Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@@H:33]1[CH2:38][CH2:37][CH2:36][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:42]([O:41][C:39]([N:35]1[CH2:36][CH2:37][CH2:38][C@@H:33]([NH:32][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:19]=2)=[O:23])[CH2:34]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.5 %

Procedure:
A round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (120 mg, 0.26 mmol), (R)-tert-butyl 3-aminopiperidine-1-carboxylate (80 mg, 0.40 mmol), HOBT (45 mg, 0.29 mmol) and EDC (56 mg, 0.29 mmol). DMF (1.2 ml) was added followed by N,N-diisopropylethylamine (0.10 ml, 0.57 mmol). The reaction mixture was stirred at room temperature for 48 h then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-50% EtOAc) to provide 139 mg (83%) of (R)-3-{[2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester as a light yellow solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]2[C:26]([CH:27]3[CH2:37][CH:28]3[CH2:29][O:30]2)=[CH:25][CH:24]=1)(=[O:21])=[O:20])=[O:9])[CH3:2].NCC1C=C(F)C=CC=1S(NC1C(C(OC)=O)=C2C(C3CC3CO2)=CC=1)(=O)=O.C(N1CCC[C@@H]1C(O)=O)C>>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[C:8]([NH:10][CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[S:19]([NH:22][C:23]1[C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]2[C:26]([CH:27]3[CH2:37][CH:28]3[CH2:29][O:30]2)=[CH:25][CH:24]=1)(=[O:20])=[O:21])=[O:9])[CH3:2]
Reactant: CCN1CCC[C@H]1C(=O)NCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Agent: CCN1CCC[C@@H]1C(=O)O
Agent: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CN)ccc2c1OCC1CC21
Product: CCN1CCC[C@@H]1C(=O)NCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Intermediate 101, starting from methyl (1aRS,7bSR)-5-(2-aminomethyl-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (Intermediate 102) and (R)-1-ethylpyrrolidine-2-carboxylic acid (Intermediate 147) as a solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][C:9]=1[NH2:10])=[O:4].[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][C:9]=1[NH:10][C:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=1)=[O:24])=[O:4]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CNC(=O)c1sc(C(C)(C)C)cc1N
Solvent: Cc1ccccc1
Product: CNC(=O)c1sc(C(C)(C)C)cc1NC(=O)Nc1ccc(F)cc1
Reaction time: 3 h
Yield: 81.1 %

