Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][O:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:12][O-:13].[Na+]>CO>[CH3:12][O:13][C:2]1[C:3]2[CH2:11][CH2:10][O:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: C[O-]
Reactant: Nc1nc(Cl)c2c(n1)OCC2
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc2c1CCO2
Yield: 76 %

Procedure:
To a suspension of 27 g of 4-chloro-5,6-dihydrofuro[2,3-d]pyrimidin-2-amine in 500 ml of anhydrous methanol was added 22 g of sodium methoxide and the mixture was heated to reflux (66°) for 5.5 hours. The solvent was then removed under reduced pressure and the residue triturated with water (500 ml) then filtered and rinsed well with water. The solid was air dried to give 20 g of 5,6-dihydro-4-methoxyfuro[2,3-d]pyrimidin-2-amine, m.p. 172°-177°. Two triplet absorptions at 3.42 and 5.02 ppm and a singlet absorption at 4.21 ppm in the nuclear magnetic resonance spectrum (60 MHz), indicated the title compound.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([O:14]C(C)=O)=[C:10]([Br:18])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl>CO.O>[C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([Br:18])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2oc(C(C)=O)c(N)c2c1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)c1oc2ccc(O)c(Br)c2c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To a mixture of 12E (6.8 g, 0.021 mol) in MeOH (40 mL) and water (20 mL) was added K2CO3 (4.5 g, 0.032 mol) in batches at room temperature. The reaction mixture was stirred at room temperature overnight, then neutralized with diluted hydrochloric acid to pH=6˜7, extracted with ethyl acetate, dried and concentrated to give 12F (5.6 g, 95.1% yield).
Reaction SMILES: F[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([CH2:27]Br)[CH:24]=[CH:23][C:22]=1[O:29][CH3:30])[CH3:18]>>[CH2:17]([O:19][C:20](=[O:31])[C:21]1[CH:26]=[C:25]([CH2:27][N:14]2[CH2:15][CH2:16][CH:11]([C:6]3[C:5]4[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=4)[NH:8][CH:7]=3)[CH2:12][CH2:13]2)[CH:24]=[CH:23][C:22]=1[O:29][CH3:30])[CH3:18]
Reactant: CCOC(=O)c1cc(CBr)ccc1OC
Reactant: Fc1ccc2c(C3CCNCC3)c[nH]c2c1
Product: CCOC(=O)c1cc(CN2CCC(c3c[nH]c4ccccc34)CC2)ccc1OC
Yield: 84.6 %

