Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4]([NH2:6])=O.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl

Procedure:
A mixture of 31.8 gm. (0.129 mole) of 2-chloro-3,5-dinitrobenzamide and 50 ml. of phosphorous oxychloride is heated under reflux for one hour. The excess phosphorous oxychloride is removed by distillation under reduced pressure. To the residue is cautiously added ice water. The light yellow-green solid is removed by filtration and washed with water. There is obtained 28.0 g. (95%) of material melting at 139°-41°.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][C:6](=O)[C:5]=12.I[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1>>[N:15]1[CH:16]=[CH:17][C:12]([CH:6]2[CH2:7][CH2:8][CH2:9][N:4]3[CH:3]=[N:2][CH:1]=[C:5]23)=[CH:13][CH:14]=1
Reactant: O=C1CCCn2cncc21
Reactant: Ic1ccncc1
Product: c1cc(C2CCCn3cncc32)ccn1

Procedure:
In analogy to Example 1 6,7-dihydro-5H-imidazo[1,5-a]pyridin-8-one [426219-51-4] and 4-iodopyridine [15854-87-2] are reacted. The title compound is obtained as a light brown foam. Rt=2.26 (Gradient I).
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[O:16]=[C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=1>C1COCC1.O>[OH:4][C:3]1[CH2:5][C:17]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:16][C:1](=[O:6])[CH:2]=1
Reactant: COC(=O)CC(C)=O
Reactant: CC(=O)Nc1ccc(CCC(=O)c2ccccc2)cc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(CCC2(c3ccccc3)CC(O)=CC(=O)O2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Methyl acetoacetate (4.5 mL, 41.7 mmol) was added dropwise to a slurry of 60% sodium hydride (1.75 g, 43.7 mmol) in THF (135 mL) at 0° C. After stirring 15 minutes, n-butyllithium (21 mL of 2.1M, 44.1 mmol) was added and the reaction stirred an additional 15 minutes at 0° C. N-[4-(3-Oxo-3-phenyl-propyl)-phenyl]-acetamide, prepared in Example Y (5.3 g, 19.8 mmol) in THF (15 mL) was added in one portion and the reaction allowed to warm to room temperature over 4 hours. H2O was added and the reaction allowed to stir overnight. The mixture was extracted with Et2O and the aqueous layer acidified with 1N HCl. The precipitate was filtered, then washed with EtOAc to give the title compound, m.p. 155°-160° C. 1H NMR (DMSO-d6) δ 2.0 (s, 3 H), 2.17 (m, 2 H), 2.50 (m, 2 H), 3.02 (dd, 2 H), 4.88 (s, 1 H), 6.99 (d, 2 H), 7.25-7.50 (m, 7 H), 9.81 (s, 1 H), 11.50 (s, 1 H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH2:20]Br)[CH:19]=1>CN(C=O)C>[Br:13][C:14]1[CH:19]=[C:18]([CH2:20][O:10][CH:7]2[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]2)[CH:17]=[N:16][CH:15]=1
Reactant: CC(=O)N1CCC(O)CC1
Reactant: BrCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(OCc2cncc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
To a cooled (0° C.) solution of 1-acetylpiperidin-4-ol (2.0 g, 14.2 mmol) in DMF (25 mL) is added sodium hydride (60% dispersion in mineral oil, 567 mg, 14.2 mmol). After stifling at 0° C. for 15 min, 3-bromo-5-bromomethyl-pyridine (2.4 g, 9.45 mmol) is added. The reaction is allowed to warm and stir at room temperature for 1 h. The reaction is quenched with the addition of saturated aqueous ammonium chloride and water and is extracted with EtOAc. The combined organic layers are dried (Na2SO4) and concentrated. The crude product is purified by silica gel column (0-10% MeOH in DCM) to provide the title compound (2.1 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[NH2:30][CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH2:37][CH2:38][CH3:39]>C(Cl)(Cl)Cl.O>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH:30][CH2:31][CH:32]4[CH2:36][CH2:35][CH2:34][N:33]4[CH2:37][CH2:38][CH3:39])(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCCN1CCCC1CN
Reactant: O=S(=O)(Cl)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCN1CCCC1CNS(=O)(=O)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Temperature: 25 °C
Yield: 28 %

