Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:13][CH:12]=2)[C:8]2[C:25]([CH2:29][OH:30])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+].O>CN(C=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:33][N:32]=[N:31][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[C:25]([CH2:29][OH:30])=[CH:26][CH:27]=[CH:28][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1nc2cccc(CO)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nc2cccc(CO)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 115 °C
Reaction time: 96 h

Procedure:
A mixture of 2-butyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-7-hydroxymethylbenzimidazole (0.4 g), sodium azide (0.98 g) and ammonium chloride (0.8 g) in DMF (4 ml) was stirred for 4 days at 110-120° C. To the reaction mixture was added water, which was extracted with ethyl acetate. The extract was washed with water and dried. After removal of the solvent, the residue was crystallized from ethyl acetate-methanol to give colorless needles, m.p. 152-153° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:11][CH2:10][N:9]([CH2:12][CH3:13])[CH2:8][CH2:7]1)=[O:5])C>CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:8][CH2:7][C:6]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:21][CH:22]=2)(=[O:16])=[O:15])([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]1)[CH3:13]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(CC)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CC)CC2)cc1

Procedure:
1-Ethyl-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-ethyl4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (7.94 g, 20 mmol) dissolved in methanol (300 ml) and 10 N NaOH (35 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 6.5 g (88%); white solid; mp 162° C.; MS:370 (M+H)+
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[CH3:24][S:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[CH3:24][S:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: CSc1ccccc1C(=O)O
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2ccccc2SC)n1
Temperature: 150 °C
Yield: 29.9 %

Procedure:
A solution was prepared using 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol), 2-(methylthio)benzoic acid (0.076 g, 0.463 mmol), HATU (0.176 g, 0.463 mmol), triethylamine (1.0 mL, 13.6 mmol) and anhydrous DMF (10 mL). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.042 g (30% yield) of pure product: MS (ES) m/z 456 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:12]([C:13]3[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:14]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[CH:11][N:10]([CH3:31])[C:5]2=[C:6]([O:8][CH3:9])[N:7]=1.CC1(C)C(C)(C)OB([C:40]2[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:41]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.O>[F:30][C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[O:22][C:14]1[CH:15]=[CH:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:13]=1[C:12]1[C:4]2[C:5](=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:40]3[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:41]=3)[CH:3]=2)[N:10]([CH3:31])[CH:11]=1
Reactant: COc1nc(Br)cc2c(-c3cc([N+](=O)[O-])ccc3Oc3ccc(F)cc3F)cn(C)c12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc2c(-c3cc([N+](=O)[O-])ccc3Oc3ccc(F)cc3F)cn(C)c12
Yield: 73.8 %

Procedure:
A mixture of Example 182B (238 mg, 0.485 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (150 mg, 0.485 mmol), phenylallylchloro[1,3-bis(diisopropylphenyl)-2-imidazol-2-ylidene]palladium(II) (31.4 mg, 0.048 mmol) and potassium phosphate (309 mg, 1.454 mmol) in 9 mL tetrahydrofuran and 3 mL water was heated at 60° C. for 3 hours. Water was added, extracted with ethyl acetate (3×), washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography on silica gel with a gradient of 0-50% ethyl acetate in heptanes to give the title compound (212 mg, 0.358 mmol, 73.8% yield) as a yellow solid.
Reaction SMILES: Br[CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[N:9]([CH3:16])[CH2:8]2)=[O:4].[C:18]([O-:21])(=[O:20])[CH3:19].[K+].C(O)(=O)C>O>[C:18]([O:21][CH:2]([CH3:17])[C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[N:9]([CH3:16])[CH2:8]2)=[O:4])(=[O:20])[CH3:19]
Reactant: CC(=O)[O-]
Reactant: CC(Br)C(=O)c1ccc2c(c1)CN(C)C(=O)N2
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OC(C)C(=O)c1ccc2c(c1)CN(C)C(=O)N2

