Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([O:7][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[C:15]([C:18]2[N:22]4[CH:23]=[CH:24][C:25]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[CH:26][C:21]4=[N:20][CH:19]=2)[CH:14]=[CH:13]3)[CH2:5][N:4](C(OCC2C=CC3C(=CC=CC=3)C=2)=O)[CH2:3]1.CCO.Cl>[Pd].C1COCC1>[CH3:31][O:30][CH2:29][CH2:28][O:27][C:25]1[CH:24]=[CH:23][N:22]2[C:18]([C:15]3[CH:14]=[CH:13][C:12]4[C:17](=[C:8]([O:7][C@@H:6]5[CH2:5][NH:4][CH2:3][C@H:2]5[OH:1])[CH:9]=[CH:10][CH:11]=4)[N:16]=3)=[CH:19][N:20]=[C:21]2[CH:26]=1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(O[C@@H]5CN(C(=O)OCc6ccc7ccccc7c6)C[C@H]5O)c4n3)cnc2c1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: COCCOc1ccn2c(-c3ccc4cccc(O[C@@H]5CNC[C@H]5O)c4n3)cnc2c1
Reaction time: 2 h
Yield: 20.2 %

Procedure:
A 25 mL flask was charged with (trans)-naphthalen-2-ylmethyl 3-hydroxy-4-(2-(7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl)quinolin-8-yloxy)pyrrolidine-1-carboxylate (0.100 g, 0.165 mmol), EtOH (1.6 mL), THF (1.6 mL), 2 N HCl (0.2 mL) and 10% Degussa type Pd/C (0.018 g, 0.017 mmol), and the reaction was placed under a balloon of H2 and stirred for 2 hours. The reaction was filtered (GF/F paper), the filter paper was washed with 2 N HCl and THF, the aqueous phase was washed with DCM, neutralized with saturated NaHCO3, and then extracted with DCM. The organic layer was dried and condensed to afford 14 mg of the desired product. MS APCI (+) m/z 421.2 (M+1) detected.
Reaction SMILES: S(O)([O:4][CH2:5][CH2:6][NH2:7])(=O)=O.[OH-].[Na+].[CH2:11]([O:18][CH2:19][CH:20]1[CH2:22]O1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[CH2:11]([O:18][CH2:19][CH:20]1[O:4][CH2:5][CH2:6][NH:7][CH2:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCOS(=O)(=O)O
Reactant: c1ccc(COCC2CO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: c1ccc(COCC2CNCCO2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
199 g of 2-aminoethyl hydrogen sulfate are added to 164 ml of 70% sodium hydroxide solution, the solution is heated to 50° C. and added dropwise to a solution of (RS)-benzyloxymethyloxirane in 280 ml of methanol. After 1 hour at 50° C. a further 280 ml of 70% sodium hydroxide solution are added thereto and the solution is stirred overnight. Then, the reaction mixture is poured on to ice and extracted with toluene. The organic phase is washed with water, dried and evaporated. After distillation there are obtained 26.8 g of rac-2-benzyloxymethylmorpholine, MS: M+ -91=116 (benzyl).
Reaction SMILES: [C:1]1([SH:8])[CH:6]=[CH:5][CH:4]=[C:3]([SH:7])[CH:2]=1.[CH3:9]C1CCCO1.COS(OC)(=O)=O.[OH-].[Na+]>C(OC)(C)(C)C>[CH3:9][S:7][C:3]1[CH:2]=[C:1]([SH:8])[CH:6]=[CH:5][CH:4]=1
Reactant: Sc1cccc(S)c1
Reactant: CC1CCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: COC(C)(C)C
Product: CSc1cccc(S)c1
Temperature: 50 °C
Yield: 78 %