Procedure:
4-(7-Chloro-4-quinolinylamino)benzenesulphonyl chloride hydrochloride (5.4 g, 0.014 mol) was added portionwise to a well-stirred two phase mixture of chloroform/water (140 ml/140 ml) containing sodium carbonate (14.8 g) and 2-aminomethyl-1-propylpyrrolidine (2.0 g, 0.014 mol) at about 10° C. The mixture was allowed to warm to room temperature, then stirred for 11/2 hours. The chloroform layer was separated, dried (MgSO4) and evaporated under reduced pressure to give a gum. The gum was crystallised from ethanol/water to give a pale yellow solid (1.8 g). A further recrystallisation from ethanol gave the title compound (0.5 g), melting point 192.5°-194° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([C:17]2[C:18]3[CH:40]=[CH:39][C:38]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:37][C:19]=3[S:20][C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([N:28]([Si](C)(C)C)[Si](C)(C)C)=[CH:24][CH:23]=2)=O)[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C1COCC1.ClCCl>[CH2:42]([O:41][C:38]1[CH:39]=[CH:40][C:18]2[C:17]([CH2:15][C:5]3[CH:6]=[CH:7][C:8]([CH2:9][N:10]4[CH2:14][CH2:13][CH2:12][CH2:11]4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=3)[S:20][C:19]=2[CH:37]=1)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: COc1cc(C(=O)c2c(-c3ccc(N([Si](C)(C)C)[Si](C)(C)C)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Agent: CC[SiH](CC)CC
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(Cc2c(-c3ccc(N)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
6-Benzyloxy-2-[4-[bis(trimethylsilyl)amino]phenyl]-benzo[b]thiophen-3-yl 3-methoxy-4-[(1-pyrrolidinyl)methyl]-phenyl ketone (0.73 g) was dissolved in THF (10 mL), cooled to 0° C. in an ice bath before treated with lithium aluminum hydride (110 mg) at 0° C. for 1 h, then quenched with water (1 mL) and sodium hydroxide (1.0 M, 1 mL). Stirring continued for 30 min. The reaction mixture was diluted with brine(30 mL) and extracted with dichloromethane (20 mL×3). The combined organic layers were dried with sodium sulfate and concentrated in vacuo to give the crude alcohol. This material was dissolved in dichloromethane (15 mL), treated with triethylsilane (1.5 mL) and trifluroacetic acid (1.5 mL) sequentially, allowed to stir at ambient temperature for 1.5 h, and concentrated under reduced pressure. The residue was extracted with dichloromethane (20 mL×3) from saturated aqueous sodium bicarbonate (30 mL). The combined organic layers were dried with sodium sulfate and concentrated. Chromatography with Et3N:MeOH:EtOAc (5:5:90) afforded the title compound as a yellow foam (0.53 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:14])=[CH:11][N:10]=2)[C:6]=1[O:7]C.[C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][C:28]=1[O:36][CH3:37])#[N:26]>>[C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:3]=[N:4][N:5]([C:9]3[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:14])=[CH:11][N:10]=3)[C:6]=2[OH:7])=[CH:29][C:28]=1[O:36][CH3:37])#[N:26]
Reactant: COc1cc(B(O)O)ccc1C#N
Reactant: COc1c(Br)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Product: COc1cc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)ccc1C#N

