Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.OS(O)(=O)=O.[N+:15]([O-])([OH:17])=[O:16]>>[Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([F:8])=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc(Cl)cc1F
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.8 %

Procedure:
To a flask was added 4-chloro-1,2-difluorobenzene (8.97 g, 60.4 mmol), followed by adding 98% con. H2SO4(16.1 mL, 302 mmol) and 65% con. HNO3 (5.0 mL, 66.4 mmol) at 0° C. The mixture was stirred at rt for 5 hours, then poured into ice water (500 mL). The resulted mixture was extracted with ethyl acetate (200 mL×3). The combined organic phase were washed with saturated aqueous NaHCO3 solution (200 mL×2) and brine (200 mL), dried over anhydrous Na2SO4, and concentrated in vacuo to give the title compound as yellow liquid (11.31 g, 96.7%).
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([NH2:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([O:27]C)(=O)[CH2:20][CH2:21][C:22]([O:24]C)=O.[CH3:29][O-:30].[Na+]>>[CH:1]1([O:7][N:8]2[C:9]([CH3:18])([CH3:17])[CH2:10][CH:11]([NH:16][C:22](=[O:24])[CH2:21][CH2:20][C:19]([NH:16][CH:11]3[CH2:10][C:9]([CH3:17])([CH3:18])[N:8]([O:30][CH:29]4[CH2:5][CH2:6][CH2:1][CH2:2][CH2:3]4)[C:13]([CH3:14])([CH3:15])[CH2:12]3)=[O:27])[CH2:12][C:13]2([CH3:14])[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[O-]
Reactant: COC(=O)CCC(=O)OC
Reactant: CC1(C)CC(N)CC(C)(C)N1OC1CCCCC1
Agent: [Na+]
Product: CC1(C)CC(NC(=O)CCC(=O)NC2CC(C)(C)N(OC3CCCCC3)C(C)(C)C2)CC(C)(C)N1OC1CCCCC1
Yield: 252.3 %

Procedure:
A mixture of 1-cyclohexyloxy-4-amino-2,2,6,6-tetramethylpiperidine (2.65 g), dimethyl succinate (1.46 g) and sodium methoxide (50 mg) is heated at 180°-190° C. for 4 hours. The crude product is recrystallized from ethanol/water to afford 1.38 g of the title compound as a white solid, m.p. 230°-34° C.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([C:33]1([O:36][CH3:37])[CH2:35][CH2:34]1)[NH2:32]>>[CH3:37][O:36][C:33]1([C:31]2[N:32]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][S:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:28][N:30]=2)[CH2:35][CH2:34]1
Reactant: O=C(O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Reactant: COC1(C(N)=NO)CC1
Product: COC1(c2noc(C3CC(c4ccc(CC(F)(F)F)cc4)CN(C(=O)N4CCSCC4)C3)n2)CC1

Procedure:
According to General Method 6A, 93.1 mg (0.224 mmol) of the compound from Example 45A and 32.0 mg (0.246 mmol) of N′-hydroxy-1-methoxycyclopropanecarboximidamide from Example 64A were reacted. Yield: 31.1 mg (27% of theory)
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([C:11](OC)(OC)[CH2:12][CH2:13][C:14]2(C2C=CC=CC=2OC)O)[CH2:9]1)C1C=CC=CC=1.C(N(CC)CC)C.FC(F)(F)C(O)=[O:40].[OH-].[Na+]>ClCCl>[C:9]1(=[O:40])[CH:10]2[CH:15]([CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:16][NH:8]1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccccc1C1(O)CCC(OC)(OC)C2CN(Cc3ccccc3)CC21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1NCC2CCCCC12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7 g of (3aRS,4RS,7aSR)-2-benzyl-7,7-dimethoxy -4-(2-methoxyphenyl)-4-perhydroisoindolol in 70 cm3 of dry dichloromethane are added 6.5 cm3 of triethylamine and 6.5 cm3 of trifluoroacetic acid. After stirring for 3 hours at room temperature, the reaction mixture, cooled to +5° C., is basified with 50 cm3 of 1N sodium hydroxide. The organic phase is separated out, washed with water, dried over magnesium sulphate and then concentrated to dryness under reduced pressure (2.7 kPa). The oil obtained is crystallized in diisopropyl ether. The solid, washed with petroleum ether, is then drained and dried under reduced pressure at 40° C. 3.4 g of (3aRS,7RS,7aSR)-2-benzyl-7-hydroxy -7-(2-methoxyphenyl)-4)-perhydroisoindolone are obtained, in the form of a cream-coloured solid. M.p.=96C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=O)[CH:8]3[CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[CH2:13][CH2:12][N:9]32)=[CH:4][CH:3]=1.B.C1COCC1.CO>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][CH2:7][CH:8]3[CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[O:17])[CH2:13][CH2:12][N:9]32)=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccc(Cl)cc2N2CCN(C(=O)OCc3ccccc3)CC12
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCN2c3cc(Cl)ccc3NCC2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.4 %