Procedure:
A mixture of 6-(2-bromopropionyl)-3,4-dihydro-3-methyl-2(1H)-quinazolinone (2 g) prepared in Step 1, potassium acetate (2.64 g) and glacial acetic acid (20 ml) is refluxed for three hours. The reaction mixture is diluted with water and extracted with methylene chloride (3×50 ml) and the combined organic layers are washed with saturated aqueous sodium bicarbonate, dried, filtered and concentrated to obtain 6-(2-acetoxypropionyl)-3,4-dihydro-3-methyl-2(1H)-quinazolinone which is used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=O)=[CH:15][CH:14]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]C#N)=[CH:26][CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]4=[N:19][O:21][C:30]([C:27]5[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=5)=[C:15]4[CH:14]=3)=[CH:11][CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccc(F)cc2)cc1
Reactant: COc1ccc(CC#N)cc1
Product: COc1ccc(-c2onc3ccc(-c4ccnn4-c4ccc(F)cc4)cc23)cc1

Procedure:
The title compound, yellow solid (35 mg, 26%), MS (ISP) m/z=386.3 [(M+H)+], mp 153° C., was prepared in accordance with the general method of example 1 from 1-(4-fluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate C) (100 mg, 353 μmol) and commercially available 2-(4-methoxy-phenyl)-acetonitrile.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[C:9][Si](C)(C)C)=[CH:6][CH:5]=[CH:4][N:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[C:8]([C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1)#[CH:9]
Reactant: C[Si](C)(C)C#Cc1cccnc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cccnc1F
Reaction time: 1 h
Yield: 86.2 %

Procedure:
2-Fluoro-3-[(trimethylsilyl)ethynyl]pyridine (8.8 g, 0.046 mol) was dissolved in a mixture of tetrahydrofuran (20 mL) and water (2 mL). A 1.0 M solution of tetra-n-butylammonium fluoride (12 g, 0.046 mol) in THF (46 ml) was then added dropwise at 0° C., and the reaction mixture was stirred for 1 hour. The reaction was extracted with ethyl acetate, and the combined organic extracts were washed with brine (3×), dried over MgSO4 and concentrated. The crude was purified via column chromatography on silica gel (10% ethyl acetate: 90% hexanes) to provide 4.8 g of the desired product. 1H NMR (400 MHz, CDCl3): δ 8.20 (m, 1H), 7.88-7.92 (m, 1H), 7.17-7.21 (m, 1H), 3.40 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C@H:10]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:11][CH:12]=[CH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.O.[Pd]>[C:1]([O:5][C:6]([NH:8][NH:9][C@H:10]([C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:11][CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[C@H](NNC(=O)OC(C)(C)C)C(C)(C)C
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CCC[C@H](NNC(=O)OC(C)(C)C)C(C)(C)C
Reaction time: 4.5 h
Yield: 92.9 %

Procedure:
(S)—N′-(1-tert-Butyl-but-3-enyl)-hydrazinecarboxylic acid tert-butyl ester (2.34 g, 9.65 mmoles) was dissolved in methanol (50 mL) in a Parr bottle. 10% Pd/C (70 mg) was added as a slurry in water (1.6 mL), and the mixture was shaken on a Parr hydrogenator for 4.5 h with a starting pressure of 55 psi. The pressure decrease was monitored as a measure of the reaction progress, indicating that the reaction was likely complete after 30 minutes. The catalyst was allowed to substantially settle, and the supernatant was removed with a pipette, passed through a 0.45 micron syringe filter, and analyzed by TLC. Solvent was removed in vacuo to yield 2.19 g (92.7%) of (S)—N′-(1-tert-butyl-butyl)-hydrazinecarboxylic acid tert-butyl ester as a faintly pale yellow oil. Rf=0.48 (5:1 hexanes:ethyl acetate, 12 visualization), 1H NMR (400 MHz, CDCl3) □ 6.0 (br, 1H), 4.0 (br, 1H), 2.5 (d, 1H), 1.5 (s, 9H), 1.1 (m, 2H), 1.6 (br, 2H), 0.94 (s, 9H), 0.94 (t, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:33][CH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH2:33][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Reactant: BrCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCCCc2ccccc2)CCc2ccc(C#N)cc2)cc1