Procedure:
The title compound was prepared in a manner similar to Example 213 using 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (50 mg, 0.127 mmol), (4-cyano-3-methoxyphenyl)boronic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.14 (d, J=10.6 Hz, 2 H) 1.55 (d, J=11.9 Hz, 3 H) 3.11 (br. s., 2 H) 3.72-3.90 (m, 7 H) 6.47 (s, 1 H) 7.41 (d, J=15.4 Hz, 3 H) 7.77 (br. s., 1 H) 8.03-8.23 (m, 3 H) 8.41-8.60 (m, 2 H) 8.77 (br. s., 1 H). MS m/z [M+H]+ 434.4.
Reaction SMILES: [CH3:1][O:2][P:3]([CH3:7])(=[O:6])[O:4][CH3:5].[Li+].CCC[CH2-].C[O:14][C:15]([C:17]1[CH:18]=[N:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:21]=1[CH3:22])=O>C1COCC1.CCCCCC>[CH3:1][O:2][P:3]([CH2:7][C:15]([C:17]1[CH:18]=[N:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:21]=1[CH3:22])=[O:14])(=[O:6])[O:4][CH3:5]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)c1cnn(-c2ccccc2)c1C
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COP(=O)(CC(=O)c1cnn(-c2ccccc2)c1C)OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
A solution of methyl-phosphonic acid dimethyl ester (2.1 g) in THF (20 mL) under an argon atmosphere was cooled to −78° C. and treated dropwise with 10.98 mL of a 1.6 M solution of N-butyllithium in hexane keeping the temperature of the reaction mixture below −65° C. After stirring for 15 minutes 5-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid methyl ester (1.9 g in 2 ml THF) were added slowly and the mixture was stirred for 30 minutes (temperature below −65° C.). The reaction mixture was allowed to warm to 0° C., quenched with 1N aqueous HCl, and then partitioned between ACOEt and water. The layers were separated, the organic layer was washed with water, dried over MgSO4, filtered and evaporated to give [2-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester (2.34 g) as a dark brown oil that was used in the next reaction without further purification. MS (ESI): 309.1 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][CH2:13]OC1C=CC(B(O)O)=CC=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B:24]([C:27]1[CH:32]=[CH:31][C:30](CCCC(O)=O)=[CH:29][CH:28]=1)([OH:26])[OH:25].C(Br)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]([CH2:11][CH2:12][CH2:13][C:30]1[CH:31]=[CH:32][C:27]([B:24]([OH:26])[OH:25])=[CH:28][CH:29]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCCOc1ccc(B(O)O)cc1)OCc1ccccc1
Reactant: O=C(O)CCCc1ccc(B(O)O)cc1
Agent: BrCc1ccccc1
Product: O=C(CCCc1ccc(B(O)O)cc1)OCc1ccccc1
Yield: 69 %

Procedure:
Using a procedure analogous to that used to prepare 1B, 2B (212 mg, 1:1 mixture of 2B and 2A) was reacted with benzyl bromide to afford 2C (90 mg, 69%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.92 (m, 2H), 2.33 (t, J=7.0 Hz, 2H), 2.62 (t, 2H), 5.08 (s, 2H), 7.11 (d, 2H), 7.25-7.35 (m, 5H), 7.69 (d, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].Cl[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17]>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17]
Reactant: CN(C)CCCN
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: Cc1ccc(NCCCN(C)C)c([N+](=O)[O-])c1
Temperature: 125 °C
Reaction time: 14 h
Yield: 92.4 %

Procedure:
N,N-Dimethyl-1,3-propanediamine (5.114 g) was added to 4-chloro-3-nitrotoluene (3.434 g) and the mixture was stirred for 14 hours at 125° C. The reaction mixture, with toluene added thereto, was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (4.93 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=1:0-10:1), thereby yielding the entitled compound (4.39 g) as reddish orange oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C@H:10]([CH2:21][OH:22])[CH2:9]1)=O)(C)(C)C.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[CH2:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[CH2:21][OH:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCN1CCN(C(=O)OC(C)(C)C)C[C@H]1CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCN1CCNC[C@H]1CO
Temperature: 25 °C

