Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[N:21]=1>Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: COc1cccc(Br)n1
Agent: Cl
Product: COc1cccc(NCCCOc2cccc(CN3CCCCC3)c2)n1
Reaction time: 5 h
Yield: 23 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (14.90 g) and 2-bromo-6-methoxypyridine (5.64 g) were heated with stirring in an oil bath at 165°-170° C. for 5 hours. The reaction mixture was cooled, dissolved in dilute hydrochloric acid to pH 3-4, washed with ether (5 times), taken to pH 9-10 with dilute sodium hydroxide, extracted into ether (5 times). The pH was adjusted after each extraction. The latter ether extracts were combined, dried (MgSO4), evaporated under reduced pressure, and subjected to medium pressure chromatography on silica using ethyl acetate as eluant, to yield the title compound as an oil (2.45 g). This was treated with maleic acid in ethanol to give 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-6-methoxypyridine dimaleate (2.71 g), m.p. 114.5°-115° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].[CH2:14](I)[CH3:15]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH2:14][CH3:15])[CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:14][CH3:15])=[C:4]([Cl:11])[N:3]=1
Reactant: CCI
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1cnc2c(Cl)nc(Cl)nc21
Product: CCn1cnc2nc(Cl)nc(Cl)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.0 g (5.29 mmol) of 2,6-dichloro-purine is dissolved in DMF (20 ml) and treated with 152 mg (80%, 5.3 mmol) of sodium hydride and the mixture is stirred at RT for 0.5 hours. After addition of 0.42 ml (5.3 mmol) of ethyl iodide, the mixture is stirred at 70° C. for 3 hours, diluted with ethyl acetate (100 ml) and extracted with concentrated brine. The organic phase is dried (sodium sulfate) and concentrated and the residue is chromatographed (silica gel, methylene chloride:methanol=19:1). An oily mixture comprising 2,6-dichloro-7-ethyl-7H-purine and 2,6-dichloro-9-ethyl-9H-purine is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[NH2:13][C:14]1[CH:22]=C[C:17](C(O)=O)=[CH:16][C:15]=1[CH3:23].[C:24]([OH:27])(=[O:26])[CH3:25]>>[C:24]([C:25]1[CH:17]=[CH:16][C:15]([CH3:23])=[C:14]([N:13]2[C:9](=[O:10])[C:4]3=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=[C:5]3[C:6]2=[O:8])[CH:22]=1)([OH:27])=[O:26]
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: CC(=O)O
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Product: Cc1ccc(C(=O)O)cc1N1C(=O)c2ccc(Cl)cc2C1=O
Temperature: 25 °C

Procedure:
The starting material is prepared as follows: The suspension of 6.0 g of 4-chlorophthalic anhydride, 5.0 g of 4-amino-3-methylbenzoic acid and 75 ml of acetic acid is refluxed for 3 hours, cooled to room temperature, filtered and the residue washed with diethyl ethyl, to yield the N-(4-carboxy-o-tolyl)-4-chlorophthalimide melting at 250°-252°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([F:16])[CH:7]=1.[C:20]([NH2:23])(=[S:22])[CH3:21]>>[CH3:1][O:2][C:3]([C:4]1[N:23]=[C:20]([CH3:21])[S:22][C:5]=1[C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([F:16])[CH:7]=1)=[O:19]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1cc(F)cc(C(F)(F)F)c1
Product: COC(=O)c1nc(C)sc1-c1cc(F)cc(C(F)(F)F)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-fluoro-5-trifluoromethyl-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=1.03 min; [M+H]+=319.8.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[O:13]([CH2:20][CH2:21][NH2:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:23][NH:24][CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1>>[CH3:23][N:24]([CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:22][CH2:21][CH2:20][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:11]=[CH:10]2
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: NCCOc1ccccc1
Reactant: CNCc1cccnc1
Product: CN(Cc1cccnc1)c1ccc2nc(NCCOc3ccccc3)ccc2c1

