Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[CH2:11]([O:13][C:14](=[O:18])[C@H:15]([CH3:17])[NH2:16])[CH3:12].[Br:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](F)[C:21]=1[N+:27]([O-:29])=[O:28].O>CN(C)C(=O)C.[NH4+].[Cl-]>[Br:19][C:20]1[C:21]([N+:27]([O-:29])=[O:28])=[C:22]([NH:16][C@@H:15]([CH3:17])[C:14]([O:13][CH2:11][CH3:12])=[O:18])[CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)[C@H](C)N
Reactant: O=[N+]([O-])c1c(F)cccc1Br
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](C)Nc1cccc(Br)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.7 %

Procedure:
DIPEA (45.1 mL, 259 mmol) was added to a stirred solution of L-alanine ethyl ester hydrochloride (Aldrich; 34.1 g, 222 mmol) and 1-bromo-3-fluoro-2-nitrobenzene (126a; Ark Pharm, Inc., Libertyville, Ill.; 16.29 g, 74.0 mmol) in N,N-dimethylacetamide (15 mL) and the resulting yellow solution was stirred at RT for 15 min. A water-cooled reflux condenser was attached to the flask, and the resulting mixture was heated at 80° C. for 18 h. The reaction was cooled to RT, diluted with saturated aq. NH4Cl (100 mL), and extracted with EtOAc (4×75 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide (S)-ethyl 2-((3-bromo-2-nitrophenyl)amino)propanoate (126b; 24.1 g) as a brown residue (contains 10% starting material by LCMS and 1H NMR), which was used directly in the subsequent step: 1H NMR (400 MHz, CDCl3) δ ppm 7.13 (1H, t, J=8.2 Hz), 7.00 (1H, d, J=8.0 Hz), 6.64 (1H, d, J=8.4 Hz), 5.89 (1H, d, J=6.8 Hz), 4.22 (2H, m, J=7.0, 7.0, 7.0 Hz), 4.14 (1H, quin, J=7.1 Hz), 1.51 (3H, d, J=7.0 Hz), 1.27 (3H, t, J=7.1 Hz). m/z (ESI, +ve) 317.0 (M+H)+.
Reaction SMILES: I[C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:12](/B(O)O)=[CH:13]\[CH3:14].C([O-])([O-])=O.[K+].[K+]>CCO.[Pd]>[CH3:11][C:10]1[C:2](/[CH:12]=[CH:13]/[CH3:14])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1I
Reactant: C/C=C/B(O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C/C=C/c1c(C)cccc1C(=O)O
Yield: 105.1 %

Procedure:
To a solution of 2-iodo-3-methyl-benzoic acid (708 mg, 2.70 mmol) and trans-1-propen-1-ylboronic acid (526 mg, 6.12 mmol) in EtOH (10 mL) is added palladium anchored homogeneous catalyst, FibreCatPd(0) (4.84% Pd, 235 mg, 0.15 mmol) and 2M aqueous solution of K2SO4 (3.06 mL, 6.12 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 7 h. After concentration in vacuo, the residue is purified by HPLC to give a pure product (162) as a pale yellow solid (500 mg, 93%).
Reaction SMILES: [C:1]([C:3]([OH:5])=[O:4])#N.[C:6]([CH2:8][CH2:9][C:10]1C=C[C:13](C(O)=O)=[CH:12][CH:11]=1)#[N:7].BrCCCCCCCC(O)=O.[C-]#N.[Na+].Cl.C#N>CO.O.CCOC(C)=O>[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:1][C:3]([OH:5])=[O:4])#[N:7]
Reactant: N#CC(=O)O
Reactant: N#CCCc1ccc(C(=O)O)cc1
Agent: C#N
Agent: Cl
Agent: O=C(O)CCCCCCCBr
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: N#CCCCCCCCC(=O)O
Temperature: 25 °C
Yield: 74 %