Procedure:
A solution of Example 1 (e) (0.53 g) in dichloromethane (20m1) and trifluoroacetic acid was stirred at 0° C. for 30 minutes and allowed to warm to room temperature over 2 hours. It was evaporated to dryness and azeotroped with toluene to afford [2S]-1-heptyl-2-hydroxymethylpiperazine trifluoroacetate salt as a foam. The salt was dissolved in acetonitrile (3 ml), and treated with diusopropylethylamine (0.544 g) until pH 6. Example 1(f) (0.509 g) and lithium perchlorate (0.179 g) were added and the mixture was stirred at room temperature for 48 hours. [method of J. E. Chateauneuf et al. J. Org. Chem. 56, 5939-5942]. The reaction rriixture was evaporated and basified with sodium carbonate solution and extracted (x3) with dichloromethane. The organic fraction was dried and chromatographed on silica gel eluting with 50-100% ethyl acetate-hexane to afford the title compound as an oil (0.248 g).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(O)(=O)C.O>[C:11]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10])(=[O:13])[CH3:12]
Reactant: O=C1Cc2ccccc2N1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)N1C(=O)Cc2ccccc21
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A solution of oxindole (5.0 g, 37.5 mmol) in acetic anhydride (7.1 mL, 75.1 mmol) and acetic acid (25 mL) was refluxed for 20 h. After cooling to room temperature, the reaction mixture was diluted with water (200 mL). The resulting solids were filtered, washed with water and dried to give N-acetyl oxindole as a white solid (5.2 g, 79%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:37])([F:36])[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33](O)=[O:34])=[CH:24][CH:23]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:25]3[CH:24]=[CH:23][C:22]([O:21][C:20]([F:36])([F:19])[F:37])=[CH:27][CH:26]=3)=[O:34])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccc(OC(F)(F)F)cc1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3ncoc3-c3ccc(OC(F)(F)F)cc3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(4-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 01b: tR=1.04 min; [M+H]+=461.10.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][N:32]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH3:8][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]([C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][N:32]=2)[CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=2)=[CH:12][CH:11]=1)([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc([N+](=O)[O-])cn2)cc1
Yield: 78.3 %

Procedure:
A mixture of ethyl 2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate (250 mg; 0.61 mmol), 2-chloro-5-nitro-pyridine (116 mg; 0.73 mmol) and K2CO3 (126 mg; 0.92 mmol) in 2 ml of dioxane was heated at 220C in a pressure tube under nitrogen for 16 hr. Upon cooling, the mixture was partitioned between ethyl acetate and water. The aqueous phase was washed with ethyl acetate and the combined organic phases were washed with brine, dried over sodium sulfate and concentrated. Purification by radial chromatography using ethyl acetate-hexane mixtures (2–30% gradient) afforded the title compound (254 mg; 78% yield).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].C([NH:15][CH2:16][CH2:17][SH:18])(OC(C)(C)C)=O.C([O-])([O-])=O.[K+].[K+].Cl.CCOC(C)=O>CC#N.CCOC(C)=O>[NH2:15][CH2:16][CH2:17][S:18][CH:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7]
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: O=C1OCCC1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NCCSC1CCOC1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 82.2 %

Procedure:
3-Bromo-dihydro-furan-2-one (2.49 g, 15.1 mmol) and 2-(Boc-amino)ethanethiol (2.9 g, 16.5 mmol) were dissolved in 40 mL of CH3CN. Then K2CO3(4.14 g, 30 mmol) was added to the solution. Let it stir at 80° C. for 16 h. The solvent was evaporated to dryness and the residue was purified by column chromatography (PE/EtOAc=4/1) to 3.8 g of BOC protected Intermediate 29 as colorless oil. The previous compound (3.7 g, 14.16 mmol) was dissolved in 10 ml of EtOAc. Then 40 mL of 4N HCl/EtOAc was added to the solution. Let it stir at 25° C. for 2 h. The white solid was filtered and washed with PE to give 2 g of Intermediate 29.
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH:4]=[N+:5]([CH2:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.BrCC(C1C=CC=CC=1)=O.[CH3:32][C:33]1[CH:34]=[N:35]C2C(C=1)=CC=CC=2>C(#N)C>[C:14]([C:13]1[N:5]2[C:6]3[C:11]([CH:12]=[C:3]([CH3:2])[C:4]2=[C:33]([C:34]#[N:35])[CH:32]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3)(=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc2ccccc2[n+](CC(=O)c2ccccc2)c1
Reactant: Cc1cnc2ccccc2c1
Agent: O=C(CBr)c1ccccc1
Agent: [Br-]
Solvent: CC#N
Product: Cc1cc2ccccc2n2c(C(=O)c3ccccc3)cc(C#N)c12