Procedure:
This compound was prepared following the procedure described in example 1 (part D) starting with 0.5 g (2.5 mmol) of 6-fluoro-3-piperidin-4-yl-1H-indole and 0.88 g (3.2 mmol) of 5-bromomethyl-2-methoxy-benzoic acid ethyl ester. After standard purification, 0.83 g (91% of yield) of 5-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-2-methoxy-benzoic acid ethyl ester were obtained.
Reaction SMILES: C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[OH:16][CH:17]([C:30]1[CH:35]=[CH:34][C:33]([C:36](=[N:38][OH:39])[NH2:37])=[CH:32][CH:31]=1)[CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][C@H:21]([C:25]([O:27]CC)=[O:26])[CH2:20]1.[Cl:40][C:41]1[CH:42]=[C:43]([C:48]2([CH2:54][CH2:55][C:56](O)=O)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[CH:44]=[C:45]([Cl:47])[CH:46]=1.C(N(C(C)C)CC)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>CN(C=O)C.C(OCC)(=O)C>[Cl:40][C:41]1[CH:42]=[C:43]([C:48]2([CH2:54][CH2:55][C:56]3[O:39][N:38]=[C:36]([C:33]4[CH:32]=[CH:31][C:30]([CH:17]([OH:16])[CH2:18][N:19]5[CH2:24][CH2:23][CH2:22][C@H:21]([C:25]([OH:27])=[O:26])[CH2:20]5)=[CH:35][CH:34]=4)[N:37]=3)[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[CH:44]=[C:45]([Cl:47])[CH:46]=1
Reactant: CCOC(=O)[C@H]1CCCN(CC(O)c2ccc(C(N)=NO)cc2)C1
Reactant: O=C(O)CCC1(c2cc(Cl)cc(Cl)c2)CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)[C@H]1CCCN(CC(O)c2ccc(-c3noc(CCC4(c5cc(Cl)cc(Cl)c5)CCCCC4)n3)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
BOP-Cl (33.4 mg, 0.131 mmol) was added to a mixture of (3S)-ethyl 1-(2-hydroxy-2-(4-(N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidine-3-carboxylate (Intermediate 3, 40 mg, 0.119 mmol), 3-(1-(3,5-dichlorophenyl)cyclohexyl)propanoic acid (35.9 mg, 0.119 mmol), and diisopropylethyl amine (0.042 mL, 0.239 mmol) in DMF (3 mL). The mixture was stirred at room temperature for 2 h, and a 1M solution of tetra-n-butylammonium fluoride in THF (0.119 mL, 0.119 mmol) was added. The mixture was heated to 80° C. overnight, diluted with ethyl acetate, and washed with saturated aqueous NaCl solution. The organic layer was dried (MgSO4), filtered and concentrated. The crude product was dissolved in acetonitrile (3 mL), treated with 6 N aq. HCl solution and heated to 50° C. overnight. The mixture was filtered, and purified by HPLC (HPLC conditions: Phenomenex Luna C18 5 micron column (250×30 mm); 25-100% AcCN/water (0.1% TFA); 25 minute gradient; 30 mL/min). Isolated fractions with the correct mass were collected and freeze-dried overnight to obtain (3S)-1-(2-(4-(5-(2-(1-(3,5-dichlorophenyl)cyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)phenyl)-2-hydroxyethyl)-3-piperidinecarboxylic acid (52 mg, 63% yield) as a white solid. HPLC retention time=3.75 minutes (Waters Sunfire C18 4.6×50 mm) eluting with 10-90% aqueous methanol with 0.1% TFA over a 4 minute gradient. LC/MS: m/e 572.16, 574.10 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:25])=[N:8][N:9]2[C:14]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])=[CH:13][CH:12]=[CH:11][C:10]=12)=[O:5])C.[OH-].[Na+]>O1CCOCC1>[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[CH2:16][O:15][C:14]1[N:9]2[N:8]=[C:7]([CH3:25])[C:6]([C:4]([OH:5])=[O:3])=[C:10]2[CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nn2c(OCc3c(F)cccc3F)cccc2c1C(=O)O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 200 mg (0.228 mmol, 43% pure) of 7-[(2,6-difluorobenzyl)oxy]-2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester from Example 129A in 3 ml of dioxane was admixed with 1 ml of 2 N sodium hydroxide solution. The resulting mixture was stirred at room temperature for 72 h. The solvent was drawn off under reduced pressure and the residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:dichloromethane-methanol 100:1 to 10:1), which gave 100 mg (77% of theory, 61% pure) of the target compound.
Reaction SMILES: [Cl:1][C:2]([Cl:19])([Cl:18])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:17])[C@@H:14]([NH2:16])[CH3:15])[NH:8]1)=[O:6].[C:20]([O:24][C:25]([N:27]([CH3:35])[C@@H:28]([CH:32]([CH3:34])[CH3:33])[C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].C(N(CC)C(C)C)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>C(#N)C>[Cl:19][C:2]([Cl:1])([Cl:18])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:17])[C@@H:14]([NH:16][C:29](=[O:30])[C@@H:28]([N:27]([C:25]([O:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:26])[CH3:35])[CH:32]([CH3:34])[CH3:33])[CH3:15])[NH:8]1)=[O:6]
Reactant: C[C@H](N)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H](C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.4 %