Procedure:
The preparation of the cyano-carboxylic acid representing substrate B10 was adapted from a procedure for the preparation of 4-(2-cyanoethyl)benzoic acid (Delia, T. J., Baumann, M., Bunker, A. Heterocycles, 35, 1397-1410 (1993)). To 501 mg (2.25 mmol) of 8-bromooctanoic acid in 7.0 mL of methanol was added 520 mg NaCN (10.6 mmol) in 2.0 mL H2O. The solution was heated at reflux for 2.5 h. After cooling to 25° C., the solution was acidified to pH˜1.5 with concentrated HCl (caution: HCN gas evolves with the addition of HCl) and diluted with 40 mL EtOAc. The resulting suspension was washed twice with 15 mL H2O. The organic layer was dried by filtration through MgSO4, and the solvent was removed in vacuo to afford 282 mg (74%) of a light brown oil. The 1H NMR spectrum agreed with previously reported data in Cotarca et al. Synthesis 1997, 328-332.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[CH2:5][CH2:6][CH2:7][C:8](=O)[C:9]=2[CH:10]=1.Cl.[NH2:13][OH:14].C([O-])(=O)C.[Na+]>CO>[Br:1][C:2]1[NH:3][C:4]2[CH2:5][CH2:6][CH2:7][C:8](=[N:13][OH:14])[C:9]=2[CH:10]=1
Reactant: NO
Reactant: O=C1CCCc2[nH]c(Br)cc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=C1CCCc2[nH]c(Br)cc21
Yield: 114.6 %

Procedure:
A solution of 2-bromo-6,7-dihydro-1H-indol-4(5H)-one (303a) (222 mg, 1.04 mmol), hydroxylamine hydrochloride (80 mg, 1.14 mmol), and sodium acetate (94 mg, 1.14 mmol) in MeOH (28 mL) was stirred under argon at 50° C. for 22 h. The reaction mixture was then concentrated in vacuo, and the residue was partitioned between saturated aq. NaHCO3 (40 mL) and EtOAc (60 mL). The organic layer was separated, and the aq. layer was extracted with EtOAc (60 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-bromo-6,7-dihydro-1H-indol-4(5H)-one oxime (273 mg) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm: (˜2:1 mixture of oxime isomers) Major isomer: 7.99 (1H, br. s.), 6.36 (1H, br. s.), 2.71 (2H, br. s.), 2.63 (2H, br. s.), 1.89-1.98 (2H, m). Minor isomer: 1H NMR (400 MHz, CDCl3) δ ppm 8.14 (1H, br. s.), 6.97 (1H, br. s.), 2.67-2.75 (2H, m), 2.47 (2H, br. s.), 1.99 (2H, br. s.). m/z (ESI, +ve) 228.9/231.1 (M+H)+.
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:11]([O-])=[CH:12][C:13](=O)[C:14]([O:16]CC)=[O:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[Cl:44][C:45]1[CH:50]=[C:49]([NH:51][NH2:52])[CH:48]=[CH:47][N:46]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:11]2[N:51]([C:49]3[CH:48]=[CH:47][N:46]=[C:45]([Cl:44])[CH:50]=3)[N:52]=[C:13]([C:14]([OH:16])=[O:15])[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: NNc1ccnc(Cl)c1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: COc1cc(Br)cc(-c2cc(C(=O)O)nn2-c2ccnc(Cl)c2)c1

