Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[CH2:10]([NH:17][C:18](=[O:40])[N:19]([C:21]1[CH:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:29][C:28]=2[OH:39])[CH:24]=[CH:25][CH:26]=1)[CH3:20])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:39][C:28]1[CH:29]=[C:30]([CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[CH:31]=[CH:32][C:27]=1[C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([N:19]([CH3:20])[C:18]([NH:17][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:40])[CH:22]=1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Reactant: Fc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCc2cccc(F)c2)c1

Procedure:
In a manner similar to that of Example (25a), by reaction of 300 μL (2.4 mmol, 2.6 eq) of 3-fluorobenzyl bromide and 400 mg (0.93 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f) in 10 ml of methyl ethyl ketone in the presence of 500 mg (3.61 mmol, 3.9 eq) of potassium carbonate at 90° C. for 3 hours, methyl 3-[2-(3-fluorobenzyloxy)-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate is obtained in oil form and is used in the following reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[O:5][CH2:6][C:7]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:8].[N+:22]([C:25]1[CH:26]=[C:27]([S:31]([CH2:34][CH2:35]O)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[N+:22]([C:25]1[CH:26]=[C:27]([S:31]([CH2:34][CH2:35][O:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:7](=[O:8])[CH2:6][O:5][C:4]2[CH:18]=[C:19]([CH3:21])[CH:20]=[C:2]([CH3:1])[CH:3]=2)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23]
Reactant: Cc1cc(C)cc(OCC(=O)NCCCCCC(=O)O)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)CCO)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C)cc(OCC(=O)NCCCCCC(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Yield: 94.8 %

Procedure:
A mixture of 6-[2-(3,5-dimethyl-phenoxy)acetylamino]hexanoic acid (Intermediate 15, 3.0 g, 10.2 mmol), 2-(m-nitrobenzenesulfonyl)ethanol (available from Aldrich 2.3 g, 10.0 mmol), and p-toluenesulfonic acid hydrate (0.5 g) in 100 mL of toluene was refluxed overnight with Dean-Stark trap. Then water was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with saturated NaHCO3 solution two times, dried over anhydrous MgSO4, and concentrated under reduced pressure. The resulting residual oil was purified by column chromatography (1% MeOH in CH2Cl2) to give Intermediate 16 (4.8 g, 89%) as a yellowish thick oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:17])[CH2:15]Cl)=[C:9]([OH:18])[CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:19])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]2[NH:13][C:14](=[O:17])[CH2:15][O:18][C:9]=2[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)CCl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc2c(c1)OCC(=O)N2
Temperature: 50 °C

Procedure:
To a stirred solution of 10-4 (4.28 g, 15.0 mmol) in DMF (50 mL) was added K2CO3 (4.50 g, 32.6 mmol). The resulting suspension was heated to 50° C. for 12 h., after which time the reaction was concentrated. The residue was partitioned between saturated NaHCO3 and EtOAc and extracted twice with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. Flash chromatography (silica gel; 25:75 EtOAc/hexanes) yielded 10-5 as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[CH:14]([CH2:23][C:24](O)=[O:25])[CH:13]3[CH3:27])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1>CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[C:14]([CH2:23][CH2:24][OH:25])=[C:13]3[CH3:27])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)C(CC(=O)O)C(C)N2c1ccnc2cc(Cl)ccc12
Solvent: CO
Product: COc1ccc2c(c1)c(CCO)c(C)n2-c1ccnc2cc(Cl)ccc12

Procedure:
Methyl 1-(7-chloroquinol-4-yl)-5-methoxy-2-methylindol-3-ylacetate (1g.) and sodium borohydride (1g.) in methanol (30ml.) were refluxed for 1 hour. Most of the methanol was then removed in vacuo, and the residue was diluted with water (50ml.), and extracted with ethyl acetate (3 × 50ml.). The combined extracts were dried (MgSO4) and evaporated to give an oil, which was chromatographed on silica gel (100g.) using, as eluant, petroleum ether (b.p. 40°-60° C.) containing an increasing proportion of ether (polarity increased by incremental addition of 10% v/v ether) to give 1-(7-chloroquinol-4-yl)-3-(2-hydroxyethyl)-5-methoxy-2-methylindole, m.p. 143°-145° C.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C(O)(C)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:23]3[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: CN1CCNCC1
Solvent: CC(C)O
Product: CN1CCN(c2nc(-c3ccc(Cl)cc3)c(CCC(=O)O)o2)CC1
Yield: 78.4 %