Procedure:
A solution of 1d (1.08 g, 2.5 mmol) in dichloromethane (35 mL) was stirred at 0° C. under nitrogen. Trimethylsilyl trifluoromethanesulfonate (682 mg, 0.55 mL, 3.1 mmol) was added and the reaction mixture was stirred at 0° C. for 45 min. N,N-diisopropylethylamine (1.29 g, 1.73 mL, 10 mmol) was added and the solvent was evaporated to afford crude (S)-1-((S)-2-amino-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (2.5 mmol), which was used in the next step. A solution of crude (S)-1-((S)-2-amino-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (2.5 mmol) in acetonitrile (30 mL) was stirred at 0° C. under nitrogen. (S)-2-(tert-Butoxycarbonyl-methyl-amino)-3-methyl-butyric acid (635 mg, 2.75 mmol, obtained from Sigma-Aldrich Inc.) and N,N-diisopropylethylamine (1.29 g, 1.7 mL, 10 mmol) was added followed by 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (1.33 g, 3.5 mmol) and the reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with water, hydrochloric acid (2 M), water, saturated sodium hydrogen carbonate solution, water and brine, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 1:1 to 0:1 to afford the title compound (756 mg, 55%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 0.88 (d, J=6.5 Hz, 3H), 0.97 (d, J=6.7 Hz, 3H), 1.28 (d, J=6.7 Hz, 3H), 1.49-1.54 (m, 9H), 1.65-2.30 (m, 5H), 2.82 (s, 3H), 2.82-2.94 (m, 1H), 3.62-4.18 (m, 3H), 4.30-4.45 (m, 1H), 4.73 (d, J=12.0 Hz, 1H), 4.95 (d, J=12.0 Hz, 1H), 5.29-5.39 (m, 1H), 6.62-6.77 (m, 1H). LCMS (m/z) 545.2/547.1 [M+H], Tr=3.02 min.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=5[O:47]COC)=[O:39])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:51]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].Cl.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:40][C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=5[OH:47])=[O:39])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:51]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ccccc4OCOC)cc2)CCN3CC(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ccccc4O)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 46.4 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[2-(methoxymethoxy)benzyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.69 g) was dissolved in methanol (13.8 ml), 4N hydrochloric acid/ethyl acetate (3.45 ml) was added to the mixture at room temperature, and the mixture was stirred for 15 minutes. The reaction mixture was added to an aqueous solution of saturated sodium bicarbonate, and extracted with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(2-hydroxybenzyl)sulfinyl]phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 221) (0.30 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21].C(=O)(O)[O-].[Na+].O>C(OCC)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])=[O:5]
Reactant: Nc1ccccc1O
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: O=C(Nc1ccccc1O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-5-nitro-benzoyl chloride in 60 mL of diethyl ether was added to an ice-cooled mixture of o-aminophenol (5.4 g) and sodium bicarbonate (8.3 g), water (36 mL) and ether (20 mL) over a period of 1 hour. The mixture was allowed to warm to room temperature and stirred overnight. The precipitate was filtered and washed sequentially with water (3×100 mL), 2N HCl (3×100 mL) and diethyl ether (3×50 mL). Yield 11.2 g (77%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][CH:18]1[CH2:23][CH2:22][CH:21]([N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:20][CH2:19]1.[CH3:29][O:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[CH:33][C:32]=1[OH:46]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][CH:18]2[CH2:19][CH2:20][CH:21]([N:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[CH2:22][CH2:23]2)=[CH:3][C:2]([C:35]2[CH:34]=[CH:33][C:32]([OH:46])=[C:31]([O:30][CH3:29])[CH:36]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1O
Reactant: CCN(CC)C1CCC(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: CCN(CC)C1CCC(Nc2c(C(=O)C3CC3)cnc3ccc(-c4ccc(O)c(OC)c4)cc23)CC1
Yield: 63.1 %

Procedure:
Following general procedure F, {6-bromo-4-[4-(diethylamino)cyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (58 mg, 0.130 mmol) was reacted with 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (34 mg, 0.136 mmol) to afford the desired product (40 mg, 60%) as a yellow glass: 1H NMR (300 MHz, CD3OD) δ 9.26 (s, 0.5H), 9.17 (s, 0.5H), 8.33 (dd, J=8.2, 1.6 Hz, 1H), 8.09 (dt, J=8.8, 1.7 Hz, 1H), 7.90 (d, J=8.7 Hz, 1H), 7.25 (dd, J=12.8, 2.1 Hz, 1H), 7.21-7.08 (m, 1H), 6.99-6.87 (m, 1H), 4.81 (s, 1H), 3.96 (d, J=3.5 Hz, 3H), 3.64-3.44 (m, 1H), 3.40-3.12 (m, 3H), 2.96-2.76 (m, 1H), 2.41 (s, 1H), 2.24 (d, J=12.4 Hz, 2H), 2.14-1.83 (m, 4H), 1.73 (t, J=9.7 Hz, 2H), 1.46-1.30 (m, 6H), 1.26-1.07 (m, 4H); ESI MS m/z 488 [C30H37N3O3+H]+; HPLC 98.9% (AUC), tR=6.24 min.
Reaction SMILES: Br[C:2]1[C:17]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:16][C:5]2[N:6]([CH3:15])[C:7](=[O:14])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[N:10][CH:9]=3.[CH3:33]B1OB(C)OB(C)O1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:15][N:6]1[C:5]2[CH:16]=[C:17]([O:18][CH2:19][C@@H:20]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH:22]([CH3:24])[CH3:23])[C:2]([CH3:33])=[CH:3][C:4]=2[C:13]2[C:8](=[CH:9][N:10]=[CH:11][CH:12]=2)[C:7]1=[O:14]
Reactant: CB1OB(C)OB(C)O1
Reactant: CC(C)C[C@@H](COc1cc2c(cc1Br)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc2c3ccncc3c(=O)n(C)c2cc1OC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 90 °C
Yield: 37 %

