Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]([C:21]1([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH2:23][CH2:22]1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1([C:24]2[CH:29]=[CH:28][C:27]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]=[O:15])=[CH:4][CH:3]=3)=[CH:26][CH:25]=2)[CH2:22][CH2:23]1)=[O:20])[CH3:17]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=O)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1.Cl.Cl.N(C1C=NC=CC=1)N.C(OC)(=[O:26])C=C.C[O-].[Na+].[O-]CC.[Na+]>>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([N:4]2[CH2:5][CH2:6][C:2](=[O:26])[NH:3]2)[CH:8]=1
Reactant: C=CC(=O)OC
Reactant: Clc1ccn(-c2cccnc2)n1
Agent: CC[O-]
Agent: C[O-]
Agent: Cl
Product: O=C1CCN(c2cccnc2)N1

Procedure:
3-(3-Chloro-1H-pyrazol-1-yl)pyridine (5b) may also be prepared through a three step, no isolation reaction sequence as disclosed in Scheme 6. In step a2, 3-hydrazinopyridine dihydrochloride is reacted with methyl acrylate in the presence of a base such as sodium methoxide or sodium ethoxide to yield 1-(pyridin-3-yl)pyrazolidin-3-one, followed by chlorination of 1-(pyridine-3-yl)pyrazolidin-3-one with phosphoryl chloride in a two-step process to yield 3-chloro-dihydropryazole (5a). In step b2, 3-(3-chloro-4,5-dihydro-1H-pyrazol-1-yl)pyridine (5a) is reacted with manganese (IV) oxide to yield the product (5b). Subsequent treatment of (5b) with an acid such as hydrochloric acid may provide the salt of the product (5b). The first step may be conducted in a polar protic solvent such as methanol or ethanol, at a temperature from about 40° C. to about 80° C. The second step may be conducted in a solvent such as chlorobenzene at a temperature from about 70° C. to about 90° C. The third step may be conducted in a solvent such as chlorobenzene at a temperature from about 70° C. to about 110° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10]C(C)(C)C)=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.Cl>CCOC(C)=O>[O:1]=[C:2]1[N:6]([CH2:7][C:8]([OH:10])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)n(-c2ccccn2)c2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)Cn1c(=O)n(-c2ccccn2)c2ccccc21

Procedure:
A solution of tert-butyl (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetate from Step B (2.27 g, 6.98 mmol) in EtOAc (100 mL) at 0° C. was saturated with HCl (g). The mixture was aged at 0° C. for a total of 3 h, and was re-saturated with HCl every 30 min. The mixture was concentrated in vacuo to give the title compound. MS: m/z=270 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[CH:19]=[C:12]2[CH:13]=[N+:14]([O-])[CH:15]=[C:16]([F:17])[C:11]2=[N:10]1.P(Cl)(Cl)([Cl:22])=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[Cl:22][C:13]1[C:12]2=[CH:19][N:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[N:10]=[C:11]2[C:16]([F:17])=[CH:15][N:14]=1
Reactant: [O-][n+]1cc(F)c2nn(-c3c(F)cccc3Cl)cc2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: Fc1cccc(Cl)c1-n1cc2c(Cl)ncc(F)c2n1
Temperature: 70 °C
Yield: 40.1 %

Procedure:
2-(2-Chloro-6-fluorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine 5 oxide (7.2 g, 25.6 mmol) was suspended in DCE (130 mL) under an atmosphere of nitrogen and phosphorus oxychloride (7.2 mL, 77.0 mmol) was added. The reaction mixture was heated at 70° C. for 5 hours and then allowed to cool to room temperature. The resultant mixture was poured cautiously onto saturated aqueous sodium carbonate solution, with stirring, and the layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (20% ethyl acetate in cyclohexane) to afford the title compound as a white solid (3.08 g, 40% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.54 (d, J=2.5 Hz, 1H), 8.22 (d, J=3.4 Hz, 1H), 7.86-7.78 (m, 1H), 7.76-7.66 (m, 2H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:4]([NH:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5].[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])=[O:22])([CH3:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[CH2:12]([C@@H:3]([C:4](=[O:5])[NH:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH:2][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][NH:23][C:21](=[O:22])[O:20][C:16]([CH3:17])([CH3:18])[CH3:19])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Reactant: COC(=O)CNC(=O)[C@@H](N)CC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)CCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-methyl 2-(2-amino-4-methylpentanamido)acetate hydrochloride (4w) in THF was added 6-((tert-butoxycarbonyl)amino) hexanoic acid, HATU and DIPEA. The reaction was stirred at room temperature for 18 h. The mixture was then filtered through Celite. The filtrate was concentrated under reduced pressure and the crude residue was purified by column chromatography (silica gel, CH2Cl2/MeOH=50/1) to give (S)-methyl 13-isobutyl-2,2-dimethyl-4,11,14-trioxo-3-oxa-5,12,15-triazaheptadecan-17-oate (6w) as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH:8]([C:10](=[O:13])[NH:11][CH3:12])[C:7]2[CH:14]=[CH:15][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:17][C:6]=2[CH2:5][CH2:4]1)[CH3:2].[CH:22]1([N:28]=[C:29]=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:1]([N:3]1[CH2:9][CH:8]([C:10](=[O:13])[NH:11][CH3:12])[C:7]2[CH:14]=[CH:15][C:16]([S:18]([NH:21][C:29]([NH:28][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:30])(=[O:19])=[O:20])=[CH:17][C:6]=2[CH2:5][CH2:4]1)[CH3:2]
Reactant: O=C=NC1CCCCC1
Reactant: CCN1CCc2cc(S(N)(=O)=O)ccc2C(C(=O)NC)C1
Product: CCN1CCc2cc(S(=O)(=O)NC(=O)NC3CCCCC3)ccc2C(C(=O)NC)C1