Procedure:
The title compound, MS: m/e=385.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-phenoxyethylamine and N-methyl-3-picolylamine.
Reaction SMILES: [N:1]12[CH2:9][CH:5]([CH2:6][CH2:7][CH2:8]1)[CH:4](O)[CH2:3][CH2:2]2.[H-].[Na+].Cl[C:14]1[N:15]=[N:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=2[F:27])=[CH:18][CH:19]=1.CN(C=[O:32])C>>[F:27][C:21]1[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=1[C:17]1[N:16]=[N:15][C:14]([O:32][CH:2]2[CH2:3][CH2:4][CH:5]3[CH2:9][N:1]2[CH2:8][CH2:7][CH2:6]3)=[CH:19][CH:18]=1
Reactant: Cc1ccc(-c2ccc(Cl)nn2)c(F)c1
Reactant: OC1CCN2CCCC1C2
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(-c2ccc(OC3CCC4CCCN3C4)nn2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (rac.)-1-Aza-bicyclo[3.3.1]nonan-4-ol (1.3 mmol) in DMF (5 ml) is treated with sodium hydride (60% in mineral oil; 1.3 mmol). After 1 hr at room temperature, a solution of 3-Chloro-6-(2-fluoro-4-methyl-phenyl)-pyridazine (1 mmol) in DMF (30 ml) is added, and the reaction mixture heated to 50 deg. for 16 hrs. After cooling to room temperature, the DMF solution is quenched with a 10% NaCl solution, extracted with ethyl acetate (2×15 ml), followed by sodium chloride solution (20 ml). The ethyl acetate is dried over anhydrous magnesium sulfate, filtered and evaporated to dryness, and the residual oil purified by silica gel column chromatography (eluent: ethyl acetate-methanol-triethylamine (50:10:2) to afford (rac.)-4-[(6-(2-Fluoro-4-methyl-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[3.3.1]nonane as a colourless solid. MS (ES+): m/e=328 (MH+)
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:14][C@H:15]([C:19]([NH:21][C@H:22]([C@H:30]([OH:49])[C@H:31]([OH:48])[C@@H:32]([NH:40][C:41](=[O:47])[C@H:42]([CH:44]([CH3:46])[CH3:45])[NH2:43])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])[CH:16]([CH3:18])[CH3:17].N=[C:51]=[NH:52]>>[N:52]1[C:51]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[C:1]([NH:14][C@H:15]([C:19]([NH:21][C@H:22]([C@H:30]([OH:49])[C@H:31]([OH:48])[C@@H:32]([NH:40][C:41](=[O:47])[C@H:42]([CH:44]([CH3:45])[CH3:46])[NH:43][C:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[O:13])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: CC(C)[C@H](N)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)C(C)C
Reactant: N=C=N
Product: CC(C)[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)c1ccc2ccccc2n1)C(C)C

Procedure:
Quinaldic acid was coupled to the resultant compound of Example 319 using the carbodiimide coupling procedure of Example 55 to provide the desired compound.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[C:14]2[CH2:15][CH2:16][CH2:17][C:13]=2[N:12]([C:18]2[CH:38]=[CH:37][C:21]([C:22]([NH:24][C@H:25]([C:27]3[NH:31][C:30]4[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:29]=4[N:28]=3)[CH3:26])=[O:23])=[CH:20][C:19]=2[C:39]([F:42])([F:41])[F:40])[N:11]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClCl>ClCCl.CO>[NH2:8][CH2:9][C:10]1[C:14]2[CH2:15][CH2:16][CH2:17][C:13]=2[N:12]([C:18]2[CH:38]=[CH:37][C:21]([C:22]([NH:24][C@H:25]([C:27]3[NH:31][C:30]4[CH:32]=[CH:33][C:34]([Cl:36])=[CH:35][C:29]=4[N:28]=3)[CH3:26])=[O:23])=[CH:20][C:19]=2[C:39]([F:42])([F:41])[F:40])[N:11]=1
Reactant: C[C@H](NC(=O)c1ccc(-n2nc(CNC(=O)OC(C)(C)C)c3c2CCC3)c(C(F)(F)F)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](NC(=O)c1ccc(-n2nc(CN)c3c2CCC3)c(C(F)(F)F)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 55 %

Procedure:
Prepared analogously to Example 17 from 4-[3-(tert-butoxycarbonylamino)methyl-5,6-dihydro-4H-cyclopentapyrazol-1-yl]-N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-trifluoromethylbenzamide and trifluoroacetic acid. Yield: 55%; Rf value: 0.25 (silica gel; dichloromethane/methanol=9:1); C24H22ClF3N6O (502.93); mass spectrum: (M−H)−=503/505 (chlorine isotope).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][C:28]=1[NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:31]3[CH:30]=[CH:29][C:28]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[C:27]([O:26][CH3:25])[CH:32]=3)[C:10]=12
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C