Procedure:
A slurry of N-methyl-3-amino-5-tert-butylthiophene-2carboxamide (7.63 g, 36 mmol) and 4-fluorophenyl isocyanate (4.93 g, 36 mmol, 1.0 equiv) in anh. toluene (100 mL) was heated at the reflux temp. for 3 h, during which the mixture clarified then generated a new precipitate, which was filtered while hot. The resulting solids were washed with hexane and dried under reduced pressure to afford N-(2-methylcarbamoyl-5-tert-butylthienyl)-N′-(4-fluorophenyl)urea (10.2 g, 81%): mp 203-4° C.; TLC (5% MeOH/CH2Cl2) Rf0.61; 1H NMR (CDCl3) δ1.34 (s, 9H), 2.73 (d, J=4.4 Hz, 3H), 7.07-7.13 (m, 2H), 7.49-7.54 (m, 2H), 7.80 (s, 1H), 7.96 (q, J=4.4 Hz, 1H), 9.88 (s, 1H), 10.46 (s, 1H); 13C NMR (CDCl3) δ25.8, 31.6 (3C), 34.5, 107.4, 115.2 (d, JC-F=22.0 Hz, 2C), 117.3, 120.1 (d, JC-F=7.3 Hz, 2C), 136.1 (d, JC-F=2.4 Hz, 2C), 143.1, 151.6, 157.4 (d, JC-F=238.1 Hz, 1C), 158.0, 164.3; EI-LRMS m/z (rel abundance) 349 (M+, 13%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][NH:22][CH3:23])[CH:18]=2)[NH:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][N:22]([CH3:23])[CH:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[CH:18]=2)[NH:13][C:12]=1[CH3:24])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCOCC1
Reactant: CNCCc1ccc2[nH]c(C)c(C(=O)OCc3ccccc3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1[nH]c2ccc(CCN(C)C3CCOCC3)cc2c1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
To a mixture of 2-methyl-5-(2-methylamino-ethyl)-1H-indole-3-carboxylic acid benzyl ester (403 mg, 1.25 mmol) and tetrahydro-4H-pyran-4-one (0.115 ML, 1.25 mmol) in dichloroethane (10 mL) was added sodium triacetoxyboro hydride (371 mg, 1.75 mmol) followed by acetic acid (0.071 mL, 1.25 mmol). The mixture was stirred at room temperature under nitrogen atmosphere for 3 hours and then partitioned between ethyl acetate and water. The organic phase was washed with saturated sodium bicarbonate solution and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a solid residue, which was purified by chromatography (5% methanol in methylene chloride) to give 270 mg (53%) of the desired product as a white foam: mp 109-11 1° C.; MS(APCI+): m/z 407.2 (MH+); Anal. Calcd for C25H30N2O3.0.25H2O: C, 73.05; H, 7.48; N, 6.82. Found: C, 72.86; H, 7.59; N, 6.78.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].CC(C)([O-])C.[K+].[Br:18][C:19]1[CH:20]=[N:21][C:22]2[C:27]([C:28]=1Cl)=[CH:26][CH:25]=[CH:24][C:23]=2[N+:30]([O-:32])=[O:31].[Cl-].[NH4+]>CN1CCCC1=O>[CH2:10]([O:9][C:1]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:28]1[C:27]2[C:22](=[C:23]([N+:30]([O-:32])=[O:31])[CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][C:19]=1[Br:18])=[O:8])[CH3:11]
Reactant: O=[N+]([O-])c1cccc2c(Cl)c(Br)cnc12
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(C(=O)OCC)c1c(Br)cnc2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a mixture of diethyl malonate (368 mg) and N-methylpyrrolidone was added potassium tert-butoxide (246 mg) at 0° C., and the mixture was stirred for 30 minutes at ambient temperature. To a mixture was added 3-bromo-4-chloro-8-nitroquinoline (300 mg), and the mixture was stirred for 30 minutes at ambient temperature and for 30 minutes at 50° C. The mixture was poured into saturated ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give 4-[bis(ethoxycarbonyl)methyl]-3-bromo-8-nitroquinoline (315.6 mg).
Reaction SMILES: [CH:1]([C:4]1[O:5][CH:6]=[C:7]([CH2:9][NH:10][CH3:11])[N:8]=1)([CH3:3])[CH3:2].[CH3:12][O:13][C:14](=[O:30])[C@H:15]([CH3:29])[NH:16][C:17]([O:19]C1C=CC([N+]([O-])=O)=CC=1)=O>>[CH3:12][O:13][C:14](=[O:30])[C@H:15]([CH3:29])[NH:16][C:17]([N:10]([CH3:11])[CH2:9][C:7]1[N:8]=[C:4]([CH:1]([CH3:2])[CH3:3])[O:5][CH:6]=1)=[O:19]
Reactant: COC(=O)[C@H](C)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNCc1coc(C(C)C)n1
Product: COC(=O)[C@H](C)NC(=O)N(C)Cc1coc(C(C)C)n1
Yield: 66 %

Procedure:
Using the procedure of Example 1S, but replacing 2-isopropyl-4-(((N-methyl)amino)methyl)thiazole with 2-isopropyl-4-(((N-methyl)amino)methyl)-oxazole and replacing N-(((4-nitrophenyl)oxy)carbonyl)-L-valine methyl ester with N-(((4-nitrophenyl)oxy)carbonyl)-L-alanine methyl ester provided the desired compound in 66% yield. 1H NMR (CDCl3) δ1.32 (d, 6H), 1.42 (d, 3H), 2.96 (s, 3H), 3.05 (m, 1H), 3.75 (s, 3H), 4.30 (s, 2H), 4.47 (m, 1H), 5.80 (br d, 1H), 7.46 (s, 1H). Mass spectrum: (M+H)+ =284.
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(COS(C)(=O)=O)C(=O)N(CC(C)C)N=1.[CH:26]1([CH2:31][N:32]2[C:37](=[O:38])[C:36]([C:39]([O:41]C)=[O:40])=[CH:35][C:34]([C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[C:45]([F:51])[CH:44]=3)=[N:33]2)[CH2:30][CH2:29][CH2:28][CH2:27]1>>[C:39]([C:36]1[C:37](=[O:38])[N:32]([CH2:31][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[N:33]=[C:34]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[C:45]([F:51])[CH:44]=2)[CH:35]=1)([OH:41])=[O:40]
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(CC2CCCC2)c1=O
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(COS(C)(=O)=O)c1=O
Product: COc1ccc(-c2cc(C(=O)O)c(=O)n(CC3CCCC3)n2)cc1F
Yield: 71.1 %