Procedure:
A solution of benzene-1,3-dithiol (50 g, 0.351 mmol) in 2-methyltetrahydrofuran (375 mL, 0.351 mmol) was treated with dimethylsulfate (33.3 mL, 0.351 mol) followed by 2-methyltetrahydrofuran (25 mL, used as line wash). The resulting solution was cooled to between 0° C. and 5° C. and sodium hydroxide (2M aqueous solution, 210.6 mL) was added drop wise maintaining the temperature of the reaction mixture below 15° C. followed by 2-methyltetrahydrofuran (25 mL, used as line wash) and heated under nitrogen to 50° C. for 4 hours. After cooling to ambient temperature the resulting solution was treated with tert-butylmethylether (500 mL) and the phases were separated. The organic phase was extracted with sodium hydroxide (2 M aqueous solution, 250 mL) and the combined aqueous phases were cooled to 10° C. and hydrochloric acid (6M aqueous solution, 500 mL) was added whilst maintaining the temperature of the mixture below 25° C. The resulting solution was extracted with tert-butylmethylether (2-fold 250 mL) and the combined organic phases were washed with water (500 mL) and concentrated in vacuo to give the title compound as a yellow oil, 78% yield, 42.9 g.
Reaction SMILES: [CH2:1]([NH:3][CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30]C)=[O:29])=[C:26]2[C:21]([CH:22]3[CH2:32][CH:23]3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].O.[OH-].[Li+]>O1CCOCC1.O>[CH2:1]([NH:3][CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([OH:30])=[O:29])=[C:26]2[C:21]([CH:22]3[CH2:32][CH:23]3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:15])=[O:16])[CH3:2]
Reactant: CCNC/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCNC/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Temperature: 120 °C
Yield: 33.2 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-[2((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 63, 0.09 g) and lithium hydroxide monohydrate (0.047 g) in a mixture of dioxane (10 mL) and water (5 mL) was stirred and heated at 120° C. for 32 hours. After cooling, the mixture was concentrated under vacuum and the residue was acidified to pH4 with formic acid. The resultant solid was collected by filtration and washed with water to give (1aRS,7bSR)-5-[2((Z)-3-ethylaminoprop-1-enyl)-4-fluorobenzene-sulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic acid (0.029 g) as a grey solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Br:15]Br.O>C(O)(=O)C>[Br:15][C:5]1[CH:4]=[C:3]([C:12]([OH:14])=[O:13])[C:2]([OH:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: BrBr
Reactant: O=C(O)c1ccc2cccnc2c1O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc(Br)c2cccnc2c1O
Yield: 100.9 %

Procedure:
8-Hydroxyquinoline-7-carboxylic acid (1.00 g) is suspended in 25 mL acetic acid. To this is added bromine (0.845 g) dropwise. The mixture is heated to reflux for 1 h, then poured into cold water. The resulting solid is collected, washed with water and dried to yield 1.43 g of the title product as a yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=O)=[CH:2]1.C(Cl)(=O)C([Cl:17])=O>C(Cl)Cl.CN(C)C=O>[CH:6]1[CH:5]=[C:4]2[C:3]([CH2:10][C:11]([Cl:17])=[O:13])=[CH:2][NH:1][C:9]2=[CH:8][CH:7]=1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To indole-3-acetic acid (186 mg, 1.06 mmol) in 3.5 mL of methylene chloride and 0.009 mL of dimethylformamide, oxalyl chloride (2 M in methylene chloride, 0.64 mL, 1.27 mmol) was added. The mixture was stirred at room temperature for 1 hour and concentrated to give 1H-indole-3-acetyl chloride.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[N:16]=[C:15]([C:17]2[S:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](=[O:23])[N:22]=2)[CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>C(#N)C>[CH2:34]([NH:36][C:37]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([C:17]2[S:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](=[O:23])[N:22]=2)[N:16]=1)=[O:38])[CH3:35]
Reactant: CCN=C=O
Reactant: NCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCNC(=O)NCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.1 %

Procedure:
A mixture of 2-[6-(2-aminoethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (0.45 g, 1.1 mmol), potassium carbonate (0.47 g, 3.4 mmol) and acetonitrile (26 ml) was stirred at room temperature for 20 minutes. Successively ethyl isocyanate (0.36 g, 5.1 mmol) was added to the mixture, and the mixture was refluxed for 3 hrs. After cooling, the precipitates were collected by filtration, dissolved in chloroform and subjected to a silica gel column chromatography. The fractions eluted with chloroform-ethanol (15:1, v/v) were collected, concentrated and recrystallized from chloroform-hexane to give the titled compound (0.25 g, 63%) as white crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[O:9])[S:6][CH:7]=1)#[CH:2].[BH4-].[Na+].O>CO>[C:1]([C:3]1[CH:4]=[C:5]([CH2:8][OH:9])[S:6][CH:7]=1)#[CH:2]
Reactant: C#Cc1csc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C#Cc1csc(CO)c1
Temperature: 0 °C
Yield: 60 %