Procedure:
trans-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4.0 g, 9.06 mmol), tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (3.48 g, 9.97 mmol), palladium tetrakistriphenyphosphine (0.63 g, 0.64 mmol) and sodium carbonate (2.30 g, 21.75 mmol) were mixed with ethylene glycol dimethyl ether (100 mL) and water (50 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (80:20) as mobile phase to give trans-tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)carbamate (4.75 g, 98%). 1H NMR (DMSO-d6) δ 1.48 (m, 11H), 2.02 (m, 6H), 2.15 (s, 3H), 2.35 (m, 5H), 2.53 (m, 4H), 3.87 (s, 3H), 4.64 (m, 1H), 7.20 (m, 2H), 7.90 (d, J=8.15, 1H), 8.03 (s, 1H), 8.22 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12]>>[CH3:4][C:3]1[CH:12]=[C:7]2[N:6]([CH:2]=1)[CH:11]=[CH:10][CH:9]=[CH:8]2
Reactant: Cc1ccccn1
Reactant: CC(=O)CCl
Product: Cc1cc2ccccn2c1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A mixture of 92.5 g monochloroacetone (1 mole) and 93 g of α-picoline (1 mole) was heated for 21/2 h on a boiling water-bath. The reaction mixture was cooled to ambient temperature (20° C.) and kept overnight. A solid black mass formed. Extraction was performed on a hot water-bath until the mass had dissolved completely (about 700 ml). The solution was filtered and washed 3 times with 100 ml of ether. A few ml of an aqueous saturated sodium carbonate solution were added and the solution was then washed again 4 times in ether. 150 g of solid sodium hydrogen carbonate was added carefully and steam distillation was carried out. The distillate was cooled and sucked off. The solid product was dissolved quickly in ether and dried on heated magnesium sulphate. The ether was evaporated and the residue dried.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][NH:17][CH:18]=3)=[CH:11][CH:12]=2)[N:7]([C:19]([O:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)=[O:20])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2].CN(C)C=O.Br[CH:33]1[CH2:38][CH2:37][S:36](=[O:40])(=[O:39])[CH2:35][CH2:34]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[N:16][N:17]([CH:34]4[CH2:33][CH2:38][CH2:37][S:36](=[O:40])(=[O:39])[CH2:35]4)[CH:18]=3)=[CH:11][CH:12]=2)[N:7]([C:19]([O:21][CH:22]2[CH2:25][CH2:24][CH2:23]2)=[O:20])[CH2:6][C@@H:5]1[CH3:26])(=[O:3])[CH3:2]
Reactant: O=S1(=O)CCC(Br)CC1
Reactant: CC(=O)N1c2ccc(-c3cn[nH]c3)cc2N(C(=O)OC2CCC2)C[C@@H]1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1c2ccc(-c3cnn(C4CCCS(=O)(=O)C4)c3)cc2N(C(=O)OC2CCC2)C[C@@H]1C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 100-mL round-bottom flask was charged with cyclobutyl (35)-4-acetyl-3-methyl-7-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydroquinoxaline-1-carboxylate (1.67 g, 4.71 mmol), N,N-dimethylformamide (10 mL), 4-bromo-1λ6-thiane-1,1-dione (1.0 g, 4.7 mmol), and cesium carbonate (3.08 g, 9.45 mmol). The resulting mixture was stirred overnight at 100° C. After cooling to room temperature, the resulting solution was diluted with water (20 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified via column chromatography on silica gel (eluting with 1:1, ethyl acetate/petroleum ether). The material was further purified by Prep-HPLC with the following conditions (Waters III): Column, Xbridge RP18 Sum, 19×150 mm; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (50% acetonitrile up to 100% in 10 min); Detector, UV 220&254 nm. This afforded cyclobutyl (3S)-4-acetyl-7-[1-(1,1-dioxo-1λ6-thian-3-yl)-1H-pyrazol-4-yl]-3-methyl-1,2,3,4-tetrahydroquinoxaline-1-carboxylate (1.01 g, 44%) as a white solid. 1H NMR (300 MHz, CD3OD) δ ppm 1.09 (d, J=6.60 Hz, 3H), 1.62-1.74 (m, 1H), 1.75-1.92 (m, 1H), 2.03-2.35 (m, 9H), 2.36-2.45 (m, 2H), 3.06-3.18 (m, 2H), 3.38-3.56 (m, 2H), 3.67 (t, J=13.20 Hz, 1H), 4.07-4.18 (m, 1H), 4.75-4.83 (m, 1H), 4.97-5.07 (m, 2H), 7.37 (s, 2H), 7.88 (s, 1H), 8.03 (s, 1H), 8.11 (s, 1H). MS (ESI, pos. ion) m/z 487 [M+H]
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([C:45]([OH:47])=[O:46])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:35][S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH2:25][C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[NH:28][CH:27]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:48][CH2:49][CH:50]([CH2:52]O)[OH:51].C(Cl)CCl>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:16]([C:45]([O:47][CH2:52][CH:50]([OH:51])[CH2:49][OH:48])=[O:46])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:35][S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:37])=[O:38])[CH2:25][CH:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[CH:27]2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2c[nH]c3ccccc23)NS(=O)(=O)c2ccccc2)C(=O)O)cc1
Reactant: OCC(O)CO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](CC2C=Nc3ccccc32)NS(=O)(=O)c2ccccc2)C(=O)OCC(O)CO)cc1
Reaction time: 8 h
Yield: 79.3 %