Procedure:
To a solution of 9-chloro-3-carbobenzyloxy-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a ]-quinoxalin-5(6H)-one (1.45 g, 3.9 mmol) in 50 ml THF was added a solution of borane-THF complex (1M in THF, 12.2 ml, 12.2 mmol). After 15 min, the reaction was heated to reflux. After MS showed the absence of starting material, the reaction mixture was cooled to rt. Methanol was added and the solution concentrated to a yellow residue. This was repeated and the crude material was purified by column chromatography using a Biotage© Flash 40i (4.0×15.0 cm column, load with methylene chloride, elute with 25-30% ethyl acetate/hexanes) to give 9-Chloro-3-carbobenzyloxy-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline as an off-white solid (898.3 mg, 65%). 1H NMR (CDCl3, 300 MHz) δ7.32-7.38 (m, 5H), 6.56-6.66 (m, 2H), 6.37-6.40 (m, 1H), 5.16 (s, 2H), 4.19 (m, 2H), 3.61-3.71 (m, 2H), 3.33-3.36 (m, 1H), 3.05-3.23 (m, 2H), 2.72-2.79 (m, 2H) ppm. MS (ESI) m/z=358 [M+H]+.
Reaction SMILES: [CH:1]1[C:14]2[CH:13]([CH2:15]O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O.C1COCC1>N1C=CC=CC=1>[Cl:19][CH2:15][CH:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:6][C:5]2[C:14]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: OCC1c2ccccc2Oc2ccccc21
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: ClCC1c2ccccc2Oc2ccccc21
Temperature: 50 °C
Yield: 95.7 %

Procedure:
To a mixture of 4.0 g of 9-xanthenemethanol and 3.0 mL of freshly distilled thionyl chloride in 30 mL of freshly distilled THF was added dropwise 1.7 mL of pyridine over a period of 15 minutes. The mixture was heated in an oil bath at 50° C. for 12 hours, cooled to room temperature, and washed with half sat'd brine (30 mL), sat'd NaHCO3 (30 mL) and water (2×30 mL). The organic layer was dried over MgSO4 and the solvent was evaporated in vacuo to give 4.16 g (95.7%) of the crude 9-chloromethylxanthene as an off-white solid. Recrystallization from CH3OH--CH2Cl2 (4:1) gave 3.53g (81.35%) of the pure 9-chloromethylxanthene as white needles, m.p. 104.5°-106° C.; 1H NMR (CDCl3 ):δ 3.67 (d, 2H, CH2), 4.32 (t, 1H, CH), 7.04-7.46 (m, 8H, aryl).
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C([C:10]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[S:12][C:11]=1[CH:18]=O)C.[CH2:20]1COC[CH2:21]1>>[CH2:20]([O:17][C:15]([C:13]1[S:12][C:11]([CH:18]=[C:1]2[C:2](=[O:3])[CH2:4][O:5][C:6]2=[O:7])=[CH:10][CH:14]=1)=[O:16])[CH3:21]
Reactant: O=C1COC(=O)C1
Reactant: C1CCOC1
Reactant: CCc1cc(C(=O)O)sc1C=O
Product: CCOC(=O)c1ccc(C=C2C(=O)COC2=O)s1
Reaction time: 0.17 h
Yield: 63 %

