Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:32]([NH2:34])=[O:33])[C:14]3[NH:15][C:16]4[C:21]([C:22]=3[CH:23]=2)=[CH:20][CH:19]=[C:18]([N:24]2[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]2)[CH:17]=4)=[CH:7][C:6]=1[Cl:35].[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:35][C:6]1[CH:7]=[C:8]([C:11]2[CH:12]=[C:13]([C:32]([NH2:34])=[O:33])[C:14]3[NH:15][C:16]4[C:21]([C:22]=3[CH:23]=2)=[CH:20][CH:19]=[C:18]([N:24]2[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]2)[CH:17]=4)[CH:9]=[CH:10][C:5]=1[O:4][CH2:3][CH2:2][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: C1COCCN1
Reactant: NC(=O)c1cc(-c2ccc(OCCBr)c(Cl)c2)cc2c1[nH]c1cc(N3CCS(=O)(=O)CC3)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2ccc(OCCN3CCOCC3)c(Cl)c2)cc2c1[nH]c1cc(N3CCS(=O)(=O)CC3)ccc12
Temperature: 75 °C
Yield: 97 %

Procedure:
3-(4-(2-Bromoethoxy)-3-chlorophenyl)-7-(1,1-dioxo-thiomorpholino)-9H-carbazole-1-carboxamide (48.6 mg, 0.076 mmol, Example 408C) was dissolved in DMF (5 ml). Morpholine (0.1 ml, 1.15 mmol) and K2CO3 (40 mg, 0.29 mmol) were added and the mixture heated to 75° C. for 2 hour. The mixture was filtered through a 0.45 um Nylon filter and purified by prep HPLC. Product containing fractions were evaporated to dryness to give 43.0 mg 3-(3-chloro-4-(2-morpholinoethoxy)phenyl)-7-(1,1-dioxo-thiomorpholino)-9H-carbazole-1-carboxamide. MS (ESI) m/e+=583/585, m/e−=581/583 [1 Cl isotope pattern]. HPLC retention time 14.31 min. (Sunfire C18 3.5 μm, 3.0×150 mm column, 15 min gradient, 10-100% B, 0.5 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA), then isocratic at 100% B. 1H NMR (DMSO-d6) δ ppm 11.12 (s, 1H), 8.53 (d, 1H, J=1.2), 8.35 (b, 1H), 8.16 (d, 1H, J=1.5), 8.11 (d, 1H, J=8.8), 7.99 (d, 1H, J=2.3), 7.82 (dd, 1H, J=8.5, 2.2), 7.53 (b, 1H), 7.34 (d, 1H, J=2.0), 7.31 (d, 1H, J=8.8), 7.00 (dd, 1H, J=8.8, 2.2), 4.26 (t, 2H, J=5.8), 3.85 (b, 4H), 3.64-3.59 (m, 4H), 3.23 (b, 4H), 2.79 (t, 2H, J=5.8), 2.58-2.54 (m, 4H).
Reaction SMILES: [C:1]([O-:8])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].CN(C(ON1N=NC2[CH:20]=[CH:21][CH:22]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:33](N(C(C)C)CC)([CH3:35])[CH3:34].N>CN(C=O)C>[CH2:35]([O:5][C:4](=[O:6])[CH2:3][CH2:2][C:1]([O:8][CH2:22][CH:21]=[CH2:20])=[O:7])[CH:33]=[CH2:34]
Reactant: O=C([O-])CCC(=O)[O-]
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: C=CCOC(=O)CCC(=O)OCC=C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
11 (240 mg, 0.46 mmol) and HATU (350 mg, 0.92 mmol) were dissolved in DMF (2 mL) and diisopropylethylamine (0.16 mL, 0.92 mmol) was added. The mixture was stirred for 15 min at ambient temperature, and then treated with anhydrous ammonia for 20 min. Stirring was continued overnight. DMF was removed in vacuo, and the residue was diluted with ethyl acetate, washed with water and brine, then dried over MgSO4. After evaporation of the solvent, the residue was purified on silica gel (5% methanol/methylene chloride) to afford product 12 as a white solid. 12, a mixture of two diastereomers, was then separated on silica gel, using increasing gradient of 20-50% ethyl acetate-methylene chloride, to give first eluting isomer 12a (43 mg, 18%) and the second eluting isomer 12b (61 mg, 25%) both as a white solids. 12a: MS m/z 521.2 (MH+). 12b: MS m/z 521.2 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([S:16]C#N)=[CH:8][C:7]=1[CH3:19].SC[C@H]([C@@H](CS)O)O>CCO>[CH3:1][O:2][C:3](=[O:20])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:9]([SH:16])=[CH:8][C:7]=1[CH3:19]
Reactant: COC(=O)COc1cc(C(C)(C)C)c(SC#N)cc1C
Agent: O[C@H](CS)[C@H](O)CS
Solvent: CCO
Product: COC(=O)COc1cc(C(C)(C)C)c(S)cc1C