Procedure:
A solution of 200 mg (0.486 mmol) of methyl 4-[(3E)-2-[2-(4-cyanophenyl)ethyl]-4-(2-hydroxyphenyl)but-3-en-1-yl]benzoate in 5 ml of acetonitrile is mixed with 145 mg (0.73 mmol) of (3-bromopropyl)benzene and 100.76 mg (0.73 mmol) of potassium carbonate and then stirred under reflux for 12 h. After cooling, the potassium carbonate is filtered off and the filtrate is evaporated. 278 mg (0.45 mmol, 93% of theory, content 86%) of the title compound are obtained.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][CH2:11][C:6]2=[CH:5][C:4]=1[NH:12][C:13](=[O:21])OC1C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>>[CH3:1][NH:2][C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][CH2:11][C:6]2=[CH:5][C:4]=1[NH:12][C:13]([N:35]1[CH2:34][CH2:33][N:32]([C:26]2[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=2)[CH2:37][CH2:36]1)=[O:21]
Reactant: CNc1nc2c(cc1NC(=O)Oc1ccccc1)CCC2
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: CNc1nc2c(cc1NC(=O)N1CCN(c3cc(OC)cc(OC)c3)CC1)CCC2
Yield: 49 %

Procedure:
Phenyl N-(2-methylamino-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: Br[C:2]1[C:7]2[O:8][C:9]([CH3:13])([CH3:12])[O:10][CH2:11][C:6]=2[CH:5]=[C:4]([Cl:14])[CH:3]=1.[C:15]1([C:21]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:22]2[CH:26]=[C:25]([C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[N:24]=[CH:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:28]([C:27]([C:2]1[C:7]2[O:8][C:9]([CH3:13])([CH3:12])[O:10][CH2:11][C:6]=2[CH:5]=[C:4]([Cl:14])[CH:3]=1)([C:25]1[N:24]=[CH:23][N:22]([C:21]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:26]=1)[OH:32])[CH2:29][CH2:30][CH3:31]
Reactant: CC1(C)OCc2cc(Cl)cc(Br)c2O1
Reactant: CCCCC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CCCCC(O)(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cc(Cl)cc2c1OC(C)(C)OC2
Yield: 54.6 %

Procedure:
This compound is prepared like the preceding compound by reacting the organomagnesium compound of 8-bromo-6-chloro-2,2-dimethyl-4H-1,3-benzodioxin with 1-(1-triphenylmethyl-1H-imidazol-4-yl)-1-pentanone. Yield: 54.6% of theory; M.P.: 124° C. (recrystallized from petroleum ether).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][CH:17]=2)[N:3]=1.[F-:31].[K+].[F-].[Na+].C1OCCOCCOCCOCCOCCOC1>CCOCC.O>[F:31][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:18][CH:17]=2)[N:3]=1
Reactant: CCCCCCCCOc1ccc(-c2ccc(CCCCCCCC)c(Cl)n2)cc1
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCCCCCCCOc1ccc(-c2ccc(CCCCCCCC)c(F)n2)cc1
Yield: 53.2 %

Procedure:
0.20 g (0.5 mmol) of 2-chloro-3-octyl-6-(4-octyloxyphenyl)pyridine is heated together with 0.5 g of potassium fluoride, 0.5 g sodium fluoride and 0.02 g of 18-crown-6 in a sealed tube at 200° C. for 18 hours. The reaction mixture is taken up in ether/water, the organic phase is washed with water, dried over sodium sulfate, filtered, the solvent is distilled off, the residue is purified by chromatography (silica gel, 8:2 hexane/ethyl acetate) and recrystallized from acetonitrile, giving 0.11 g of 2-fluoro-3-octyl-6- (4-octyloxyphenyl ) pyridine. ##STR16##
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[CH2:14]([N:16]([CH2:19]C)[CH2:17][CH3:18])[CH3:15].N1CCCC1>O1CCCC1>[N:16]1([CH2:19][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)[CH2:17][CH2:18][CH2:15][CH2:14]1
Reactant: CCN(CC)CC
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(ncn2CN2CCCC2)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Equivalent amounts of theophylline and triethylamine were allowed to equilibrate with 2 equivalents of 37% aqueous H2C=O for a few minutes until a solution was obtained. Then, 2 equivalents of pyrrolidine was added and the mixture was diluted with tetrahydrofuran and allowed to stir at room temperature overnight. The solution was then concentrated in vacuo at <40°. The residue was triturated with ether and the suspension filtered. The residue from the suspension was dried to give the desired 7-(1-pyrrolidinyl)methyltheophylline in 72% yield; mp 105°-108°, lit mp 108° (J. Org. Chem. 24, 562 (1959); NMR, UV and TLC consistent with the desired product.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[CH:2]=[CH2:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1)=[O:19]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24](/[CH:3]=[CH:2]/[C:1]([NH2:5])=[O:4])=[CH:23][CH:22]=1)=[O:19]
Reactant: O=C(Nc1ccc(I)cc1)Nc1cc(C(F)(F)F)ccc1F
Reactant: C=CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: NC(=O)/C=C/c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Reaction time: 2.5 h
Yield: 48.3 %