Procedure:
0.494 gm of tetronic acid (FW=100, 4.94 mmole) and 2.00 gm of ethyl-5-carboxy-2-thiophenecarboxaldehyde (FW=184, 10.9 mole) in 2mL of THF and 10 mL of concentrated HC1 was reacted as before by applying heat and efficient stirring. The total reaction time was 10 minutes. Workup and recrystallization from methanol gave 0.827 gm (63%) of the product. M. p. 204°-205.5° C. C12H10O4S: %C 564.13; %H 3.79; found %C 53.93; %H 4.00. NMR results: 1HNMR (d6DMSO (H2)/TMS δ1.39 (3H, t, 7HZ); 4.39 (2H, q, 7Hz); 7.83 (1H, d, 4Hz); 8.21 (2H, m).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([F:36])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:23][CH2:22]3)[CH:16]=1)[C:11]([CH3:35])([CH3:34])[CH2:10]2)=[O:4].O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[F:36][C:7]1[CH:8]=[C:9]2[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=1)[NH:13][CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[CH2:25][CH2:26]3)[CH:16]=1)[C:11]([CH3:35])([CH3:34])[CH2:10]2
Reactant: COC(=O)c1cc(F)cc2c1NC(c1cccc(N3CCN(c4ccccc4C)CC3)c1)C(C)(C)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1N1CCN(c2cccc(C3Nc4c(cc(F)cc4C(=O)O)CC3(C)C)c2)CC1
Temperature: 60 °C
Reaction time: 12 h
Yield: 51.5 %

Procedure:
A mixture of 6-fluoro-3,3-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (0.80 g, 1.64 mmol), lithium hydroxide hydrate (690 mg, 16.4 mmol), water (1.0 mL) in methanol (5 mL) and tetrahydrofuran (20 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 6-fluoro-3,3-dimethyl-2-[3-(4-o-tolyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (400 mg, 52%) as a white solid: LC/MS m/e calcd for C29H32FN3O2 (M+H)+: 474.6, observed: 474.3.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:13][C:14]1[NH:19][C:18](=[O:20])[CH:17]=[C:16]([NH2:21])[N:15]=1>>[NH2:13][C:14]1[NH:19][C:18](=[O:20])[C:17]2[CH:2]=[C:3]([CH2:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:21][C:16]=2[N:15]=1
Reactant: Nc1cc(=O)[nH]c(N)n1
Reactant: O=C(CCl)CCc1ccccc1
Product: Nc1nc2[nH]c(CCc3ccccc3)cc2c(=O)[nH]1
Yield: 39 %

Procedure:
FIG. 19 presents the method used to synthesize 2-amino-6-phenethyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one 9. Phenylpropanoyl chloride7 was reacted with CH2N2 in the presence of gaseous hydrogen chloride and ether to produce 1-chloro-4-phenyl-2-butanone 8. 1-chloro-4-phenyl-2-butanone 8 was reacted with 2,6-diamino-3H-pyrimidin-4-one 1 to produce 2-amino-6-phenethyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one 9 at a 39% yield.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20].C(N(CC)CC)C>ClCCl.C(OCC)(=O)C.CN(C1C=CC=CN=1)C>[CH:1]([N:14]1[CH2:17][CH:16]([O:18][C:19](=[O:21])[CH3:20])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a stirred solution of N-benzhydryl-azetidin-3-ol (3.56 g, 14.9 mmol.) in dichloromethane (60 mL) was added acetic anhydride (2.1 mL, 22.4 mmol.), triethylamine (3.1 mL, 22.4 mmol.) and dimethylaminopyridine (ca. 10 mg). The mixture was stirred for 3 hours then diluted with ethyl acetate (200 mL) and washed with saturated aqueous ammonium chloride solution (100 mL), 1N aqueous sodium hydroxide (100 mL) and brine (100 mL), dried (MgSO4) and evaporated to leave N-benzhydryl-3-acetoxy-azetidine (4.2 g) which was used without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCC(O)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1CCN(C2CNC2)CC1
Temperature: 25 °C
Reaction time: 7 h
Yield: 93.4 %