Procedure:
1.00 g (3.4 mmol) of (5-tert-butyl-2-methyl-4-thiocyanato-phenoxy)acetic acid methyl ester prepared in Example KKK was combined with 3.16 g (20 mmol) dithiothreitol (DTT) in a solution of 10 mL 0.02 M K2PO4 buffer and 40 mL of EtOH. The reaction was refluxed overnight, then cooled and partially concentrated. After dilution with water, the mixture was extracted with EtOAc, and the organic layer washed with saturated aqueous brine, dried (Na2SO4) and concentrated. The residue was chromatographed on silica gel eluting with 3:1 hexanes:EtOAc, to give the title compound. 1H NMR (CDCl3) δ 1.44 (s, 9 H), 2.19 (s, 3 H), 3.46 (s, 1 H), 3.80 (s, 3 H), 4.62 (s, 2 H), 6.76 (s, 1 H), 7.06 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][CH2:16][NH:17][CH3:18]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:17]([CH3:18])[CH2:16][CH2:15][CH2:14][N:13]([CH3:19])[CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: CNCCCN(C)C
Product: CN(C)CCCN(C)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round bottom flask at 0° C. was added 4-Bromo-1-fluoro-2-nitrobenzene (10 g, 45 mmol) and N,N,N′-Trimethyl-propane-1,3-diamine (6.99 ml, 47.7 mmol). The reaction was allowed to warm to RT and stirred for 16 h. The reaction was extracted into EtOAc, washed once with saturated aqueous NaHCO3, twice with water, and then dried over Mg2SO4. The organic layer was filtered and concentrated to yield the title compound as a bright orange solid. MS (M+H+)=316, 318; Calc'd for C12H18BrN3O2=316.19.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[NH2:7][C:8]([NH2:10])=[S:9]>CC(C)=O>[ClH:1].[Cl:1][CH2:2][C:3]1[N:7]=[C:8]([NH2:10])[S:9][CH:5]=1
Reactant: O=C(CCl)CCl
Reactant: NC(N)=S
Solvent: CC(C)=O
Product: Cl
Product: Nc1nc(CCl)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 128.8 %

Procedure:
To a solution of 1,3-dichloroacetone (150 g, 1.18 mol) in acetone (600 mL) was added a solution of thiourea (91.7 g, 1.23 mol) in acetone (3000 mL). The mixture was stirred overnight at room temperature. The resulting suspension was concentrated to dryness in vacuo. Ethanol (1.2 L) was added and the mixture was stirred for 3 h. The insolubles were removed by filtration and the filtrate was concentrated to 500 mL. Heptanes (1.5 L) were slowly added resulting in the formation of a white precipitate. This was isolated by filtration, washed with heptane and dried in vacuo to afford 4-(chloromethyl)thiazol-2-amine hydrochloride as a white solid (141.3 g, 0.76 mol, 64%). 1H NMR (DMSO-d6): δ 9.50 (bs, 2H); 7.00 (s, 1H); 4.68 (s, 2H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:12]2C=CC=CC=2N=N1.[CH2:28]([C:35]1[N:39]([CH3:40])[N:38]=[C:37]([CH3:41])[C:36]=1[C:42]([OH:44])=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[C:45]12(NC)[CH2:54][CH:49]3[CH2:50][CH:51]([CH2:53][CH:47]([CH2:48]3)[CH2:46]1)[CH2:52]2.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:45]12([CH2:12][NH:8][C:42]([C:36]3[C:37]([CH3:41])=[N:38][N:39]([CH3:40])[C:35]=3[CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:44])[CH2:46][CH:47]3[CH2:48][CH:49]([CH2:50][CH:51]([CH2:53]3)[CH2:52]1)[CH2:54]2
Reactant: Cc1nn(C)c(Cc2ccccc2)c1C(=O)O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CNC12CC3CC(CC(C3)C1)C2
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(C)c(Cc2ccccc2)c1C(=O)NCC12CC3CC(CC(C3)C1)C2
Reaction time: 14 h