Procedure:
To a solution of 4-ethynylthiophene-2-carboxaldehyde (1.5 g, 11 mmol) that was obtained in Example 9 (9b) in methanol (30 ml) was added sodium borohydride (0.49 g, 13 mmol) at 0° C. with stirring, and then the resulting mixture was stirred at room temperature for 15 minutes. After cooling the reaction mixture to 0° C., water (100 ml) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:9 to 3:7) as the eluent to afford the title compound (0.88 g) in a yield of 60% as a brown oily product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][CH:11]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.C([O-])([O-])=O.[K+].[K+]>C(C(C)=O)C>[N:32]1([CH2:31][CH2:30][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:13]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=4)=[CH:12][CH:11]=[C:10]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:9]=3)=[CH:6][CH:7]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: ClCCN1CCCC1
Reactant: COc1ccc(-c2ccc(-c3ccccc3)nc2-c2ccc(O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(-c2ccc(-c3ccccc3)nc2-c2ccc(OCCN3CCCC3)cc2)cc1
Yield: 93.2 %

Procedure:
The 2-(4-hydroxyphenyl)-3-(4-methoxyphenyl)-6-phenylpyridine (2.0 g, 5 mmol), N-(2-chloroethyl)pyrrolidine hydrochloride (1.0 g, 5 mmol), and powdered K2CO3 (4.2 g, 30 mmol) were stirred in 200 mL methyl ethyl ketone and refluxed 20 h. The reaction mixture was worked up and the residue triturated with pet. ether, filtered, and dried in vacuo to give 2.1 g (84% yield) of an off-white solid: mp 100°-103° C.; 1H NMR (CDCl3) d 1.81-1.84 (m, 4H, pyrrolidine), 2.61-2.65 (m, 4H, pyrrolidine), 2.88-2.92 (t, 2H, J=6 Hz, NCH2), 3.83 (s, 3H, ArOCH3), 4.10-4.14 (t, 2H, J=6 Hz, OCH2), 6.81-6.87 (m, 4H, ArH), 7.15-7.18 (d, 2H, J=9 Hz, ArH) 7.42-7.50 (m, 5H, ArH), 7.73 (s, 2H, ArH), 8.13-8.16 (d, 2H, J=9 Hz, ArH); MS(FD) 450(M+). Anal. Calcd for C30H30N2O2 : C, 79.97; H, 6.71; N, 6.22. Found: C, 79.86; H, 6.09; N, 6.16.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:14]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+].COCCOC>O>[C:14]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:3]=2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: Brc1cccc(-c2ccccn2)c1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)c1ccc(-c2cccc(-c3ccccn3)c2)cc1

Procedure:
13.7 g (0.058 mol) of 2-(3-bromophenyl)pyridine was added to 12.5 g (0.070 mol) of 4-tert-butylphenylboronic acid, 3.4 g (0.003 mol) of Pd(Ph3)4, 22.0 g (0.16 mol) of K2CO3, 50 mL of DME and 50 mL of water. The reaction mixture was refluxed for 20 hours and separated on silica gel column. MS confirmed the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][N:13]([CH2:24][C:23]4[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=4)[CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Product: COc1ccc(CN2CCc3c(c(=O)oc4cc(OC)ccc34)C2)cc1
Yield: 54 %

Procedure:
Prepared by the procedure of Example 3 from 8-methoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one and 4-methoxybenzaldehyde. Yield 54%; mp 101°-103° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH3:25][CH2:26][CH:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH2:28][CH3:29]>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:33]3[CH2:34][CH2:35][N:30]([CH:27]([CH2:28][CH3:29])[CH2:26][CH3:25])[CH2:31][CH2:32]3)=[O:21])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CCC(CC)N1CCNCC1
Product: CCC(CC)N1CCN(C(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4C)c3O)nc2)CC1

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-(pentan-3-yl)piperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (t, J=7.33 Hz, 6 H) 1.29 (dt, J=14.08, 6.98 Hz, 2 H) 1.47 (dt, J=14.08, 6.98 Hz, 2 H) 2.26 (t, J=6.57 Hz, 1 H) 2.43 (s, 3 H) 2.56 (br. s., 4 H) 3.37-3.48 (m, 2 H) 3.62 (br. s., 2 H) 7.64 (dd, J=8.08, 1.52 Hz, 1 H) 7.71 (s, 1 H) 7.82 (d, J=8.08 Hz, 1 H) 8.05 (dd, J=8.59, 2.27 Hz, 1 H) 8.12 (s, 1 H) 8.39 (d, J=8.59 Hz, 1 H) 8.53 (d, J=2.27 Hz, 1 H) 12.82 (br. s., 1 H); ESI-MS m/z [M+H]+ 459.3.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.I[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-:18])=[O:17].C([O-])([O-])=O.[K+].[K+].CCCCCC>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:16]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)([O-:18])=[O:17]
Reactant: OB(O)c1cccs1
Reactant: O=[N+]([O-])c1ccccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccccc1-c1cccs1
Temperature: 80 °C
Yield: 107.7 %