Procedure:
500 mg (1.19 mmol) of the compound of Example 6A is reacted analogously to the synthesis of the compound of Example 20A with 322 mg (1.79 mmol) of 2-chloropyridin-4-yl-hydrazine hydrochloride. After hydrolysis, 259 mg (53% of theory) of the title compound is obtained.
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.C(O[CH:13]([O:15][CH2:16][CH:17]1[CH2:31][N:21]2[S:22](=[O:30])(=[O:29])[C:23]3[S:28][CH:27]=[CH:26][C:24]=3[CH:25]=[C:20]2[CH2:19][NH:18]1)[CH3:14])C>C1COCC1>[CH3:14][CH:13]1[N:18]2[CH2:19][C:20]3[N:21]([CH2:31][CH:17]2[CH2:16][O:15]1)[S:22](=[O:30])(=[O:29])[C:23]1[S:28][CH:27]=[CH:26][C:24]=1[CH:25]=3
Reactant: CCOC(C)OCC1CN2C(=Cc3ccsc3S2(=O)=O)CN1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: C1CCOC1
Product: CC1OCC2CN3C(=Cc4ccsc4S3(=O)=O)CN21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methane sulfonic anhydride (0.78 g, 4.53 mmol) was added to a solution of the product of Step F (1,3 g, 3.78 mmol) in THF (40 mL) at 0° C. This mixture was stirred for 1 h and then allowed to warm to room temperature and stirred for an additional 2 h. The reaction mixture was washed with a saturated solution of sodium bicarbonate and extracted with ethyl acetate (3×100mL). The combined extracts were dried (MgSO4) and evaporated to a residue which was purified by column chromatography (silica, acetone/hexane, 1:1) to give 1 g (83%) of an off white amorphous solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][CH:18]=3)[CH:13]=2)[N:3]=1.COC1C=C2C(C=CC(OCCO)=C2)=CC=1.[NH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C([O-])([O-])=O.[K+].[K+]>>[CH3:23][O:22][C:16]1[CH:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([O:11][CH2:10][CH2:9][O:8][C:4]3[CH:5]=[N:6][CH:7]=[C:2]([N:40]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)[N:3]=3)=[CH:13]2)=[CH:18][CH:17]=1
Reactant: COc1ccc2ccc(OCCOc3cncc(Cl)n3)cc2c1
Reactant: C1CNCCN1
Agent: COc1ccc2ccc(OCCO)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc2ccc(OCCOc3cncc(N4CCNCC4)n3)cc2c1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-[2-(7-methoxy-naphthalen-2-yloxy)-ethoxy]pyrazine [1.19 g, 3.60 mmol; obtained according to the procedure of example 50, step 1, starting from 2-(7-methoxy-naphthalen-2-yloxy)ethanol*], piperazine (1.25 g, 14.5 mmol) and K2CO3 (0.60 g, 4.3 mmol) with the exception that the final filtration through alumina was omitted. The yield of the of the title compound was 0.98 g (71%) which was obtained as an oil that solidified when refrigerated. Purity 100% (HPLC). MS m/z 380 (M)+. HRMS m/z calcd for C21H24N4O3 (M)+ 380.1848, found 380.1851.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([CH:23]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([CH:14]=[C:15]([NH:17][C:18]([CH:20]3[CH2:22][CH2:21]3)=[O:19])[N:16]=2)[N:13]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:20]1([C:18]([NH:17][C:15]2[N:16]=[C:11]3[CH:10]=[CH:9][C:8]([O:7][C:6]4[CH:23]=[C:2]([NH:1][C:30](=[O:31])[C:29]5[CH:33]=[CH:34][CH:35]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=5)[CH:3]=[CH:4][C:5]=4[CH3:24])=[N:13][N:12]3[CH:14]=2)=[O:19])[CH2:22][CH2:21]1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 72.8 %

Procedure:
Using N-[6-(5-amino-2-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol), 3-(trifluoromethyl)benzoic acid (93 mg, 0.49 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (94 mg, 0.49 mmol), 1-hydroxybenzotriazole (66 mg, 0.49 mmol) and N,N-dimethylformamide (7.0 mL) as starting materials and in the same manner as in Example 318, the title compound (166 mg, 72%) was obtained as a white powder.
Reaction SMILES: C([O:5][C:6](=[O:43])[C@@H:7]([NH:12][C:13](=[O:42])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[N:22][C:23]3[N:24]([C:26]([C:29]4([C:32]5[CH:33]=[C:34]6[C:39](=[CH:40][CH:41]=5)[N:38]=[CH:37][CH:36]=[CH:35]6)[CH2:31][CH2:30]4)=[N:27][N:28]=3)[N:25]=2)=[CH:16][CH:15]=1)[C:8]([CH3:11])([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:9][C:8]([CH3:11])([CH3:10])[C@H:7]([NH:12][C:13](=[O:42])[C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:21]=[N:22][C:23]3[N:24]([C:26]([C:29]4([C:32]5[CH:33]=[C:34]6[C:39](=[CH:40][CH:41]=5)[N:38]=[CH:37][CH:36]=[CH:35]6)[CH2:30][CH2:31]4)=[N:27][N:28]=3)[N:25]=2)=[CH:18][CH:19]=1)[C:6]([OH:43])=[O:5]
Reactant: CC(C)(C)OC(=O)[C@@H](NC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@H](NC(=O)c1ccc(-c2cnc3nnc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1)C(=O)O
Reaction time: 1.5 h