Procedure:
A mixed solution of 3-[2-chloro-4-(4-chlorophenyl)-5-oxazolyl]propionic acid (1.43 g), 1-methylpiperazine (2.5 g) and isopropyl alcohol (20 mL) was heated under reflux for 10 hrs. The reaction mixture was concentrated, diluted with water, and acidified with 2N aqueous hydrochloric acid solution. The precipitated crystals were collected by filtration and recrystallized from ethanol to give 3-[4-(4-chlorophenyl)-2-(4-methyl-1-piperazinyl)-5-oxazolyl]propionic acid (1.37 g, yield 70%) as colorless prism crystals. melting point: 157–160° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[O:16]1[CH2:18][CH:17]1[CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>CN(C)C=O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([S:13][CH2:18][CH:17]([OH:16])[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Sc1ccc(-c2ccccc2)cc1
Reactant: c1cncc(CCC2CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(CCc1cccnc1)CSc1ccc(-c2ccccc2)cc1
Yield: 29.9 %

Procedure:
Prepared according to the method described in Example 1 from 4-phenylthiophenol (0.186 g), sodium hydride (0.044 g) and (±)-3-(2-oxiranylethyl)pyridine (0.150 g) in dimethylformamide (3 ml) at room temperature to give the title compound as a solid (0.100 g).
Reaction SMILES: [CH3:1][S:2]([C:5]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]([N:26]([C:35]4[CH:40]=[CH:39][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:37][CH:36]=4)[C:27](=[O:34])C4C=CC=CC=4)[CH3:25])[CH:21]=[CH:22][CH:23]=3)[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6])(=[O:4])=[O:3].[CH:45]([N:48]=C=O)([CH3:47])[CH3:46].C(Cl)Cl>CCOC(C)=O>[CH:45]([NH:48][C:27](=[O:34])[N:26]([CH:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[CH:17]=[C:8]([C:5]([S:2]([CH3:1])(=[O:3])=[O:4])([CH3:7])[CH3:6])[CH:9]=[C:10]3[C:15]=2[N:14]=[CH:13][CH:12]=[CH:11]3)[CH:19]=1)[CH3:25])[C:35]1[CH:36]=[CH:37][C:38]([S:41]([CH3:44])(=[O:43])=[O:42])=[CH:39][CH:40]=1)([CH3:47])[CH3:46]
Reactant: CC(c1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1)N(C(=O)c1ccccc1)c1ccc(S(C)(=O)=O)cc1
Reactant: CC(C)N=C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)N(c1ccc(S(C)(=O)=O)cc1)C(C)c1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 41 but using (1-{3-[6-(1-Methanesulfonyl-1-methyl-ethyl)-quinolin-8-yl]-phenyl}-ethyl)-(4-methylsulfanyl-phenyl)-amine (EXAMPLE 44, step 1) and iso-propyl isocyanate as the starting materials. Flash chromatography (CH2Cl2:EtOAc; 4:1) afforded the title compound as a foam.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[C:9]([CH3:11])=[CH:10][C:5]2=[N:4][CH:3]=1>C(N)CCC>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:4][CH2:5][CH2:10][CH2:9][CH3:8])[C:9]([CH3:11])=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Cc1cc2ncc(Br)n2nc1Cl
Solvent: CCCCN
Product: CCCCNc1nn2c(Br)cnc2cc1C
Temperature: 160 °C