Procedure:
14.07 g (110 mmol) of 2-thiophene-boronic acid, 24.9 g (100 mmol) of 1-iodo-2-nitrobenzene, and 5.78 g (5 mmol) of tetrakis(triphenylphosphine)palladium(0) were dissolved in 250 ml of ethylene glycol dimethyl ether (DME), and 70 ml of 2M K2CO3 aqueous solution was added to the solution, and then the mixture was refluxed at 80° C. for 12 hours. After the reaction was completed, an organic layer was isolated and concentrated, and then isolated by column chromatography using hexane, thereby obtaining 22.1 g (yield: 98%) of 2-(2′-nitrophenyl)-thiophene (A′).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.[OH:16][C:17]1[C:18]([CH:25]=[O:26])=[CH:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[C:3]([CH2:2][O:16][C:17]3[C:18]([CH:25]=[O:26])=[CH:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)=[CH:8][CH:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: COc1cc(C=O)c(O)cn1
Reactant: ClCc1cccnc1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C=O)c(OCc2cccnc2-c2ccc(Cl)cc2)cn1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 3-(chloromethyl)-2-(4-chlorophenyl)pyridine (309 mg, 1.30 mmol, 1.00 equiv), 5-hydroxy-2-methoxypyridine-4-carbaldehyde (200 mg, 1.31 mmol, 1.00 equiv), and potassium carbonate (361 mg, 2.61 mmol, 2.00 equiv) in CH3CN (20 mL). The resulting solution was stirred for 4 h at 70° C., and then it was concentrated under vacuum. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (Prep-HPLC-010): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and MeCN (20.0% MeCN up to 60.0% in 10 min, up to 95.0% in 2 min, down to 20.0% in 1 min); Detector, Waters 2545 UvDector 254 & 220 nm. This resulted in 148.2 mg (20%) of 5-[[2-(4-chlorophenyl)pyridin-3-yl]methoxy]-2-methoxypyridine-4-carbaldehyde; bis(trifluoroacetic acid) as a yellow solid. 1HNMR (300 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.69 (m, 1H), 8.16 (m, 2H), 7.64 (m, 2H), 7.50 (m, 3H), 5.32 (s, 2H), 3.81 (s, 3H); MS (ESI) m/z 355 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3][CH2:2]1.[CH3:13]OC(OC)N(C)C>>[N:1]12[CH:13]3[N:9]([CH2:8][CH2:7][CH2:6][N:5]3[CH2:4][CH2:3][CH2:2]1)[CH2:10][CH2:11][CH2:12]2
Reactant: C1CNCCCNCCCNC1
Reactant: COC(OC)N(C)C
Product: C1CN2CCCN3CCCN(C1)C23
Yield: 73.1 %

Procedure:
In a manner similar to that of Example 1 (C), 5.00 g (29.2 mmol) of 1,5,9-triazacyclododecane and 3.48 g of dimethylformamide dimethyl acetal were reacted to give 3.87 g of 1,5,9-triazatricyclo[7.3.1.05,13 ]tridecane as a clear, colorless liquid, bp 93° (three fractions) (0.35 mm), which solidified on standing at room temperature. One fraction was analyzed.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15]([O:17]C)=[O:16])=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.O.[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:19])[CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15]([OH:17])=[O:16])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccn1CC(=O)c1ccc(Br)cc1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Cn1cccc1C(=O)O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 144.5 %