Procedure:
Following the procedure of Example 1 (7), 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reacted to yield the title compound as a yellow powder (yield: 71.1%).
Reaction SMILES: O.[ClH:2].[F:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1.[Cl:25][CH2:26][CH2:27][N:28]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][C:29]1=[O:39].C(=O)(O)[O-].[Na+].[I-].[K+].Cl>C(O)CCC>[ClH:25].[ClH:2].[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH2:26][CH2:27][N:28]3[C:37](=[O:38])[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[NH:30][C:29]3=[O:39])[CH2:14][CH2:13]2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(NC(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)n1CCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: O
Solvent: CCCCO
Product: O=c1[nH]c2ccccc2c(=O)n1CCN1CCC(C(Nc2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 42.5 %

Procedure:
A mixture of 2.89 g (7.52 mmol) of N,α-bis(4-fluorophenyl)-4-piperidinemethanamine hydrochloride hydrate, 1.74 g (7.75 mmol) of 3-(2-chloroethyl)-2,4(1H,3H)quinazolinedione, 7.56 g (90 mmol) of sodium bicarbonate, and 0.20 g (1.20 mmol) of potassium iodide in 250 mL of 1-butanol was heated at reflux for 20 h. The solvent was removed in vacuo, and the residue was partitioned between CH2Cl2 and dilute NaOH. The organic phase was dried (Na2SO4), and the solvent was removed in vacuo. The residue was subjected to flash chromatography (silica gel, eluted with 1-3% CH3OH in CH2Cl2) to give the free base of the product. This was converted to the HCl salt, and the salt was recrystallized from CH3OH/diethyl ether to give 1.80 g (42.7%) of the title compound as a white solid, mp 213°-220° C.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][CH2:8][S:9][CH2:10][C:11]2[O:12][C:13]([CH2:16][N:17]([CH3:19])[CH3:18])=[CH:14][CH:15]=2)C(=O)C2=CC=CC=C12.NN.[C:28]([N:30]=[C:31]([S:34][CH3:35])SC)#[N:29]>>[C:28]([NH:30][C:31](=[N:5][CH2:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[O:12][C:13]([CH2:16][N:17]([CH3:18])[CH3:19])=[CH:14][CH:15]=1)[S:34][CH3:35])#[N:29]
Reactant: CSC(=NC#N)SC
Reactant: CN(C)Cc1ccc(CSCCCN2C(=O)c3ccccc3C2=O)o1
Agent: NN
Product: CSC(=NCCCSCc1ccc(CN(C)C)o1)NC#N

Procedure:
When 1-phthalimido-3-[(5-dimethylaminomethyl-2-furyl)methylthio]propane is treated with hydrazine and the resultant substituted propylamine is reacted with dimethyl cyanodithioimidocarbonate there is produced N-cyano-N'-{3-[(5-dimethylaminomethyl-2-furyl)methylthio]propyl}-S-methylisothiourea, and when this is reacted with propargylamine according to the general procedure of Example 3 the title compound is produced.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19].O>O1CCCC1>[NH:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:18](=[O:19])[O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1nc2ccccc2[nH]1)OCC(Cl)(Cl)Cl
Yield: 54.8 %

Procedure:
To a solution of 2-aminobenzimidazole (1.00 g, 7.51 mmol) and pyridine (0.714 ml, 9.01 mmol) in tetrahydrofuran (25 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.25 ml, 9.01 mmol), and the mixture was stirred at room temperature for 1 hour and half. Water was poured to the reaction mixture, and 1.27 g (54.6%) of the desired product as a solid was separated by filtration.
Reaction SMILES: FC1C=CC=CC=1CO.[H-].[Na+].Cl[C:13]1[C:22]2[C:17](=[C:18]([OH:23])[CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([CH3:24])[CH:14]=1>CN(C=O)C>[CH3:24][C:15]1[CH:14]=[CH:13][C:22]2[C:17](=[C:18]([OH:23])[CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Agent: OCc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2cccc(O)c2n1
Temperature: 130 °C