Procedure:
BOP (44 mg, 0.1 mmol) is added to a solution of 5-benzyl-1,3-dimethyl-1H pyrazole-4-carboxylic acid (20 mg, 0.087 mmol), admantan-1-yl-methylamine (15 mg, 0.09 mmol), HOBt (5 mg) and DIEA (17 μL, 0.1 mmol) in DMF (0.5 mL) at it. The mixture is stirred for 14 h. H2O is added, and the mixture is extracted with EtOAc (3×10 mL). The organic phase is dried. The title compound is obtained by PTLC using 20% EtOAc in hexane. 1H NMR (CDCl3): 7.29-7.21 (m, 3H), 7.12-7.11 (in, 2H), 5.39 (m, 1H), 4.33 (s, 2H), 3.65 (s, 3H), 3.07 (m, 2H), 2.46 (s, 3H), 1.94 (m, 3H), 1.70-1.56 (m, 12H). MS (M+1)=378.22; RT=1.67 min. *IC50.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Br:13][C:14]1[C:15]([C:19]([OH:21])=[O:20])=[CH:16][S:17][CH:18]=1.CN(P(N(C)C)(N(C)C)=O)C.CON(C)[C:36]([C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1)=[O:37]>C1COCC1>[Br:13][C:14]1[C:15]([C:19]([OH:21])=[O:20])=[C:16]([C:36](=[O:37])[C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)[S:17][CH:18]=1
Reactant: CON(C)C(=O)c1ccncc1
Reactant: O=C(O)c1cscc1Br
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: O=C(c1ccncc1)c1scc(Br)c1C(=O)O
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
To a solution of (i-Pr)2NH (5.3 g, 53 mmol) in anhydrous THF (40 mL) at −78° C. was added n-BuLi (23.2 mL, 58 mmol, 2.5M in hexane) dropwise. The mixture was stirred at the same temperature for 0.5 h. Then a solution of 4-Bromothiophene-3-carboxylic acid (5.0 g, 24 mmol) and HMPA (0.86 g, 4.8 mmol) in anhydrous THF (50 mL) was slowly added. The mixture was stirred at the same temperature for 1 h and N-methoxy-N-methyl-4-pyridine carboxamide (8.0 g, 48 mmol) was added dropwise to the stirring mixture at −78° C. The reaction mixture was stirred for another hour at room temperature and was then quenched with H2O. The aqueous layer was acidified with 5% aq. HCl to pH 1˜2. The precipitate was removed by filtration and the resulting filtrate extraxted with CH2Cl2 (3×200 mL). The organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude product was washed with CH2Cl2 to give the title compound (1.6 g, 20% yield) as a yellow solid. LC-MS (Method A): m/z 312 (M+H)+, Rt: 0.55 min. 1H NMR (400 MHz, DMSO-d6): δ=13.61 (s, 1H), 8.81-8.80 (m, 2H), 8.25 (s, 1H), 7.67-7.65 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[C:4]([N+:13]([O-:15])=[O:14])[CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C1C=CC=CC=1>CO>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([OH:29])[CH2:24][CH2:25][N:26]([CH2:9][CH2:10][NH:8][C:6](=[O:7])[C:5]3[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=3[N+:13]([O-:15])=[O:14])[CH2:27][CH2:28]2)=[CH:19][CH:18]=1
Reactant: O=C(c1ccc(F)cc1[N+](=O)[O-])N1CC1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Solvent: CO
Solvent: c1ccccc1
Product: O=C(NCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccc(F)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
A mixture of 15 parts of 1-(4-fluoro-2-nitrobenzoyl)-aziridine, 11 parts of 4-(4-chlorophenyl)-4-piperidinol, 55.8 parts of benzene and 8.8 parts of methanol is stirred and refluxed for 1.50 hours. After stirring is continued overnight at room temperature, the reaction mixture is evaporated. The residue is dissolved in trichloromethane. The solution is washed with water and 8 parts of methanol are added. The whole is stirred for 10 minutes with silica gel. The latter is filtered off and the filtrate is evaporated. The residue is triturated with 2,2'-oxybis propane. The precipitated product is filtered off and crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 9.5 parts of N-{2-[4-(4-chlorophenyl)-4- hydroxy-1-piperidinyl]ethyl}-4-fluoro-2-nitrobenzamide; mp. 144.3° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][N+:3]=1[O-:11].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=1>C(O)C>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][NH:21][C:2]2[N+:3]([O-:11])=[CH:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=2)=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(Cl)c1
Reactant: COc1ccc(CN)cc1
Solvent: CCO
Product: COc1ccc(CNc2cc([N+](=O)[O-])cc[n+]2[O-])cc1
Temperature: 25 °C
Yield: 43.6 %