Procedure:
In a 10 mL round-bottomed flask, (S)-tert-butyl (1-((9-bromo-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (as prepared in Ex. 3, Part A) (150 mg, 0.297 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (41.1 mg, 0.327 mmol), Cs2CO3 (291 mg, 0.892 mmol) and PdCl2(dppf) (21.76 mg, 0.030 mmol) were taken up in a mixture of 1,4-dioxane (2 mL) and water (0.1 mL). The reaction mixture was purged with nitrogen for 5 min and heated at 90° C. for 15 h. 1,4-dioxane was removed under reduced pressure and the residue was dissolved in ethyl acetate (20 mL). The ethyl acetate layer was washed with water (10×2 mL) and dried over sodium sulfate. Removal of the solvent gave crude product (0.08 g), which was filtered through silica-gel column (24 g silica-gel, MeOH—CHCl3 mixture). The product was isolated as off-white solid (0.05 g, 0.11 mmol, 38% yield). LC/MS (ES-API) m/e 440.2 [(M+H)+, calcd for C25H34N3O4, 440.3]; LC/MS retention time (method B): tR=1.95 min.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][C:25]=1[C:34](Cl)=[O:35]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:34]([C:25]5[CH:26]=[N:27][C:28]6[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=6)[N:24]=5)=[O:35])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(Cl)c1cnc2ccccc2n1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4cnc5ccccc5n4)nc3cc21

Procedure:
Quinoxaline-2-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 2-quinoxalinecarbonyl chloride (170 mg, 0.89 mmol). The title compound was obtained as yellow powder (158 mg, 42%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][C:15]1=[O:20].[CH3:21][C:22]1[C:30]2[CH2:29][O:28][C:27](=[O:31])[C:26]=2[CH:25]=[CH:24][C:23]=1[C@H:32]1[CH2:34][O:33]1>CCO>[OH:33][C@@H:32]([C:23]1[CH:24]=[CH:25][C:26]2[C:27](=[O:31])[O:28][CH2:29][C:30]=2[C:22]=1[CH3:21])[CH2:34][N:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][C:3]2[CH:4]=[CH:5][C:6]3[C:7](=[O:11])[O:8][CH2:9][C:10]=3[C:2]=2[CH3:1])[C:15](=[O:20])[CH2:16]1
Reactant: Cc1c(CCN2CCNCC2=O)ccc2c1COC2=O
Reactant: Cc1c([C@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c(CCN2CCN(C[C@@H](O)c3ccc4c(c3C)COC4=O)CC2=O)ccc2c1COC2=O
Temperature: 100 °C