Procedure:
3-Methyl-1-phenacyl-quinolinium bromide: The title compound was prepared from 2-bromo-1-phenyl-ethanone (481 mg, 2.405 mmol), 3-methyl-quinoline (296 mg, 2.08 mmol) and acetonitrile (5 mL), similar to Example 1a, and yielded 640 mg (89%) as an off white solid: 1H NMR (CDCl3) 0.38 (d, J=1.8 Hz, 1H), 8.74 (s, 1H), 8.31 (m, 1H), 8.28 (m, 1H), 8.17 (dd, J=1.5, 8.4 Hz, 1H), 8.01 (m, 1H), 7.94–7.87 (m, 2H), 7.71 (m, 1H), 7.57 (t, J=7.8 Hz, 2H), 7.49 (s, 2H), 2.81 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1cccc(-c2ccccc2)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccccc5)n4)cc3)cc2)CC1
Temperature: 110 °C

Procedure:
1-[4′-(4-Amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.250 g, 0.689 mmol), 2-bromo-6-phenyl-pyridine (0.1457 g, 0.62 mmol), cesium carbonate (0.2694 g, 0.826 mmol) and (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.032 g, 0.052 mmol) were dissolved in toluene (3 mL) and the solution was degassed with bubbling N2 (g). Tris(dibenzylideneacetone)dipalladium(0) (0.0158 g, 0.017 mmol) was added and the reaction was heated to 110° C. for 24 hours. After cooling the reaction was submitted to standard aqueous workup and silica gel chromatography to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([O:8]CCC)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>O>[OH:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: CCCOC(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(O)cc1

Procedure:
891 g of n-propyl 4-hydroxybenzoate were neutralised in 712 ml of water with 260 ml of 50% strength sodium hydroxide solution in two stages. After the first stage of the neutralisation (247 ml of sodium hydroxide solution), the resulting clear solution was kept at 20° C. for 96 hours. When the neutralisation had been completed (13 ml of sodium hydroxide solution), spray-drying resulted in a product with a 4-hydroxybenzoic acid content of 0.1 percent by weight and a water content of 0.3% by weight.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH:15]=[N:16][N:17]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]4)[CH:18]=3)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[O:32]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>CCOC(C)=O.O>[O:32]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[C:4]([C:8]3[N:9]=[CH:10][C:11]([C:14]4[CH:15]=[N:16][N:17]([CH:19]5[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:21][CH2:20]5)[CH:18]=4)=[CH:12][N:13]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:33]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(-c4cccc(N)c4)nc3)cn2)CC1
Reactant: OB(O)c1ccoc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(-c4cccc(-c5ccoc5)c4)nc3)cn2)CC1
Temperature: 120 °C
Yield: 102.7 %

Procedure:
Tert-butyl 4-4-[2-(3-iodophenyl)pyrimidin-5-yl]-1H-pyrazol-1-ylpiperidine-1-carboxylate (intermediate 5; 100 mg; 0.19 mmol; 1.0 eq.), furan-3-boronic acid (25 mg; 0.23 mmol; 1.2 eq.), Pd(Ph3)4 (11 mg; 0.01 mmol; 0.05 eq.) and potassium carbonate (78 mg; 0.56 mmol; 3.0 eq.) were flushed with nitrogen before the addition of dioxane: water (1.5:0.75 mL). The reaction mixture was heated in MW at 120° C. for 30 min. It was then diluted with EtOAc and water. Aqueous phase was extracted with EtOAc (three times) and combined organic phases were dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (heptane:EtOAc, gradient from 80:20 to 50:50 afforded the title compound as a white solid (92 mg; 100%). 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 2H), 8.57-8.54 (m, 2H), 8.30-8.27 (m, 2H), 8.15 (s, 1H), 7.75 (t, J=1.7 Hz, 1H), 7.78-7.74 (m, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.03 (dd, J=1.7 Hz, 1.0 Hz, 1H), 4.47-4.40 (m, 1H), 4.09-4.05 (m, 2H), 2.94 (m, 2H), 2.09-2.05 (m, 2H), 1.88-1.74 (m, 2H), 1.43 (s, 9H). HPLC (Condition A): Rt 5.13 min (purity 92.1%). MS (ESI+): 472.3.