Procedure:
Tert-butyl-(2S)-3,3-dimethyl-2-({4-[3-(1-quinolin-6-ylcyclopropyl)-[1,2,4]triazolo[4,3-b][1,2,4]triazin-6-yl]benzoyl}amino)butanoate was dissolved in methylene chloride (0.7 ml). To the solution was added TFA (0.7 ml). The mixture was stirred for 1.5 h. The volatiles were removed under reduced pressure to yield the desired product. Analytical LCMS: (M+H)+=522.2.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]([OH:10])=[O:9])[CH2:3]1.[CH2:11](O)[CH3:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:11]([O:9][C:8]([CH:4]1[CH2:5][CH2:6][CH2:7][C:2](=[O:1])[CH2:3]1)=[O:10])[CH3:12]
Reactant: O=C1CCCC(C(=O)O)C1
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCCC(=O)C1
Yield: 100 %

Procedure:
To a round bottom flask was added 3-oxo-1-cyclohexanecarboxylic acid (3.85 g, 27.1 mmol), ethanol (7.91 mL), p-toluenesulfonic acid (0.097 g, 0.56 mmol) and toluene (65.9 mL). The mixture was refluxed with Dean-star trap overnight. The reaction mixture was cooled down and concentrated under reduced pressure to afford 4.61 g (100%) of the title compound, 3-oxo-cyclohexanecarboxylic acid ethyl ester, as a yellow oil, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:22]([CH2:30][CH3:31])[CH:23]2[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:22]([CH2:30][CH3:31])[CH:23]2[CH2:24][CH2:25][CH:26]([OH:29])[CH2:27][CH2:28]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8]
Reactant: CCN(c1cc(Cl)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCN(c1cc(Cl)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCC(O)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-chloro-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(4-oxocyclohexyl)amino)-2-methylbenzamide (0.30 g, 0.68 mmol) in MeOH was added NaBH4 (0.038 g, 1.01 mmol) slowly at 0° C. The resulting reaction mixture was stirred at 0° C. for 2 h. On completion, the reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water, dried, concentrated under reduced pressure and the crude material obtained was purified by acetonitrile and ether washings to afford the title compound as a mixture of isomers (175 mg, 58%). LCMS: 446.35 (M+1)+; HPLC: 74.32% & 24.18% (@ 210-370 nm) (Rt; 5.157 & 5.276); Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.49 (s, 1H), 8.25 (s, 1H), 7.17 (s, 1H), 6.96 (s, 1H), 5.86 (s, 1H), 4.25 (d, 2H, J=4 Hz), 3.33 (m, 1H), 3.04 (m, 2H), 2.19 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H), 1.78 (m, 2H), 1.66 (m, 2H), 1.38 (m, 3H), 1.10 (m, 2H), 0.78 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Solvent: c1ccncc1
Product: O=C(Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1)c1ccccc1