Procedure:
To the 3-bromo-6-chloro-7-methyl-imidazo[1,2-b]pyridazine from Part B was added n-BuNH2 (10 ml). The mixture was heated in a microwave at 160° C. for 60 min (30+30 min.). The mixture was concentrated and the residue was subjected to ISCO (40 g column, hexane 3 min., 0-100% EtOAc in hexane over 25 min. the EtOAc 10 min.) to five the titled compound (348 mg). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.97 (t, J=7.39 Hz, 3H) 1.29-1.50 (m, 2H) 1.61-1.71 (m, 2H) 2.14 (s, 3H) 3.44 (q, J=6.62 Hz, 2H) 4.39 (br. s., 1H) 7.34 (s, 1H) 7.37 (s, 1H). LRMS (ESI) m/z 283 and 285 [(M+H)]+, calc'd for C11H15BrN4: 283.17.
Reaction SMILES: [CH2:1]([C:3]1[CH:22]=[CH:21][C:6]([N:7]=[CH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[BH4-].[Na+].CC1C=CC(NCC2C=C(OC)C(OC)=C(OC)C=2)=CC=1>>[CH2:1]([C:3]1[CH:22]=[CH:21][C:6]([NH:7][CH2:8][C:9]2[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(N=Cc2cc(OC)c(OC)c(OC)c2)cc1
Agent: COc1cc(CNc2ccc(C)cc2)cc(OC)c1OC
Agent: [BH4-]
Agent: [Na+]
Product: CCc1ccc(NCc2cc(OC)c(OC)c(OC)c2)cc1
Yield: 76.6 %

Procedure:
From 108b (7.0 g, 23.4 mmol) and NaBH4 (4.4 g, 117 mmol), a similar procedure as described for 109a gave 109b (5.4 g, 76.6%) as white crystals: mp 64°-6° C. after recrystallization from ethanol. 1H NMR (200 MHz, CDCl3) δ7.03 (d, J=8 Hz, 2H), 6.61 (s, 2H), 6.62 (d, J=8 Hz, 2H), 4.24 (s, 2H), 3.84 (s, 9H) 2.55 (q, J=8 Hz, 2H), 1.19 (t, J=Hz, 3H). EIMS m/e 301 (M+, 34).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:26][N:27]([CH3:38])[C:28]1[CH:37]=[CH:36][C:31]([C:32]([NH:34]O)=[NH:33])=[CH:30][N:29]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]2[O:9][N:33]=[C:32]([C:31]3[CH:30]=[N:29][C:28]([N:27]([CH3:38])[CH3:26])=[CH:37][CH:36]=3)[N:34]=2)[CH:5]=1
Reactant: CN(C)c1ccc(C(=N)NO)cn1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [F-]
Product: COC(=O)c1cccc(-c2nc(-c3ccc(N(C)C)nc3)no2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 50 ml round flask, a mixture of 5.6 (31.1 mmol) of isophtalic acid monomethyl ester and 6.71 g (34.2 mmol, 1.1 eq.) of carbonyl-diimidazole is stirred for 1 h at rt. Then, 5.60 g (31.1 mmol) of 6-dimethylamino-N-hydroxy-nicotinamidine is added and the resulting mixture stirred for another 3 h. After completion of the reaction, the solvent is removed. The resulting residue is suspended in water, vigorously stirred and then filtered. The obtained solid is washed two times with diethyl-ether and dried. This yields 10.0 g (94%) of a light yellow solid. Mass spectrum: m/z (M+H)+: 343.1The crude intermediate (9.8 g (28.7 mmol) is then redissolved in 200 ml of THF and 1.81 g (5.7 mmol, 0.2 eq.) of tetrabutyl-ammonium fluoride tri-hydrate TBAF) is added. After 1.5 h, another 0.2 eq. of TBAF is and the mixture stirred at rt for 20 h. Then, solvent is removed under vacuo, and the residue taken up in 200 ml of dichloro-methane and washed twice with NaHCO3 (5%). The combined aqueous phases are extracted three times with dichloro-methane, the combined organic phases dried (Na2SO4) and concentrated. This yields the title compound as light yellow solid, which is used for the next step without purification. Mass spectrum: m/z (M+H)+: 325.2
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:19])[N:7]=[C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[CH:9]=1)=O.[AlH4-].[Li+].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[Cl:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:10][C:8]1[CH:9]=[C:5]([CH2:3][OH:2])[N:6]([CH3:19])[N:7]=1
Reactant: COC(=O)c1cc(NCc2cccc(Cl)c2)nn1C
Agent: O=S(=O)([O-])[O-]
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(NCc2cccc(Cl)c2)cc1CO
Temperature: -40 °C
Reaction time: 0.75 h