Procedure:
To a stirred solution of 2-fluorobenzyl alcohol (1.95 g, 15.5 mmol) in anhydrous DMF (35 mL) was added sodium hydride (60% in mineral oil, 0.62 g, 15.5 mmol). After 30 min the 4-chloro-2-methylquinolin-8-ol (1.00 g, 5.16 mmol) was added and resulting mixture was heated at 130° C. for 20 h under nitrogen atmosphere. The mixture was cooled, poured into ice/NaHCO3 and extracted with EtOAc. Evaporation gave a crude oil that was purified by silica chromatography eluting with a gradient of 1% to 10% of MeOH/DCM to give 44(2-fluorobenzyl)oxy)-2-methylquinolin-8-ol as an oil that solidified on standing (0.39 g, 27%). LCMS (+APCI) 284 (M+1), mp 124-125° C. 1H-NMR (CDCl3, δ): 7.75 (d, J=8.4 Hz, 1H), 7.50 (d, J=7.6 Hz, 2H), 7.43 (s, 1H), 7.35 (m, 3H), 7.20 (d, J=7.6 Hz, 1H), 7.06 (d, J=8.0 Hz), 5.45 (s, 2H), 2.78 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)C(C3C=CC=CC=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:31]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)=[CH:35][CH:34]=1)#[CH:32]>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:1]1([C:32]2[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:31]=2[C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=3)=[CH:35][CH:34]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C(c2ccccc2)=C(c2ccccc2)C(c2ccccc2)=C1c1ccccc1
Reactant: C#Cc1ccc(-c2ccccn2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: c1ccc(-c2cc(-c3ccc(-c4ccccn4)cc3)c(-c3ccccc3)c(-c3ccccc3)c2-c2ccccc2)cc1
Temperature: 210 °C
Yield: 124.6 %

Procedure:
A solution of 2,3,4,5-tetraphenylcyclopentadienone (4) (Morgenroth et al, Tetrahedron 1997, 53, 15349) (1.14 g, 2.96 mmol) and (3) (354 mg, 1.98 mmol) in diphenyl ether (3 mL) was deoxygenated and heated at 210° C. under argon for 3 hours. The reaction mixture was purified by column chromatography over silica using a dichloromethane/light petroleum mixture (1:1) as eluent to give (5) (988 mg, 93%).
Reaction SMILES: [Cl-].[CH3:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([CH3:10])[N+:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:18]>C(O)C>[Cl-:9].[CH3:2][C:3]1[CH:8]=[C:7]([N:19]([CH2:17][CH3:18])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[C:5]([CH3:10])[N+:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCNc1ccccc1
Reactant: Cc1cc(Cl)cc(C)[n+]1-c1ccccc1
Agent: [Cl-]
Solvent: CCO
Product: CCN(c1ccccc1)c1cc(C)[n+](-c2ccccc2)c(C)c1
Yield: 56 %

Procedure:
A mixture of 2,6-dimethyl-N-phenyl-4-chloropyridinium chloride (previously reported in Annalen, 1958, 617, 181-202) (2.19 g, 10 mM), N-ethylaniline (3.6 g, 30 mM) and ethanol (100 ml) was heated under reflux for 30 minutes. The solvent was removed by evaporation and the resultant syrup was purified by flash chromatography (Merck 9385 silica column, 180 g) using a 1:19 v/v mixture of methanol/methylene chloride as eluant. The resultant syrup was further purified by flash column chromatography using a neutral alumina column (ICN type N32-63, 150 g) and eluting with an increasing gradient (0-5% v/v) of methanol in dichloromethane. There was thus obtained 2,6-dimethyl-4-(N-ethylanilino)-N-phenylpyridinium chloride (1.9, 56% yield) as a pale orange glass; microanalysis, found: C,70.7; H,6.5; N,7.6; Cl,9.7%; C21H23N2Cl .H2O requires: C,70.7; H,7.0; N,7.85; Cl, 9.93%; NMR: 1.2-1.3(3H, t,CH2CH3), 2.1(6H,5 pyridine-CH3), 3.9-4.05(2H,q,CH2CH3), 6.7-7.1(2H,br, pyridine-3H and -5H), 7.35-7.7 (10H, complex, aromatic).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([O-])=[O:8])[CH:4]=[CH:3][C:2]=1[C:10]([O:12][CH3:13])=[O:11].S(Cl)([Cl:16])=O>>[C:10]([C:2]1[CH:3]=[CH:4][C:5]([C:7]([Cl:16])=[O:8])=[CH:6][N:1]=1)([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccc(C(=O)[O-])cn1
Reactant: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(=O)Cl)cn1