Procedure:
A 25 mL round-bottomed flask was charged with a solution of 3-(4-hydroxypiperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (0.34 g, 1.33 mmol) in DCM/TFA (4 mL/4 mL). The reaction mixture was stirred for 7 h at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 1-Azetidin-3-ylpiperidin-4-ol as a colourless oil (0.194 g, 94%). 1H NMR (CDCl3, 400 MHz) δ 3.75-3.68 (m, 1 H); 3.67-3.51 (m, 4 H); 3.25-3.17 (m, 1 H); 2.66-2.56 (m, 3 H); 2.03-1.84 (m, 5 H); 1.65-1.53 (m, 2 H).
Reaction SMILES: C#CC(N1CCCC1C)C.[CH2:11]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH3:20])[CH2:12][C:13]#[CH:14].[Br:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[C:24](I)[CH:23]=1.C(NC(C)C)(C)C>[Cu]I.BrC1C=CC2SC(CCO)=NC=2C=1>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[C:24]([C:14]#[C:13][CH2:12][CH2:11][N:15]2[CH2:19][CH2:18][CH2:17][C@H:16]2[CH3:20])[CH:23]=1
Reactant: C#CCCN1CCC[C@H]1C
Reactant: Nc1ccc(Br)cc1I
Agent: [Cu]I
Agent: C#CC(C)N1CCCC1C
Agent: OCCc1nc2cc(Br)ccc2s1
Solvent: CC(C)NC(C)C
Product: C[C@@H]1CCCN1CCC#Cc1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
To a solution of 1-butyn-3-yl-2-methyl-pyrrolidine in CH3CN (prepared in Example 65A assuming 100% conversion, 89 mmol) was added 4-bromo-2-iodo-phenylamine (12.0 g, 40 mmol) under nitrogen followed by addition of CuI (0.38 g, 2.0 mmol), PdCl2(PPh3) 2 (0.70 mg, 1.0 mmol) and diisopropylamine (33.6 mL, 240 mmol). The resulting solution was stirred at room temperature for 2 hours, at which time analytical HPLC analysis indicated that all 4-bromo-2-iodo-phenylamine was consumed. The solvent CH3CN was removed under vacuo and the residue was extracted with IPAC (500 mL) and 5% NaHCO3 (2×300 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give the title compound as a thick oil (11.96 g), which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][OH:17])[N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[CH:21]=[C:22](O)[CH:23]=[CH:24][C:25]=1[N+:26]([O-:28])=[O:27]>>[C:1]([O:5][C:6](=[O:18])[N:7]([CH3:8])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][O:17][C:22]2[CH:23]=[CH:24][C:25]([N+:26]([O-:28])=[O:27])=[C:20]([CH3:19])[CH:21]=2)[N:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(CCO)n1
Product: Cc1cc(OCCc2cccc(N(C)C(=O)OC(C)(C)C)n2)ccc1[N+](=O)[O-]
Yield: 81 %