Procedure:
A sealed tube containing 1-[2-(4-Methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-2-one (60 mg, 0.19 mmol) and 4-methyl-5-[(2S)-oxiran-2-yl]-2-benzofuran-1(3H)-one dissolved in 1 mL of EtOH was heated to 100° C. overnight. After 16 hrs the solvent was removed and the material purified via flash chromatography to give desired product. LC-MS (IE, m/z): 465 [M+1]+.
Reaction SMILES: [CH:1]1[NH:2][CH:3]=[CH:4][C:5]2[C:6]=1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2.[C:12]([O:15]C(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:15][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]2[C:5]=1[CH:4]=[CH:3][NH:2][CH:1]=2)(=[O:14])[CH3:13]
Reactant: C1=CC=C2C=CNC=C2C=C1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC1=C2C=CNC=C2C=CC=C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Cyclohepta[1,2-c]pyridine, N-oxide (24.00 g, 0.147 mole) was added portionwise to a stirred solution of acetic anhydride (140 ml). The resulting yellow mixture was then stirred for 2 hours at its reflux temperature and overnight at room temperature. Excess acetic anhydride was removed by evaporation at ~55° C. on a rotary evaporator and the dark brown, oily residue was distilled (170°, 0.03 mm) and chromatographed on silica gel eluting with a mixture of ethyl acetate in methylene chloride (1:4) to give the desired product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[C:8]1([CH2:14][CH2:15][CH2:16]Br)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C>[C:8]1([CH2:14][CH2:15][CH2:16][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: c1c[nH]cn1
Reactant: BrCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(CCCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
To a stirred solution of imidazole (6.808 g, 0.1 mol) in dry DMF (100 ml) at 0° C. under argon was added portionwise 4 g (0.1 mol) of 60% sodium hydride and the mixture was stirred for 30 minutes at room temperature, and cooled to 0° C. To the above mixture was added 3-phenylpropyl bromide (19.91 g, 0.1 mol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was heated on a steam-bath for 4 hours and stirred at room temperature overnight. The solvent was concentrated in vacuo, the residue was partitioned between methylene chloride and water, the organic layer was dried over sodium sulfate, and concentrated in vacuo. The residual oil was dried in vacuo and purified by silica gel column chromatography to afford 16.1 g (86%) of 1-(3-phenylpropyl)imidazole.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.Cl.Cl.[CH3:20][NH:21][C:22](=[O:36])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[C:25]([CH3:35])[CH:24]=1.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[CH3:20][NH:21][C:22](=[O:36])[C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:31][CH2:30]2)=[C:25]([CH3:35])[CH:24]=1
Reactant: CNC(=O)c1ccc(N2CCNCC2)c(C)c1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)c(C)c1
Temperature: 90 °C
Yield: 14.2 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (100 mg, 0.429 mmol), N,3-dimethyl-4-(piperazin-1-yl)benzamide dihydrochloride (131 mg, 0.429 mmol), (cyanomethyl)trimethylphosphonium iodide (167 mg, 0.686 mmol) and N,N-diisopropylethylamine (374 μl, 2.143 mmol) were suspended in propiononitrile (Volume: 1287 μl) and heated in a closed vial at 90° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature and purified using HPLC (NH4HCO3 buffered, 20-70% ACN in water). The fractions were concentrated in vacuo and the resulting solid was recrystallized from MeCN (5 mL), filtered off, washed with water (2 mL) and dried in vacuum to afford (S)—N,3-dimethyl-4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (27.4 mg, 0.061 mmol, 14.25% yield) as a light beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31-1.57 (m, 3H) 1.64 (d, J=11.87 Hz, 1H) 1.85 (d, J=11.37 Hz, 1H) 2.04 (d, J=11.87 Hz, 1H) 2.25 (s, 3H) 2.51-2.70 (m, 5H) 2.56-2.70 (m, 2H) 2.74 (d, J=4.29 Hz, 3H) 2.87 (br. s., 4H) 3.37-3.45 (m, 2H) 3.84 (dd, J=11.24, 2.40 Hz, 1H) 4.50 (d, J=13.14 Hz, 1H) 6.98 (d, J=1.77 Hz, 1H) 7.01 (d, J=8.34 Hz, 1H) 7.61 (dd, J=8.46, 1.64 Hz, 1H) 7.65 (dd, J=12.25, 1.64 Hz, 2H) 8.23 (q, J=4.13 Hz, 1H) 10.48 (s, 1H); [M+H] calc'd for C25H32N6O2, 449; found, 449.
Reaction SMILES: C(OC([N:8]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([Cl:39])[CH:37]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][CH3:25])[CH:11]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[C:9]1=[O:40])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:39][C:36]1[CH:37]=[C:38]2[NH:8][C:9](=[O:40])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][CH3:25])[CH:11]3[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[C:33]2=[CH:34][CH:35]=1
Reactant: CCN1C(=O)CC(c2cccc(Cl)c2)C2(C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)C1c1ccccc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN1C(=O)CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C1c1ccccc1C
Yield: 67.5 %

Procedure:
In a manner similar to the method described in example 24d, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-ethyl-2,3-dihydro-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (0.2 g, 0.34 mmol) prepared in example 26a was reacted with trifluoroacetic acid in dichlormethane to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-ethyl-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white foam (Yield: 0.11 g, 69%).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][CH:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1.[ClH:31]>O1CCOCC1>[ClH:31].[F:30][C:2]([F:1])([F:29])[O:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[NH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc3ccccc3n2CCOC(F)(F)F)CC1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)OCCn1c(NC2CCNCC2)nc2ccccc21
Reaction time: 1 h

Procedure:
Combine (1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine and a solution of hydrochloric acid in dioxane (10 mL, 4 M). After 1 hour, evaporate in vacuo to give the title compound.