Procedure:
To a solution of 0.75 g. of 5-amino-2-nitro-3-phenylbenzofuran in 5 ml. of pyridine is added 1 ml. of benzoyl chloride. The mixture is heated on a steam bath for about 1 hour, then decanted into 50 ml. of 2 N hydrochloric acid. A yellow residue forms which is recrystallized from a mixture of isopropanol, methanol and water to provide yellow crystals of 5-benzamido-2-nitro-3-phenylbenzofuran having the structure ##STR11##
Reaction SMILES: I[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:36][N:37](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:27][O:26][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][CH2:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH2:9][N:6]1[C:5]2[CH:28]=[CH:29][C:2]([C:36]#[N:37])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: CN(C)C=O
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)ccc43)cc2OC)cn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [C-]#N
Product: COc1ccc(COc2ccc(Cn3cnc4cc(C#N)ccc43)cc2OC)cn1
Temperature: 150 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a stirred solution of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole (1.00 g, 1.99 mmol) in N,N-dimethylformamide (20 mL) was added zinc(II) cyanide (0.64 g, 3.52 mmol), tetrakis(triphenylphosphine)palladium(O) (0.46 g, 0.40 mmol) and potassium carbonate (0.63 g, 4.54 mmol). The mixture was heated to 150° C. After 4 h, the mixture was allowed to cool to room temperature and was concentrated. The residue was purified by silica gel chromatography (2% methanol/dichloromethane elute) to give 0.70 g (87%) of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole-5-carbonitrile as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:20]3[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=3[S:18][C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=3)[CH2:4][CH2:3]1.[CH2:26]([OH:37])[C@H:27]([C@H:29]([C@@H:31]([C@@H](CO)O)O)O)[OH:28].C([O-])(=O)CCCCCCCCCCCCCCCCC.[Mg+2].C([O-])(=O)CCCCCCCCCCCCCCCCC>>[CH3:10][N:11]1[C@@H:12]2[CH2:17][C:16]3[CH:31]=[CH:29][C:27]([OH:28])=[C:26]([OH:37])[C:15]=3[C:14]3[C:13]2=[C:22]([CH:23]=[CH:24][CH:19]=3)[CH2:21][CH2:20]1.[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][N:11]2[C:20]3[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:19]=3[S:18][C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=3)[CH2:4][CH2:3]1
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: CN1CCN(CCCN2c3ccccc3Sc3ccc(Cl)cc32)CC1
Agent: [Mg+2]
Product: CN1CCc2cccc3c2[C@H]1Cc1ccc(O)c(O)c1-3
Reaction time: 0.03 h

Procedure:
Separately, prochlorperazine was added to and blended with the mannitol (Part B). Parts A and B were then combined and mixed for about 5 minutes in a V-shaped blender. Next, magnesium stearate was added to the blender, followed by continued blending for about 2 minutes.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH:11]2[O:15][N:14]=[C:13]([CH3:16])[CH2:12]2)=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[OH:21][C:22]1[CH2:27][CH2:26][CH2:25][C:24](=[O:28])[CH:23]=1.C(N(CC)CC)C.C[Si](C#N)(C)C>C(#N)C.O>[CH3:1][C:2]1[C:10]([CH:11]2[O:15][N:14]=[C:13]([CH3:16])[CH2:12]2)=[C:9]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:8]=[CH:7][C:3]=1[C:4]([C:23]1[C:22](=[O:21])[CH2:27][CH2:26][CH2:25][C:24]=1[OH:28])=[O:5]
Reactant: O=C1C=C(O)CCC1
Reactant: CC1=NOC(c2c(S(C)(=O)=O)ccc(C(=O)Cl)c2C)C1
Agent: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC1=NOC(c2c(S(C)(=O)=O)ccc(C(=O)C3=C(O)CCCC3=O)c2C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2.3 g (7.7 mmol) of 2-methyl-3-(3-methyl-4,5-dihydroisoxazol-5-yl)-4-methylsulfonylbenzoyl chloride in 50 ml of acetonitrile was added dropwise at 0-5° C. to a solution of 0.86 g (7.7 mmol) of 1-hydroxycyclohex-1-en-3-one and 2.13 ml (15.4 mmol) of triethylamine in 50 ml of acetonitrile. After the mixture had been stirred for three hours at room temperature, a further 0.64 ml (4.6 mmol) of triethylamine and 0.16 g (15 mmol) of trimethylsilyl cyanide were added and the mixture was stirred for twelve hours at room temperature. The reaction mixture was then stirred into 800 ml of water and washed with methylene chloride. The aqueous phase was then brought to pH 4 using 10% strength hydrochloric acid and extracted with methylene chloride. After the organic phase had been dried, the solvent was removed and the residue was taken up in diethyl ether and digested. The resulting residue was filtered off with suction. This gave 1.3 g (3.3 mmol; 43% of theory) of the title compounds.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[C@H:10]([CH2:21][CH3:22])[CH2:11][C:12]2=[O:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:23][CH3:24])[CH:4]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].[N:31]#CBr>C(Cl)(Cl)Cl>[C:19]([N:18]1[CH2:17][CH2:16][C@:14]23[C:15]4[C:2]5[O:1][C@H:13]2[C:12](=[O:20])[CH2:11][C@@H:10]([CH2:21][CH3:22])[C@H:9]3[C@H:8]1[CH2:7][C:6]=4[CH:5]=[CH:4][C:3]=5[O:23][CH3:24])#[N:31]
Reactant: N#CBr
Reactant: CC[C@@H]1CC(=O)[C@@H]2Oc3c(OC)ccc4c3[C@@]23CCN(C)[C@H](C4)[C@H]13
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC[C@@H]1CC(=O)[C@@H]2Oc3c(OC)ccc4c3[C@@]23CCN(C#N)[C@H](C4)[C@H]13
Yield: 94 %