Procedure:
5-(3-Chloro-benzylamino)-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (646, 0.944 g, 3.37 mmol) was combined with tetrahydrofuran (20 mL) and the solution was cooled to −40° C. 1.0 M lithium tetrahydroaluminate in tetrahydrofuran (3.7 mL) was added and the reaction was stirred for 45 min at −20° C. 1.0 M lithium tetrahydroaluminate in tetrahydrofuran (3.7 mL) was added at −40° C. and the reaction was stirred to 10° C. Sodium sulfate decahydrate was added in small portions and the mixture was stirred for two hours at room temperature, then filtered through Celite and concentrated. The resulting compound (647, 0.821 g, 97%) was washed with a mixture of ethyl acetate:hexanes and dried under reduced pressure.
Reaction SMILES: Cl.C([O:4][CH:5](OCC)[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[C:13]([F:15])[F:14])=[CH:8][CH:7]=1)C>CCOCC>[F:14][C:13]([F:15])=[CH:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[O:4])=[CH:7][CH:8]=1
Reactant: CCOC(OCC)c1ccc(C=C(F)F)cc1
Agent: Cl
Solvent: CCOCC
Product: O=Cc1ccc(C=C(F)F)cc1
Temperature: 25 °C
Reaction time: 3.75 h

Procedure:
In a nitrogen stream, a 2M hydrochloric acid aqueous solution (2.5 mL) was added to a solution of 1-diethoxymethyl-4-(2,2-difluorovinyl)benzene (998.1 mg, 4.12 mmol) in ether (4 mL) cooled in an ice bath and the reaction mixture was stirred at the same temperature for three minutes and at room temperature for 3.75 hours. The reaction mixture was extracted with ether and the organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and dried over sodium sulfate. The solvent was distilled under reduced pressure to obtain a crude compound.
Reaction SMILES: ClC#CCCCCCC.CCCCCCC.Cl/C=C/CCCCCC.C#CCCCCCC.C[O-].[Na+].[CH3:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].II.[I:48]C#CCCCCCC.C[Al](C)C.Cl>COCCOCCOC.CCCCCC.CCCCC>[I:48][C:38](=[CH:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH3:37]
Reactant: CCCCCCC#CI
Reactant: C/C=C\CCCCCC
Agent: C#CCCCCCC
Agent: CCCCCC/C=C/Cl
Agent: CCCCCCC#CCl
Solvent: CCCCCC
Solvent: CCCCC
Solvent: COCCOCCOC
Product: CCCCCCC=C(C)I
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a mixture of 0.24 g (8.0 mmol) of 80% sodium hydride and 8 mL of dry diglyme was added at 0° C. 3.75 mL (7.50 mmol) of 2.0M trimethylaluminum in hexane. The reaction mixture was warmed to room temperature, stirred for 2 hours, and then was filtered under argon through a medium glass frit. The hexane contained in the filtrate was removed under reduced pressure (25° C., 30 torr), and the clear solution of sodium trimethylaluminum hydride obtained was treated at 0° C. with 0.72 g (5.0 mmol) of 1-chloro-1-octyne and 0.70 mL (5.0 mmol) of n-heptane as an internal GC standard. The solution was stirred for one hour at 0° C. (hydrolysis of an aliquot at this point revealed by GC 89% trans-1-chloro-1-octene and 11% 1-octyne) and to the solution was added 0.40 g (7.5 mmol) of sodium methoxide. The mixture was then warmed to 50° C. and stirred overnight. Hydrolysis and GC analysis of an aliquot showed 69% cis-2-nonene (containing <0.5% trans-2-nonene) and 31% 1-octyne. The reaction was cooled to -78° C. and treated with a solution of 1.59 g (6.25 mmol) of iodine in 5 mL of diglyme. After warming the