Procedure:
Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-(N′α-benzenesulfonyl-L-tryptophanyl)-L-lysine (170 mg, 0.25 mmol) dissolved in a solution of DMF (1 mL) was treated with glycerol (100 μL, 1.37 mmol) and EDC (100 mg, 0.5 mmol) and stirred overnight. Then, the solution was poured in 5% citric acid and extracted with EtOAc. The solvent was evaporated and the residue purified by preparative HPLC to give 150 mg (79%) of the final product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].I[CH2:18][CH3:19].O>CN(C=O)C>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6])[CH3:19]
Reactant: CCI
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
Step A To a solution of methyl 3-hydroxy-4-nitrobenzoate (Aldrich) (3 g, 15.2 mmol) in anhydrous DMF (25 mL) were added NaH (Aldrich, 60%) (0.91 g, 22.8 mmol) and iodoethane (2.61 g, 16.7 mmol) sequentially. The reaction mixture was stirred at room temperature for 2 h. Water was added. The mixture was extracted with ethyl acetate. The organic extract was washed with water, brine, dried over MgSO4, and concentrated to give methyl 3-ethoxy-4-nitrobenzoate as a light yellow solid (1.0 g, 29%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]3([CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]([CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[C:10]2=[O:28])=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2].CO.[OH-].[Na+]>O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]3([CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:10]2=[O:28])=[CH:5][C:4]=1[C:29]([F:30])([F:32])[F:31])#[N:2]
Reactant: CCOC(=O)CCCN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C12CCOCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(N2C(=O)N(CCCC(=O)O)C3(CCOCC3)C2=O)cc1C(F)(F)F
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
522 mg of the product of Example 6 and 20 ml of methanol were mixed together and the solution was heated to 30° C., then returned to ambient temperatures 2 ml of 2N sodium hydroxide were added and the reaction medium stood for 4 hours and 30 minutes, then was poured into 30 ml of water and adjusted to pH 2-3. Extraction was carried out 3 times with ethyl acetate and the organic phase was washed with water, then with salt water, dried and purified on silica with methylene chloride-methanol: 9-1 as eluant. Then, solidification was carried out by trituration in 0.2 ml of isopropanol and 5 ml of ether to obtain 345 mg of the expected product (white crystals) melting at 151-152° C.
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:17]=C[C:15](CN)=[CH:14][CH:13]=1.C([N:22]([CH2:25][CH3:26])CC)C>CN1C(=O)CCC1.O>[Cl:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([NH:22][CH2:25][C:26]2[CH:15]=[CH:14][CH:13]=[C:12]([F:11])[CH:17]=2)[N:9]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCN(CC)CC
Reactant: N#Cc1ccc(Cl)nc1Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: N#Cc1ccc(Cl)nc1NCc1cccc(F)c1
Temperature: 50 °C
Yield: 79.7 %