Procedure:
A mixture of 2-chloro-4-nitropyridine-1-oxide (75 g, 0.43 mol) and 1-(4-methoxyphenyl)-methanamine (125 g, 0.91 mol) in ethanol (1 L) was heated at reflux for 5 h. The reaction was allowed to cool to room temperature and cooled in a freezer overnight. The resulting cold mixture was filtered. The isolated solid was further slurried in methanol (100 mL) and filtered to give N-(4-methoxybenzyl)-4-nitropyridin-2-amine 1-oxide (51.62 g, 40% yield) as an orange solid. LCMS: (FA) ES+ 276; 1H NMR (400 MHz, d6-DMSO) δ ppm 8.34 (dd, J=6.5, 0.8 Hz, 1H), 8.27 (t, J=6.7, 6.7 Hz, 1H), 7.39-7.34 (m, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.89 (d, J=8.6 Hz, 1H), 4.52 (d, J=6.6 Hz, 1H), 3.70 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[Br:11]Br>C(Cl)(Cl)(Cl)Cl>[Br:11][C:8]1[C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][C:6]=2[O:10][CH:9]=1
Reactant: BrBr
Reactant: Clc1nccc2occc12
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1nccc2occ(Br)c12
Temperature: 25 °C
Yield: 96.3 %

Procedure:
A solution of 4-chlorofuro[3,2-c]pyridine (10.60 g, 69 mmol, 1.0 eq) in carbon tetrachloride (135 mL) was cooled to −15° C. and bromine (12.13 g, 80 mmol, 1.2 eq) was added drop-wise over a fifteen minute time period. The mixture was stirred at ambient temperature for eighteen hours. The solvent was removed in vacuo, and the residue was dissolved in methanol (250 mL). A solution of 20% aqueous sodium hydroxide (35 mL) was added and the mixture was stirred 1 hour at ambient temperature. The methanol was removed in vacuo, and the residue was partitioned between water (100 mL) and dichloromethane (50 mL). The layers were separated and the aqueous phase was extracted with dichloromethane (50 mL). The combined organic layers were dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to give the title compound (15.45 g, 96%) as a solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.54 (s, 1H), 8.37 (d, 1H), 7.87 (d, 1H); RP-HPLC (Conditions f) Rt 11.46 min.; MS: MH+ 232, 234.
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:2].Cl[CH2:11][CH2:12][C:13]12[CH2:20][CH2:19][CH2:18][N:17]1[CH2:16][CH2:15][CH2:14]2>>[N:17]12[CH2:18][CH2:19][CH2:20][C:13]1([CH2:12][CH2:11][N:3]([CH:1]=[O:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:14][CH2:15][CH2:16]2
Reactant: ClCCC12CCCN1CCC2
Reactant: O=CNc1ccccc1
Product: O=CN(CCC12CCCN1CCC2)c1ccccc1