Procedure:
A mixture of acrylamide (6.2 mg, 0.087 mmol), 1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-(4-iodophenyl)urea (9.2 mg, 0.022 mmol), and palladium(II) acetate (1.9 mg, 0.0087 mmol) in 0.6 mL degassed DMF:triethylamine (1:1) was reacted at 90° C. After 2.5 hours, the heating was stopped and the reaction stored at rt for 3 days in the dark. Then a catalytic amount of palladium(II) acetate was added and the heating resumed at 90° C. for 7.5 hours, then the temperature lowered to 65° C. for 16 hours. The reaction was partitioned between EtOAc and H2O/brine mixture. The EtOAc layer was washed with dilute aqueous HCl, then aqueous NaHCO3, brine, dried with anhydrous Na2SO4 and evaporated. The resulting solid was chromatographed eluting with CHCl3/MeOH and then triturated with a CHCl3 plus 40% EtOAc/hexane mixture to give the title compound as a light tan solid (3.9 mg, 49%). 1H NMR (Acetone-d6) δ: 8.76-8.83 (m, 2H), 8.40 (d, J=2.6 Hz, 1H), 7.58-7.63 (m, 2H), 7.37-7.57 (m, 5H), 6.91 (br. s, 1H), 6.63 (d, J=15.8 Hz, 1H), 6.32 (br. s, 1H)
Reaction SMILES: [CH:1]1([C:4]2[N:14]=[C:7]3[N:8]=[C:9]([CH3:13])[CH:10]=[C:11](O)[N:6]3[N:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:17])=O.C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:17][C:11]1[N:6]2[N:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[N:14]=[C:7]2[N:8]=[C:9]([CH3:13])[CH:10]=1
Reactant: Cc1cc(O)n2nc(C3CC3)nc2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(Cl)n2nc(C3CC3)nc2n1

Procedure:
A suspension of Intermediate 19 (0.15 g, 0.789 mmol) in phosphorous oxychloride (ALDRICH, 1 ml, 10.73 mmol) was heated under reflux for 1 h. The reaction mixture was added dropwise into iced water, neutralized with solid Na2CO3 and product was extracted with DCM. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. The crude mixture was purified by flash chromatography (Si, eluting with Hexane:EtOAc mixtures from 100:0 to 40:60%) to yield the title compound as a white solid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].[CH:32](=[O:34])[CH3:33]>C1COCC1>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26]([CH:32]([OH:34])[CH3:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC=O
Reactant: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C(C)O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 0.35 mL (2.5 mmol) of diisopropylamine in 10 mL of THF at 0° C. was treated with 1.6 mL of 1.0 M n-butyllithium solution in hexanes. The resulting mixture was stirred at 0° C. for 10 min, then cooled to −78° C. A solution of 540 mg (2.0 mmol) of ethyl 2-(1-tert-butoxycarbonyl-piperidin-4-yl)acetate (from Piperidine 35, Step A) in 2 mL of THF was added and the resulting solution was stirred cold for 30 min. Acetaldehyde (0.17 mL, 3.0 mmol) was added and the resulting mixture was warmed to 0° C. The reaction was quenched with 10 mL of sat'd NH4Cl and the resulting mixture was partitioned between 50 mL of ether and 25 mL of water. The organic layer was separated, dried over MgSO4 and concentrated. Flash chromatography on 20 g of silica gel using 2:1 v/v hexanes/EtOAc as the eluant afforded the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([NH:7][CH3:8])=[CH:5][CH:4]=1)#[N:2].[C:11]1([N:17]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:18]([C:20]2[CH:21]=[CH:22][C:23]3[S:27][C:26]([CH2:28]OC)=[N:25][C:24]=3[CH:31]=2)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl.C(O)C>[C:11]1([N:17]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:18]([C:20]2[CH:21]=[CH:22][C:23]3[S:27][C:26]([CH2:28][N:7]([C:6]4[CH:9]=[CH:10][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[CH3:8])=[N:25][C:24]=3[CH:31]=2)=[O:19])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CNc1ccc(C#N)cc1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2sc(COC)nc2c1)c1ccccc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2sc(CN(C)c3ccc(C#N)cc3)nc2c1)c1ccccc1
Yield: 57 %