Procedure:
2,6-dichloronicotinonitrile (0.500 g, 2.89 mmol), (4-fluorophenyl)methanamine (0.816 mL, 0.904 g, 7.23 mmol), and triethylamine (1.21 mL, 0.877 g, 8.67 mmol) were all mixed in NMP (10 mL). The resulting solution then was heated at 50° C. for 18 hr. The reaction mixture was then poured in H2O (25 mL), and extracted with EtOAc (3×25 mL). The combined extracts were washed with H20 (4×25 mL), and brine (1×25 mL). The organic layer was separated and dried (Na2SO4), filtered, and the solvent removed in vacuo. The resulting residue was purified using silica gel column chromatography. Elution using 1 EtOAc/3 hexanes to 3 EtOAc/1 hexanes afforded 0.6024 g (80%) of 6-chloro-2-(3-fluorobenzylamino)nicotinonitrile. LCMS (m/z): 350.0 (MH+), retention time=0.96 min. 1H NMR (300 MHz, CDCl3) δ 4.58 (d, J=5.86 Hz, 2 H) 5.48 (br. s., 1 H) 6.30 (d, J=8.50 Hz, 1 H) 6.96-7.06 (m, 2 H) 7.10 (d, J=7.62 Hz, 1 H) 7.28-7.38 (m, 1 H) 7.58 (d, J=8.79 Hz, 1 H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:32]1[N:41]=[CH:40][CH:39]=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35]>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:12]1[CH:11]=[C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][C@H:3]2[CH2:2][NH:1][C:32]2[C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=[CH:40][N:41]=2)[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: COC(=O)c1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccnc1NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 100 °C
Reaction time: 48 h
Yield: 44.1 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (200 mg) in DMF (4 mL) were added potassium carbonate (110 mg) and methyl 2-chloronicotinate (137 mg) at room temperature, and the mixture was stirred at 100° C. for 48 hr. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (120 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[N:18]12[CH2:25]C[CH:21]([CH2:22][CH2:23]1)[C@@H:20](O)[CH2:19]2.[Na].C1(C)C=CC=CC=1>CCCCCCC>[N:18]12[CH2:23][CH2:22][CH:21]([CH2:20][CH2:19]1)[C@@H:1]([O:2][C:3]([C:5]1([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4])[CH2:25]2
Reactant: COC(=O)C1(c2ccccc2)CCCCCC1
Reactant: O[C@H]1CN2CCC1CC2
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Reaction time: 72 h
Yield: 82.7 %

Procedure:
1-Phenyl-cycloheptanecarboxylic acid methyl ester (Example 1d) (1.0 g) and (R)-quinuclidin-3-ol (0.39 g) were refluxed in heptane (50 mL) containing sodium (˜5 mg in a Dean and Stark apparatus for 24 hours. Heptane (20 mL) was replaced with toluene (20 mL) and the reflux was continued for 3 days. The reaction was partitioned between water (50 mL) and ether (50 mL) and the ether layer was separated, dried (MgSO4) and evaporated. The crude product was purified by column chromatography on silica elutting with ethyl acetate/triethylamine (99/1) to afford the titled compound as an oil (0.83 g).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([CH:13]=O)=[CH:7][C:6]=1[Br:15])(=[O:3])[CH3:2].[C:16](#[N:20])[CH2:17][C:18]#[N:19].[OH:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][N:26]2[CH3:31]>C(O)C>[NH2:19][C:18]1[O:21][C:22]2[C:30]([CH:13]([C:8]3[CH:9]=[C:10]([O:11][CH3:12])[C:5]([O:4][C:1](=[O:3])[CH3:2])=[C:6]([Br:15])[CH:7]=3)[C:17]=1[C:16]#[N:20])=[CH:29][CH:28]=[C:27]1[N:26]([CH3:31])[CH:25]=[CH:24][C:23]=21
Reactant: COc1cc(C=O)cc(Br)c1OC(C)=O
Reactant: Cn1ccc2c(O)cccc21
Reactant: N#CCC#N
Solvent: CCO
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2c3ccn2C)cc(Br)c1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.3 %

Procedure:
To a mixture of 2-bromo-4-formyl-6-methoxyphenyl acetate (273 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) in 10 mL of ethanol was added 4-hydroxy-1-methylindole (147 mg, 1 mmol) and the solution was stirred at room temperature overnight. The solvent was removed in vacuo. The crude material was purified by column chromatography (2:1, hexane:ethyl acetate) to yield 25 mg (5.3%) of the title compound 1H NMR (CDCl3): 7.07-7.04 (m, 2H), 6.92 (s, 1H), 6.79-6.77 (m, 2H), 6.57 (s, 1H), 4.81 (s, 1H), 4.70 (s, 2H), 3.79 (s, 6H), 2.34 (s, 3H).