Procedure:
The procedures described in Example 2 were repeated except that formanilide (1.80 g, 14.9 mmol) and 5-(2-chloroethyl)-1-azabicyclo[3.3.0]octane (hydrochloride, 3.43 g, 16.3 mmol ) were employed. In this case, the desired compound was obtained as a pale yellow liquid (3.39 g, 88.1 %).
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:10](B(O)O)=[C:6]2[C:5](=[O:22])[N:4]([CH3:23])[C:3]1=[O:24].Br[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1.[OH-].[Ba+2].[OH-].O>C(OCCCC)(=O)C.Cl>[F:32][C:28]1[CH:27]=[C:26]([C:10]2[N:9]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=[C:7]3[C:6]=2[C:5](=[O:22])[N:4]([CH3:23])[C:3](=[O:24])[N:2]3[CH3:1])[CH:31]=[CH:30][CH:29]=1
Reactant: Cn1c(=O)c2c(B(O)O)n(COCC[Si](C)(C)C)cc2n(C)c1=O
Reactant: Fc1cccc(Br)c1
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CCCCOC(C)=O
Product: Cn1c(=O)c2c(-c3cccc(F)c3)n(COCC[Si](C)(C)C)cc2n(C)c1=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1,3-dimethyl-2,4-dioxo-6-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-ylboronic acid (Intermediate Ga Step 2) (7.31 g, 20.7 mmol), 1-bromo-3-fluorobenzene (2.10 mL, 18.8 mmol), Pd-118 (245 mg, 0.38 mmol), and barium hydroxide (6.44 g, 37.6 mmol) in n-butyl acetate (64 mL) was heated to 80° C. Water (4.06 mL, 226.0 mmol) was added and the mixture was stirred vigorously at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature diluted with 1M HCl(aq) (100 mL) and was extracted with DCM (3×100 mL). The combined organic layers were washed with saturated brine (1×100 mL), dried over magnesium sulfate and the evaporated under vacuum. The residue was recrystallised from methanol to afford the title compound.
Reaction SMILES: O1CCN(C=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])CC1.[O:18]=O>Cl[Cu].CS(C)=O>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:8]=[O:18])([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccccc1C=CN1CCOCC1
Reactant: O=O
Agent: Cl[Cu]
Solvent: CS(C)=O
Product: O=Cc1ccccc1[N+](=O)[O-]
Reaction time: 1.5 h

Procedure:
50 mmol of β-morpholino-2-nitrostyrene and 1 g of CuCl were initially introduced into 120 ml of DMSO and aerated at 60° C. for 90 min. using oxygen. After concentrating and customary working-up, 0.41 mol of o-nitrobenzaldehyde was isolated.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11]Cl)[C:5]=2[O:4][CH2:3][CH2:2]1.[C-:13]#[N:14].[Na+].CS(C)=O>C(OCC)(=O)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][C:13]#[N:14])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: ClCc1cccc2c1OCCO2
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#CCc1cccc2c1OCCO2
Temperature: 65 °C
Reaction time: 18 h
Yield: 68.8 %

Procedure:
Add (2,3-Dihydrobenzo[1,4]dioxin-5-yl)chloromethane (1.9 g, 10.2 mmol) and sodium cyanide (655 mgs, 13.3 mmol) to dimethylsulfoxide (20 mL). Stir under nitrogen at 65° C. for 18 hours. Dilute the reaction with ethyl acetate, wash with 0.1 molar aqueous sodium carbonate and aqueous saturated sodium chloride. Dry the organic phase over anhydrous magnesium sulfate, filter and concentrate under reduced pressure. Chromatograph on flash silica using a gradient from neat hexane to 50% ethyl acetate in hexane to obtain 1.23 g (68%) of the desired compound as a white solid.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.Cl.[CH3:23][N:24]1[CH2:30][C:29]2[CH:31]=[C:32](/[CH:35]=[CH:36]/[C:37](O)=O)C=N[C:28]=2[NH:27][C:26](=O)[CH2:25]1.CNCC1N(C)C2C(C=1)=CC=CC=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([N:27]([CH3:28])[CH2:26][C:25]2[N:24]([CH3:23])[C:30]3[C:36]([CH:37]=2)=[CH:35][CH:32]=[CH:31][CH:29]=3)=[O:13])=[CH:5][C:4]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1
Reactant: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Reactant: CN1CCN(Cc2cc(/C=C/C(=O)O)cnc2N)CC1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CNCc1cc2ccccc2n1C
Agent: Cl
Product: CN1CCN(Cc2cc(/C=C/C(=O)N(C)Cc3cc4ccccc4n3C)cnc2N)CC1
Yield: 14 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-[6-amino-5-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (136 mg, 14%) was prepared as an off-white powder and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.7 (br s, 1H), 8.39 (s, 1H), 8.33 (s, 1H), 8.07 (br s, 2H), 7.55-7.01 (m, 6H), 6.41-6.17 (m, 1H), 5.07-4.85 (m, 2H), 3.73-3.62 (m, 7H), 3.11-2.98 (m, 8H), 2.73 (s, 3H);
Reaction SMILES: [I-:1].[CH3:2][C:3]([C:6]1[CH:15]=[CH:14][C:13]2[N:12]3[C:16]4[CH:25]=[CH:24][C:23]5[CH:22]=[C:21](F)[CH:20]=[CH:19][C:18]=5[N+:17]=4[CH:27]=[C:11]3[CH:10]=[CH:9][C:8]=2[CH:7]=1)([CH3:5])[CH3:4].C[N:29]1[CH2:33][CH2:32][CH2:31][C:30]1=O.N1CCCC1>C(OCC)(=O)C>[I-:1].[CH3:2][C:3]([C:6]1[CH:15]=[CH:14][C:13]2[N:12]3[C:16]4[CH:25]=[CH:24][C:23]5[CH:22]=[C:21]([N:29]6[CH2:33][CH2:32][CH2:31][CH2:30]6)[CH:20]=[CH:19][C:18]=5[N+:17]=4[CH:27]=[C:11]3[CH:10]=[CH:9][C:8]=2[CH:7]=1)([CH3:5])[CH3:4]
Reactant: CC(C)(C)c1ccc2c(ccc3c[n+]4c5ccc(F)cc5ccc4n32)c1
Reactant: CN1CCCC1=O
Agent: [I-]
Solvent: C1CCNC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc2c(ccc3c[n+]4c5ccc(N6CCCC6)cc5ccc4n32)c1