Procedure:
To a solution of crude methyl 1-[2-(4-bromophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (2.39 g, 2.47 mmol) in THF (30 mL) and water (20 mL) was added lithium hydroxide monohydrate (0.63 g, 15.1 mmol). The dark solution was stirred at room temperature. The outcome of the reaction was monitored by LCMS and after 1 h another portion of lithium hydroxide monohydrate (300 mg) was added to the reaction mixture. After 16 h the reaction mixture was diluted with a aqueous solution of NaOH (1M) (50 mL) then extracted with CH2Cl2 (100 mL). The pH of the aqueous fraction was adjusted to 1 with aqueous HCl (1M) and then extracted with CH2Cl2 containing 10% of propan-2-ol (3×75 mL). The organic extracts (from acidic aqueous) were combined, dried (MgSO4) and concentrated in vacuo to give crude (˜50% pure) 1-[2-(4-bromophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylic acid as a yellow solid (1.10 g, yield 72%) The crude material was used without purification.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([F:20])=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1.C1(C)C=CC(S([N:30]=[N+:31]=[N-])(=O)=O)=CC=1.Cl>CCCCCC.CCOCC.CCOCC.CCCCCC>[F:6][C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([F:20])=[CH:14][CH:15]=3)[C:10](=[N+:30]=[N-:31])[C:9]=2[CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: Fc1ccc2c(c1)Cc1cc(F)ccc1-2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: [N-]=[N+]=C1c2cc(F)ccc2-c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37 %

Procedure:
Under nitrogen, n-butyllithium (20 mL of a 2.5M solution in hexane, 1 eq) was added dropwise to a stirred, -20 ° C. solution of commercially available (Alfred Bader Library of Rare Chemicals) 2,7-difluorofluorene (24) (10 g, 49.5 mmoL) [which may also be prepared according to U.S. Pat. No. 4,436,745] in 250 mL of anhydrous ether. After 10 min., this mixture was transferred via a cannula using nitrogen pressure into a 0° C. solution of p-toluenesulfonylazide [prepared by the method described in Doering, et al. J. Am. Chem. Soc. (1953) 75, 5955] in 200 mL of anhydrous ether over 20 min. The reaction was allowed to warm to room temperature over 1.5 h and was then acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (3×200 mL). The combined organics were washed with brine (3×100 mL), dried (MgSO4), and concentrated to provide 10 g of crude material which was leached with ether/hexane to provide 4 g (37%) of product (25): mp 148°-150 ° C.; IR (KBr) 2070, 1600, 1575, 845 cm-1 ; 1H NMR (CDCl3, 200 MHz) 7.77 (ddd, 2H, J=0.5, 5.0, 8.7Hz), 7.14 (ddd, 2H, J=0.5, 2.5, 8.5Hz), 7.0 (ddd, 2H, J=2.3, 8.5, 9.3Hz); MS m/z 228 (M+), 200 (base peak). Anal. Calcd. for C13H6N2F2 : C, 68.42;H, 2.65; N, 12.28. Found: C, 68.25;H, 2.78; N, 12.50.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11](OS(C(F)(F)F)(=O)=O)=[C:10]([C:27]2[O:31][N:30]=[C:29]([CH3:32])[CH:28]=2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)[CH3:35].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:11]([C:39]2[CH:40]=[CH:41][C:36]([CH2:34][CH3:35])=[CH:37][CH:38]=2)=[C:10]([C:27]2[O:31][N:30]=[C:29]([CH3:32])[CH:28]=2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1ccc(B(O)O)cc1
Reactant: Cc1cc(-c2c(OS(=O)(=O)C(F)(F)F)c3cc(Cl)ccc3n(Cc3ccccc3)c2=O)on1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCc1ccc(-c2c(-c3cc(C)no3)c(=O)n(Cc3ccccc3)c3ccc(Cl)cc23)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 1-benzyl-6-chloro-3-(3-methyl-isoxazol-5-yl)-2-oxo-1,2-dihydro-quinolin-4-yl ester (40 mg, 0.080 mmol), 4-ethylbenzeneboronic acid (14.4 mg, 0.096 mmol), Pd(PPh3)4 (9.2 mg, 0.0080 mmol) and Na2CO3 (80 ul, 0.16 mmol, 2.0 M)in 1 ml of 1,4-dioxane was stirred at 100° C. for 1 h, then cooled to rt. Treated with 40 ml of EtOAc, the mixture was washed with H2O (2×10 ml), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (25% EtOAc/hexane) gave 29.5 mg (81%) of product as a white solid: 1H-NMR (CDCl3; 400 MHz) δ7.41 (dd, 1H, J=9.0, 2.2 Hz), 7.24-7.38 (m, 8H), 7.15 (d, 2H, J=8.0 Hz), 6.48 (s, 1H), 5.64 (s, 2H), 3.71 (s, 1H), 2.74 (q, 2H, J=7.6 Hz), 2.23 (s, 3H), 1.31 (t, 2H, J=7.6 Hz),. Mass spectrum (ESI, m/z): Calcd. for C28H23ClN2O2, 455.1 (M+H), found 455.1.