Procedure:
In step a, the carboxylic acid functionality of the appropriate 2,5-pyridinedicarboxylic acid, 2-methyl ester 10 (Nippon Kagaku Zasshi, 1967, 88, 563) is converted to its acid chloride using techniques and procedures well known and appreciated by one of ordinary skill in the art, such as thionyl chloride, to give the corresponding 6-carbomethoxynicotinoyl chloride 11.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH2:11][O:12]C)[N:8]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:7](=[O:19])[C:6]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[NH:37][C:36](=[O:38])[O:35][N:34]=2)=[CH:23][CH:22]=1)[CH2:2][CH2:3][CH3:4].B(Br)(Br)Br.[OH-].[Na+].Cl>C(OCC)(=O)C.ClCCl>[CH2:1]([C:5]1[N:10]=[C:9]([CH2:11][OH:12])[N:8]([CH2:14][C:15]([CH3:17])([CH3:18])[CH3:16])[C:7](=[O:19])[C:6]=1[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[NH:37][C:36](=[O:38])[O:35][N:34]=2)=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(COC)n(CC(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: BrB(Br)Br
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCc1nc(CO)n(CC(C)(C)C)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
A mixture of 6-butyl-3-(2,2-dimethylpropyl)-2-(methoxymethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one (0.5 g), boron tribromide (1.0 M dichloromethane solution, 2.9 mL) and dichloromethane (20 mL) was stirred at room temperature for 3 hr, 0.5 M aqueous sodium hydroxide solution (10 mL) was added, and the mixture was further stirred for 1 hr. To the reaction mixture was added 1 M hydrochloric acid and adjusted to pH 5. Ethyl acetate was added, and the mixture was extracted. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.48 g, 98%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH2:16])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([C@H:23]([CH2:27]C)[C:24]([OH:26])=O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:24](=[O:26])[C@H:23]([C:17]3[CH:18]=[CH:19][C:20]([CH2:1][CH:2]([CH3:7])[CH3:3])=[CH:21][CH:22]=3)[CH3:27])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](C(=O)O)c1ccccc1
Reactant: N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21
Product: CC(C)Cc1ccc([C@H](C)C(=O)N[C@H]2CC[C@@H]3CN(Cc4ccccc4)C[C@@H]32)cc1

Procedure:
The title compound was prepared by substituting (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 33 for (3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine and substituting (S)-2-(4-isobutylphenyl)propanoic acid for (S)-2-phenylbutanoic acid in Step F of the procedure used to prepare Example 16: 1H NMR (400 MHz, CDCl3) δ ppm 7.28 (d, J=4.4, 3H), 7.25-7.18 (m, 1H), 7.15 (dd, J=2.3, 8.2, 2H), 7.09 (dd, J=1.8, 8.2, 2H), 5.17 (d, J=7.2, 1H), 4.03-3.89 (m, 1H), 3.58 (d, J=13.0, 1H), 3.51-3.41 (m, 2H), 2.55-2.48 (m, 3H), 2.45 (d, J=7.2, 2H), 2.39 (dd, J=7.3, 9.0, 1H), 2.27-2.20 (m, 1H), 2.19-2.06 (m, 1H), 2.05-1.91 (m, 1H), 1.85 (dt, J=6.8, 13.5, 1H), 1.72-1.61 (m, 2H), 1.48 (d, J=7.2, 3H), 1.44-1.28 (m, 2H), 0.89 (d, J=6.6, 6H); MS (ESI+) m/z 405 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH3:27][NH2:28].Cl>C(#N)C>[CH3:27][NH:28][CH2:12][C@@H:13]1[O:18][C:17]2[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=2[O:15][CH2:14]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Reactant: CN
Agent: Cl
Solvent: CC#N
Product: CNC[C@H]1COc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 3 using [(2R)-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.4 g, 1 mmol), methanamine (33% in EtOH, 1 ml) and ACN (3 ml). Yield: 0.2 g, 89%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 248° C. MS m/z (rel. intensity, 70 eV) 257 (M+, bp), 79 (86), 70 (59), 63 (50), 51 (71). [α]=−59° (MeOH).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[C:5]([Cl:19])=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:28]=[C:27]([N:29]2[CH2:34][CH2:33][CH:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)[CH2:31][CH2:30]2)[CH:26]=[CH:25][C:23]=1[NH2:24].C(=O)(O)[O-].[Na+]>COCCO>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)=[N:7][C:2]([NH:24][C:23]2[CH:25]=[CH:26][C:27]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:31][CH2:30]3)=[CH:28][C:22]=2[O:21][CH3:20])=[N:3][CH:4]=1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Reactant: CP(C)(=O)c1ccc(Nc2nc(Cl)ncc2Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCO
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc(Cl)c(Nc2ccc(P(C)(C)=O)cc2)n1
Temperature: 110 °C
Reaction time: 18 h
Yield: 16.1 %

Procedure:
To the compound 2,5-dichloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (0.005 g, 0.16 mmol) in 1 mL of 2-methoxyethanol was added 2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (0.71 g, 0.16 mmol). The mixture was stirred at 110° C. for 18 h. The mixture was basified with saturated sodium bicarbonate solution and extracted with limited amount of ethyl acetate. The aqueous layer was purified by chromatography to give the final product (0.015 g, 20% yield). MS/ES+: m/z=583.