooling bath was removed and the resulting mixture was stirred at room temperature for 1.5 h. The mixture was quenched with water and was extracted repeatedly from EtOAc. The combined organic extracts were washed with water (twice) and brine. After drying over magnesium sulfate, solvent was removed. The resulting solid was taken in hexane and sonicated for 30 min, filtered to provide the product, 4-bromo-1-methyl-indole-3-carboxaldehyde (0.687 g, 85% yield). A mixture of 4-bromo-1-methyl-indole-3-carboxaldehyde (109 mg, 0.45 mmol), phenyl boronic acid (85 mg, 0.69 mmol) in DMF (4 mL) was degassed (argon). To the mixture was added bis(triphenylphosphine)-palladium II chloride (25 mg, 0.035 mmol) followed by addition of 2M Na2CO3 solution (2 mL, 4 mmol) and the mixture was stirred under argon at 100° C. for 18.5 h and then at reflux for 3 h. The mixture was cooled to room temperature. The reaction mixture was diluted with water and extracted repeatedly with ethyl acetate. The combined extract was washed with water (twice) and brine. After drying over anhydrous magnesium sulfate, solvent was removed in vacuo and the crude product was purified by flash chromatography (hexane:EtOAc 1:1). The desired product was isolated as syrup (79% yield). MS: 236, 238.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][C:5]1[N:9]=[C:8]([CH2:10][N:11]2[C:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[S:19][C:15]=3[C:14](=[O:26])[N:13]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:12]2=[O:33])[O:7][N:6]=1.[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:50]=[CH:51][C:52]([C:53]([N:30]4[CH2:31][CH2:32][CH:27]([N:13]5[C:14](=[O:26])[C:15]6[S:19][C:18]([C:20]7[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=7)=[CH:17][C:16]=6[N:11]([CH2:10][C:8]6[O:7][N:6]=[C:5]([CH2:4][O:3][CH3:2])[N:9]=6)[C:12]5=[O:33])[CH2:28][CH2:29]4)=[O:54])=[CH:56][CH:57]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: COCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nc(COC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-{[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]methyl}-6-phenyl-3-piperidin-4-ylthieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (148 mg; compound B40) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (120 mg; compound C10) and HBTU (126 mg) in DCM (8 ml) in the presence of DIPEA (155 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [silica gel, eluation gradient: cyclohexane/EtOAc, 1/1.5 to 0/1 (v/v)] as a solid.