Procedure:
The title compound was synthesized from [6-(2-hydroxy-ethyl)-pyridin-2-yl]-methyl-carbamic acid tert-butyl ester and the commercially available 3-methyl-4-nitro-phenol using the procedure described in Example 16, step (b), in 81% yield. 1H NMR (Cl3CD), δ: 1.52 (s, 9H), 2.62 (s, 3H), 3.21 (t, 2H, J=8.00 Hz), 3.36 (s, 3H), 4.44 (t, 2H, J=8.00 Hz), 6.80 (m, 2H), 6.94 (dd, 1H, J=2.4, 5.6 Hz), 7.55 (m, 2H), 8.05 (d, 1H, J=8.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:20][C:21]1[C:25]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[O:27])=[CH:24][NH:23][C:22]=1[CH:35]=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:35][C:22]4[NH:23][CH:24]=[C:25]([C:26]([N:28]5[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]5)=[O:27])[C:21]=4[CH3:20])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2ncnc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 96 h
Yield: 50.8 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (70.7 mg, 0.3 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 4 days. The precipitate was collected by vacuum filtration, washed with ethanol to give 63 mg (51%) of the title compound as a yellow solid. 1H NMR (360 MHz, DMSO-d6) δ 13.29 (br s, 1H, NH), 11.73 (br s, 1H, NH), 9.16 (br s, 1H), 8.31 (s, 1H), 7.72 (dd, J=2.7 & 6.5 Hz, 1H), 7.46 (d, J=2.7 Hz, 1H), 7.43 (m, 1H), 7.40 (s, 1H), 7.34 (t, J=9.05 Hz, 1H), 3.49 (m, 4H, 2×CH2), 2.29 (m, 4H, 2×CH2), 2.19 (s, 3H, CH3), 2.18 (s, 3H, CH3). MS 496 [M++1].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1)#[N:2].Cl.N#[C:13][NH2:14]>C(O)CC>[C:13]([N:2]=[C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1)[O:10][CH2:9][CH2:7][CH3:6])#[N:14]
Reactant: N#Cc1cncc(CO)c1
Reactant: N#CN
Agent: Cl
Solvent: CCCO
Product: CCCOC(=NC#N)c1cncc(CO)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
After 3-cyano-5-hydroxymethylpyridine (0.79 g, 5.9 mmol) was dissolved in 1-propanol (30 ml) and hydrogen chloride gas was passed into the solution under ice-cooling for 30 minutes, the reactor was tight sealed for stirring the mixture at room temperature for 20 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was neutralized with a saturated aqueous sodium carbonate solution and extracted with chloroform (30 ml×3). The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in acetonitrile (20 ml), and an aqueous solution (30 ml) of cyanamide (0.50 g, 11.9 mmol), Na2HPO4 (0.84. g, 5.9 mmol) and NaH2PO4 ·2H2O (3.79 g, 23.7 mmol) was added to the solution. The mixture was stirred at room temperature for 10 hours. After the completion of the reaction, the mixture was extracted with chloroform (100 ml×3). The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product of propyl N-cyano-5-hydroxymethyl-3-pyridinecarboximidate.
Reaction SMILES: [Br-].[CH:2]12[C:14](=[N+]3CCCC3)[CH:11]([CH2:12][CH2:13]1)[CH2:10][C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:3]2.Cl.[OH2:21]>>[CH:2]12[C:14](=[O:21])[CH:11]([CH2:12][CH2:13]1)[CH2:10][C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:3]2
Reactant: O
Reactant: c1ccc2c(c1)CC1CCC(C2)C1=[N+]1CCCC1
Agent: Cl
Agent: [Br-]
Product: O=C1C2CCC1Cc1ccccc1C2

Procedure:
1-Tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-ylidene-pyrrolidinium bromide (225 mg, 0.70 mmol) was dissolved in water (5 mL) and 2 M aqueous HCl (5 mL) was added. The mixture was heated at reflux for 16 h, cooled and extracted into DCM. The organic extracts were concentrated to give tricyclo[8.2.1.03,8]trideca-3(8),4,6-trien-13-one (130 mg) as a white crystalline solid. 1H NMR (CDCl3, 360 MHz) δ 7.19 (4 H, s, aromatic), 2.99-2.86 (4 H, m, benzylic), 2.61-2.57 (2 H, m, bridgehead H), 1.90-1.80 (2 H, m), 1.33-1.26 (2 H, m).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:4][CH:3]=1.C([Li])CCC.CN([CH:29]=[O:30])C>C1COCC1.CCCCCC>[CH:29]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:4][CH:3]=1)=[O:30]
Reactant: CN(C)C=O
Reactant: Brc1ccc(CCOC2CCCCO2)c2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc(CCOC2CCCCO2)c2ccccc12
Reaction time: 0.5 h
Yield: 54 %