Procedure:
Prepared analogously to Example 9e from 4-cyano-N-methylaniline and 2-methoxymethylbenzothiazole-5-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide. Yield: 57% of theory; Rf value: 0.46 (silica gel; dichloromethane/ethanol=19:1).
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH2:6][C:5]1=O)(=O)[CH3:2].[NH2:19][C:20]1[N:29]=C(C)C2C(=O)CC(C3C=CC(F)=CC=3)CC=2[N:21]=1>>[NH2:29][C:20]1[N:21]=[C:1]([CH3:2])[C:4]2[C:9](=[O:10])[CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[CH2:6][C:5]=2[N:19]=1
Reactant: Cc1nc(N)nc2c1C(=O)CC(c1ccc(F)cc1)C2
Reactant: CC(=O)C1C(=O)CC(c2ccccc2F)CC1=O
Product: Cc1nc(N)nc2c1C(=O)CC(c1ccccc1F)C2

Procedure:
The title compound was prepared from 2-acetyl-5-(2-fluoro-phenyl)-cyclohexane-1,3-dione (200 mg, 0.81 mmol), from stage 1, following the procedure describing the synthesis of 2-amino-7-(4-fluoro-phenyl)-4-methyl-7,8-dihydro-6H-quinazolin-5-one (example 3/a stage 2/3) except that the title compound was further purified by recrystallisation in methanol.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[CH3:21])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[C:15]([CH3:21])[CH:16]=1
Reactant: Cc1cc(Cl)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Cl)ccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(4-chloro-2-methyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.26 g, 0.837 mmol) in dichloromethane cooled at 0° C. was treated with trifluoroacetic acid (20%) and warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The organics were separated and dried over sodium sulfate and concentrated. The product was used without further purification ESI-MS m/z: 211 (M+1), UV retention time: 1.25 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=O.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[N:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1
Reactant: Nc1ccc(-c2ccc(O)cc2)cc1
Reactant: O=Nc1ccc([N+](=O)[O-])cc1Cl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(N=Nc2ccc(-c3ccc(O)cc3)cc2)c(Cl)c1
Temperature: 70 °C
Yield: 81.6 %

Procedure:
A suspension of 0.840 g of 2-chloro-4-nitro-1-nitrosobenzene in 20 ml of glacial acetic acid was heated to 70° C. and treated while stirring with a solution, heated to 110° C., of 0.926 g of 4-amino-4'-hydroxybiphenyl [prepared according to Chem. Berichte 27 (1894) 2627] in 43 ml of glacial acetic acid. The dark solution was stirred at 70° C. for a further 2.25 hours, then cooled to room temperature and extracted with methylene chloride. The extracts were washed with water, 10% sodium hydrogen carbonate solution and again with water, dried over sodium sulphate and concentrated in vacuo. Thus yielding 1.3 g of crude 2-chloro-4-nitro-4'-(4-hydroxyphenyl)azobenzene as brown crystals.