reaction mixture to 25° C., GC examination of an aliquot showed complete iodination had occurred, as no residual cis-2-nonene was present after hydrolysis. However, due to the formation of some 1-iodo-1-octyne, the reaction solution was additionally treated with 1.0 mL (2.0 mmol) of 2.0M trimethylaluminum in hexane, which after 24 hours at room temperature had converted all 1-iodo-1-octyne into 1-octyne (after protonolysis), thereby simplifying the isolation procedure. The reaction mixture was slowly poured into a mixture of 3N HCl and pentane. The aqueous layer was extracted with pentane and the combined organic phase was washed sequentially with 3N HCl, saturated NaHCO3, 20% Na2SO3, and saturated NaCl. Concentration and short-path distillation provided 0.79 g (63%) of the 2-iodo-2-nonene: bp=45./0.1 torr; IR (neat) 3020 (w), 2950 (s), 2920 (s), 2850 (s), 1638 (m), 1465 (m), 1455 (m), 1385 (m), 1135 (m), 1060 (m) cm-1 ; 1H--NMR (CDCl3, TMS) 0.90 (t, 3H), 1.2-1.5 (br s, 8H), 2.05 (m, 2H), 2.35 (d, J=1.5 Hz, 3H), 6.15 (tq, J=7.2, 1.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:12](OC)=[O:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:3]=[C:4]([CH2:12][OH:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)c1nc(Cl)cc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1nc(Cl)cc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of methyl 3-chloroisoquinoline-1-carboxylate (5.1 g, 23.0 mmol) in MeOH (50 mL) was added NaBH4 (2.17 g, 57.5 mmol). The reaction mixture was stirred at RT for 2 hours. The reaction was quenched with saturated aqueous NH4Cl and the mixture was extracted with EtOAc. The organic layer was separated and dried over Na2SO4, and the solvent was evaporated under reduced pressure to give the title compound as a yellow solid (3.94 g, 88%). ESI-MS m/z [M+H]+ 194.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.Br[C:17]1[CH:27]=[CH:26][C:20]2[S:21][C:22]([F:25])=[C:23]([CH3:24])[C:19]=2[CH:18]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][N:12]([C:17]3[CH:27]=[CH:26][C:20]4[S:21][C:22]([F:25])=[C:23]([CH3:24])[C:19]=4[CH:18]=3)[C:11]2=[O:15])[CH2:3][CH2:2]1
Reactant: Cc1c(F)sc2ccc(Br)cc12
Reactant: O=C1NCCN1c1cnccc1C1CC1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1c(F)sc2ccc(N3CCN(c4cnccc4C4CC4)C3=O)cc12
Yield: 66.3 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropyl-pyridin-3-yl)-imidazolidin-2-one (I-1d: 100 mg, 0.4926 mmol) was reacted with 5-bromo-2-fluoro-3-methyl-benzo[b]thiophene (I-24c: 120 mg, 0.4926 mmol), copper iodide (9.3 mg, 0.04926 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (7.0 mg, 0.04926 mmol), potassium phosphate (313 mg, 1.4778 mmol) and 1,4-dioxane (5 ml) to afford the crude product. Purification by column chromatography on silica gel (2% methanol in chloroform) afforded 120 mg of product (66% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])=[O:5].[CH:20](OC)(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>C(Cl)Cl>[CH3:19][C:16]1[CH:15]=[C:3]2[C:2](=[CH:18][CH:17]=1)[N:1]=[CH:20][N:6]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:8]1=[O:14])[C:4]2=[O:5]
Reactant: Cc1ccc(N)c(C(=O)NC2CCC(=O)NC2=O)c1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc2ncn(C3CCC(=O)NC3=O)c(=O)c2c1
Yield: 9 %