Procedure:
A solution of 1-bromo-4-(2-tetrahydropyranyloxyethyl)naphthalene in anhydrous THF (15 mL) under nitrogen was cooled to −78° C. n-Butyl lithium (1.4 mL of a 2.5 M solution in hexane) was added via syringe, and the mixture was stirred at the same temperature for 30 min. DMF (1.1 mL) was added, and the mixture was allowed to reach room temperature. It was diluted with satd. NH4Cl solution (10 mL), extracted with ether (3×10 ml), dried (MgSO4) and concentrated. Flash chromatography using hexane/ethyl acetate 5:1 as eluent provided 408 mg (54%) of a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH2:22].Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH:22][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: N#Cc1cnc2cc3ccccc3cc2c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: N#Cc1cnc2cc3ccccc3cc2c1Nc1ccc(F)c(Cl)c1
Yield: 77.9 %

Procedure:
Following the procedure of Example 3, the reaction mixture of 141.8 mg (0.60 mmol) of 4-chlorobenzo[g]quinoline-3-carbonitrile, 87.3 mg (0.60 mmol) of 3-chloro-4-fluoroaniline and 57.8 mg (0.50 mmol) of pyridine hydrochloride in 8.0 mL of 2-ethoxyethanol is heated at 110–120° C. for 1 hour to yield 162.5 mg (77.9%) of the product as a bright yellow solid, mp 257–259° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)(O)=O.[C:13](=[O:16])([O-])[OH:14].[K+].BrC[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30]>CN(C)C=O>[OH:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:1][C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[O:11][C:13]([OH:14])=[O:16])=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: O=C([O-])O
Reactant: OCCCCCCCCCCCBr
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)OB(O)c1ccc(CCCCCCCCCCCO)cc1
Temperature: 60 °C

Procedure:
A mixture of 4-carboxyphenylboronic acid (1.0 grams), potassium hydrogen carbonate (2.01 g), 11-bromo-1-undecanol, and N,N-dimethylformamide (60 mL) was heated at 60° C. under a nitrogen atmosphere for 18 hours. After the heating period, the mixture was allowed to cool to room temperature. The mixture was then filtered and the filtrate was concentrated on a rotary evaporator. The concentrated filtrate was diluted with ethyl acetate (500 mL) and the ethyl acetate was washed successively with saturated aqueous sodium bicarbonate (3×300 mL), followed by saturated aqueous sodium chloride (300 mL). After drying over sodium sulfate, the ethyl acetate extract was concentrated on a rotary evaporator and dried under reduced pressure to afford 2.2 grams of the desired product as a light yellow viscous oil that solidified upon standing to a white powder.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:2]1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([O-:21])=[O:20].C(N(C(C)C)CC)(C)C>ClCCCl>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([S:28]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:2]2)(=[O:30])=[O:29])=[CH:26][CH:27]=1)([O-:21])=[O:20]
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2C1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC1Cc2ccccc2N(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 75 °C
Reaction time: 15 h
Yield: 87 %

Procedure:
To a solution of tert-butyl 1,2,3,4-tetrahydroquinolin-3-ylcarbamate (3.03 g, 12.2 mmol) and 4-nitrobenzene-1-sulfonyl chloride (2.99 g, 13.5 mmol) in 1,2-dichloroethane (60 mL) was added diisopropylethylamine (6.6 mL, 4.90 g, 37.9 mmol). The mixture was stirred at 75° C. for 15 hours. The mixture was quenched by addition of saturated aqueous sodium bicarbonate (80 mL) and extracted with dichloromethane (3×50 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by chromatography on silica gel (30% EtOAc/hexane) to give tert-butyl 1-(4-nitrophenylsulfonyl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (4.6 g).