Procedure:
4,5α-Epoxy-8α-ethyl-3-methoxy-17-methylmorphinan-6-one 3 (6.50 g, 19.8 mmole) was dissolved in chloroform (100 ml). After the addition of K2CO3 (4.12 g, 29.8 mmole), the stirred suspension was treated dropwise with a solution of cyanogen bromide (2.50 g, 23.8 mmole) in 50 ml of chloroform. After the addition was complete, the mixture was heated to reflux and refluxed for 2 hours. Cooling was followed by removal of the insoluble material by filtration. The filtrate was evaporated to a residue which crystallized on coevaporation with ethanol. The crystals were suspended in hot ethanol, the mixture cooled and the crystals collected to give 6.30 g (94%) of 5 as white needles, mp 212°-217°, in two crops.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(N(CC)CC)C>>[N:20]1([CH2:19][CH2:18][CH2:17][NH:16][S:12]([C:3]2[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[Cl:1])(=[O:14])=[O:13])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Reactant: NCCCN1CCOCC1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)NCCCN2CCOCC2)c1Cl
Yield: 74.5 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (2.0 g, 6.88 mmol), 4-(3-aminopropyl)morpholine (993 mg, 6.88 mmol) and triethylamine(1.92 mL, 13.76 mmol) were reacted to form the desired product (2.04 g, 74%). LC-MS (m/z) 398.0 (M+).
Reaction SMILES: [CH:1]1[C:17]2[C:4]([CH:5]=[CH:6][C:7]3[C:16]=2[CH:15]=[C:14]2[C:9](=[CH:10][CH2:11][C:12](=[O:18])[CH2:13]2)[CH:8]=3)=[N:3][N:2]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(O)(=O)C>[C:19]([N:2]1[CH:1]=[C:17]2[C:4]([CH:5]=[CH:6][C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][C:16]=32)[CH2:13][C:12](=[O:18])[CH:11]=[CH:10]4)=[N:3]1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CC=c2cc3ccc4c(c3cc2C1)C=NN=4
Solvent: CC(=O)O
Product: CC(=O)n1cc2c(ccc3cc4c(cc32)CC(=O)C=C4)n1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Due to limited solubility of Compound 1, purification of the same may be achieved by first derivatizing Compound 1 to a more soluble intermediate, such as the corresponding acetate, recrystallizing the intermediate, and then converting the intermediate to yield purified Compound 1 in good yield. More specifically, to solution of the pyrazoloanthrone (9.67 g, 43.9 mmol) in acetic acid (700 mL) is added acetic anhydride (12.4 mL, 132 mmol). The solution is heated to 80° C. for 5 hours and then cooled to room temperature. After 16 hours, the reaction is cooled to 0° C. for 2 hours. The reaction is then filtered to give the N-acetylpyrazoloanthrone intermediate. This intermediate is recrystallized in acetic acid to give the pure intermediate (5.96 g, 52%). 1H NMR (CDCL3) δ 10.6 (br s, 1 H), 8.46 (d, 1 H), 8.33 (d, 1 H), 8.26 (d, 1 H), 8.08 (d, 1 H), 7.96-7.87 (m, 2H), 7.78 (t. 1H), 2.83 (s, 3H); ES-MS (m/z) 263 [M+1]+. To a solution of the pure intermediate, (5.96 g, 23 mmol) in methanol (600 mL) is added ammonium hydroxide (60 mL). The reaction is stirred at room temperature for 16 hours and then filtered and dried in a vacuum oven. A second crop of crystals is recovered to give a total of 4.8 g of Compound 1 at greater than 98% purity. ES-MS (m/z) 221 [M+I]30 .