Procedure:
A mixture of 141 g. of 10-(1,1-dimethylethyl)-3-fluoroimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide, 725 ml. of N-methyl-2-pyrrolidinone and 75 ml. of pyrrolidine is stirred and heated at reflux for 1 hour, then cooled and diluted with 3.6 l. of ethyl acetate. The resulting precipitate of 10-(1,1-dimethylethyl)-3-(1-pyrrolidinyl)imidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration, washed with water and dried; m.p. >360° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[C:12]([NH2:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[C:18]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[C:12]([NH:19][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(OCc2ccccc2)c2c1OCCO2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Nc1ccc(OCc2ccccc2)c2c1OCCO2
Reaction time: 7 h

Procedure:
To a solution of 30 g of 5-benzyloxy-8-amino-1,4-benzodioxane (XX), code number 760 727, in 250 ml of chloroform, 21.3 ml of triethylamine, then slowly, at 0° C., 15.2 g of ethyl chloroformate were added. The solution was stirred for 7 hours, filtered and the filtrate was washed with a diluted hydrochloric acid solution, with water, with a solution of sodium bicarbonate and with water. The solvent was evaporated and the residue recrystallized in ethylacetate.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Br:26]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:26])[N:6]2[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1nc(NCc2ccccc2)nc2c1ncn2Cc1ccccc1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Nc1nc(NCc2ccccc2)nc2c1nc(Br)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
6-Amino-9-benzyl-2-(N-benzylamino)purine (60 mg, 0.18 mmol) and bromine (0.5 ml) were dissolved in 50 ml of methylene chloride and the solution was stirred at room temperature for 1 hour. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on sodium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (37 mg, yield 50%).
Reaction SMILES: [CH3:1][C:2]([NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)([CH3:6])[C:3]([OH:5])=[O:4].[CH2:15]=O.[H][H]>CCO.[OH-].[OH-].[Pd+2]>[CH3:6][C:2]([N:7]([CH3:15])[CH2:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(NCC1CCOCC1)C(=O)O
Reactant: C=O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CN(CC1CCOCC1)C(C)(C)C(=O)O
Temperature: 100 °C
Reaction time: 24 h
Yield: 84.1 %

Procedure:
1.00 g (4.97 mmol) of 2-methyl-2-[(tetrahydro-pyran-4-ylmethyl)-amino]propionic acid is suspended in 20 mL of EtOH. 350 mg Pd(OH)2 (0.50 mmol, w=20%) are added, followed by 0.74 mL of formaldehyde (9.88 mmol; 37% in water). The suspension is stirred for 24 h at 100° C. and 2916 kPa hydrogen pressure. The reaction mixture is filtered through celite and washed with EtOH. The solvent is removed under reduced pressure to afford 0.90 g of 2-methyl-2-[methyl-(tetrahydro-pyran-4-ylmethyl)-amino]-propionic acid. Yield: 84%; ESI-MS: 216 [M+H]+