Procedure:
A solution of 2-amino-N-(2,6-dioxo-piperidin-3-yl)-5-methyl-benzamide (0.45 g, 1.7 mmol) and trimethyl orthoformate (4 mL) and p-toluene sulfonic acid (80 mg) was heated to 160° C. in a microwave oven for 8 minutes. To the suspension, was added methanol (20 mL), methylene chloride (20 mL), and Celite (5 mL). The solvent was removed in vacuo. The reside was placed in a SIM and was purified with column chromatography (Silca Gel, methanol/methylene chloride 0% gradient 10% in 15 min) to give as 3-(6-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione as a blue solid (50 mg, 9% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 2.78 min (96.1%); mp: 285-287° C.; 1H NMR (DMSO-d6) δ 2.11-2.18 (m, 1H, CHH), 2.46 (s, 3H, CH3), 2.56-2.74 (m, 2H, 2CHH), 2.82-2.93 (m, 1H, CHH), 5.48 (br, 1H, NCH), 7.61 (d, J=8 Hz, 1H, Ar), 7.70 (dd. J=2, 8 Hz 1H, Ar), 7.94 (br, 1H, Ar), 8.33 (s, 1H, CH), 11.15 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.72, 22.51, 30.91, 57.00 (br), 121.09, 125.38, 127.00, 135.89, 137.07, 145.46, 146.45, 159.60, 169.88, 172.44; LCMS: MH=272; Anal Calcd for C14H13N3O3: C, 61.99; H, 4.83; N, 15.49. Found: C, 61.78; H, 4.57; N, 15.34.
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][NH:4][C:3](=[O:12])[CH2:2]1.[C:13]1([CH2:19][CH2:20]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C)C=O.C(N(CC)CC)C>[C:13]1([CH2:19][CH2:20][N:9]2[CH2:8][CH2:7][C:6]3([O:1][CH2:2][C:3](=[O:12])[NH:4][CH2:5]3)[CH2:11][CH2:10]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1COC2(CCNCC2)CN1
Reactant: BrCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COC2(CCN(CCc3ccccc3)CC2)CN1

Procedure:
A solution of 3.0 g of 1-oxa-4,9-diazaspiro[5.5]undecan-3-one and 5 ml of phenylethyl bromide in 60 ml of dimethylformamide and 10 ml of triethylamine was heated at 70° C. for 3 hours. The mixture was poured into water, extracted with methylene chloride and the extract was washed with water and evaporated. Crystallization of the residue from ethyl acetate gave 1.2 g of 9-(2-phenylethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one, m.p. 140°-141° C. The HCl salt of 9-(2-phenethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one was prepared by dissolving the free base in methanolic HCl and precipitating with ether, m.p. 247°-250° C.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:19])[CH2:9][CH:10]([CH3:18])[CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.Cl>[C:21]1([CH2:20][N:13]2[C:12]3[CH2:11][CH:10]([CH3:18])[CH2:9][C:8](=[O:19])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CC(C)C3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2)CC(C)CC1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 97 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-2-methyl-9H-carbazol-4(3H)-one (2.0 g, 7.77 mM), benzyl bromide (0.94 ml, 7.93 mM), and potassium carbonate (2.15 g, 15.5 mM) in 39 mL DMF was stirred at room temperature for 22 hours. The mixture was diluted with ethyl acetate and 1N HCl. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined ethyl acetate layers were extracted with 1N HCl twice, once with water and once with brine. After drying (NaSO4), evaporation in vacuo afforded 2.61 g (97%) of 9-[(phenyl)methyl]-5-carbomethoxy-2-methyl-1,2-dihydrocarbazol-4(3H)-one. 1H NMR (CDCl3) δ7.6-7.4 (m, 6H), 7.0 (m, 2H), 5.4 (s, 2H), 4.05 (s, 3H), 3.0 (m, 1H), 2.65-2.45 (m, 3H), 2.3 (dd, J=15 and 9 Hz, 1H), 1.1 (d, J=7 Hz, 3H). MS (ES) m/e 316, 348.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C([O:18][C:19](OCC)(N(C)C)[CH2:20][CH3:21])C>C(OCC)(=O)C>[N+:13]([C:3]1[C:2]([CH2:1][C:19](=[O:18])[CH2:20][CH3:21])=[CH:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6])([O-:15])=[O:14]
Reactant: CCOC(CC)(OCC)N(C)C
Reactant: CCOC(=O)c1cccc(C)c1[N+](=O)[O-]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(CC(=O)CC)c1[N+](=O)[O-]
Temperature: 145 °C
Yield: 29.6 %

Procedure:
A stirred mixture of ethyl 3-methyl-2-nitrobenzoate (0.96 g) and N,N-dimethylpropionamide diethyl acetal (2.3 g) was heated at 145° C. for 36 hours. The reaction mixture was dissolved in ethyl acetate. The solution was washed with dilute hydrochloric acid and then water, dried and concentrated to dryness. The residue was purified by column chromatography on silica gel to give a pale brown syrup (0.36 g, 33%).