Procedure:
By the reaction of 3-ethylmethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide with cyclohexylisocyanate in a manner analogous to that described in Example 1, there is obtained 1-[(3-ethylmethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]-3-cyclohexylurea. The starting material can be prepared by first reacting ethylmethylamine with phosgene to give ethylmethylcarbamoyl chloride and subsequently bringing the latter to reaction with 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide hydrochloride.
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:27])[NH:15][CH2:16][C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[Mg]>CO>[C:1]1([C@H:13]2[C@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:16][NH:15][C:14]2=[O:27])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O=C1NCC(c2c[nH]c3ccccc23)=C1c1cn2c3c(cccc13)CCC2
Agent: [Mg]
Solvent: CO
Product: O=C1NC[C@@H](c2c[nH]c3ccccc23)[C@@H]1c1cn2c3c(cccc13)CCC2
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 26.7 %

Procedure:
A mixture of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1,5-dihydro-pyrrol-2-one (700 mg, 2 mmol), MeOH (25 mL) and magnesium turnings (963 mg, 40 mmol) was heated at 60° C. for 4 h. The reaction mixture was then allowed to cool to room temperature and evaporated. The residue was stirred in 1M HCl (70 mL) for 15 mins and extracted twice with EtOAc. The organics were evaporated and the residue purified using column chromatography (SiO2, EtOAc/MeOH). Tituration with hot EtOAc afforded (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidin-2-one as an off-white powder (190 mg, 27%). M.p.=241-243° C.; 1H NMR (400 MHz, DMSO-d6) δ: 10.86 (d, J=1.6 Hz, 1H), 7.92 (s, 1H), 7.44 (d, J=7.6 Hz, 1H), 7.33-7.23 (m, 3H), 7.17 (s, 1H), 7.03 (m, 1H), 6.90 (m, 1H), 6.86-6.78 (m, 2H), 4.03 (m, 4H), 3.81 (m, 1H), 3.31 (m, 1H), 2.87 (t, J=6.4 Hz, 2H), 2.08 (m, 2H); LCMS: 356 [M+H].
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=O)[C:13]([CH3:16])([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH2:48]([NH:55][NH2:56])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.CCN(CC)CC>>[CH2:4]([O:3][C:1](=[O:2])[NH:11][C@H:12]([C:17]([NH:56][NH:55][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:19])[C:13]([CH3:14])([CH3:15])[CH3:16])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: NNCc1ccccc1
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN1CCOCC1
Product: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NNCc1ccccc1
Yield: 67 %

Procedure:
The general procedure for the preparation of hydrazides described above was followed using Cbz-(L)-tert-leucine (2.00 g, 4.48 mmol), EDAC (0.969 g, 5.05 mmol), HOBT (0.669 g, 4.95 mmol), NMM (0.542 mL, 4.93 mmol), benzylhydrazine×2HCl (0.962 g, 4.93 mmol) and Et3N (1.38 mL, 9.85 mmol) which gave the title compound (1.11 g, 67%) as a low melting solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:11])[CH2:9]O)=[CH:4][CH:3]=1.[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:11])[CH2:9][N:16]2[C:12](=[O:22])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:17])=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[C@H](CO)c1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](CN1C(=O)c2ccccc2C1=O)c1ccc(F)cc1
Reaction time: 72 h
Yield: 59.4 %

Procedure:
To a solution of (S)-2-(4-fluorophenyl)propan-1-ol (824 mg, 5.35 mmol, 1.0 equiv), phthalimide (0.824 g, 5.6 mmol, 1.05 equiv), and triphenyl phosphine (2.11 g, 8.03 mmol, 1.5 equiv) in dry THF (18 mL) was added dropwise diethyl azadicarboxylate (DEAD) (3.65 mL, 15% in toluene, 8.03 mmol, 1.5 equiv). The reaction mixture was stirred over 72 h and then concentrated in vacuo. Purification by silica gel chromatography (15-25% EtOAc/Hexanes) provided the title compound (0.9 g, 59%) which was characterized by 1H NMR.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26]([CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[S:26]([CH:29]1[CH2:34][CH2:33][N:32]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:31][CH2:30]1)(=[O:27])=[O:28]
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: O=S(=O)(c1ccc2ccccc2c1)C1CCNCC1
Product: O=C(C1CCN(c2ccncc2)CC1)N1CCC(S(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 33 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 4-(2-naphthylsulphonyl)piperidine to give 4-(2-naphthylsulphonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperidine in 33% yield;
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:13]2)=[O:11])[CH2:5][CH2:4]1.[Cl:34][Si](C)(C)C>CC(CC)=O>[ClH:34].[CH3:33][N:2]([CH3:1])[C:3]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:8][CH2:7][CH:6]([CH2:9][C:10]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:13]2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(CC(=O)N2CCCC(c3c[nH]c4ccccc34)C2)CC1
Solvent: CCC(C)=O
Product: Cl

Procedure:
2-(4-dimethylamino-4-phenylcyclohexyl)-1-[3-(1H-indol-3-yl)piperidine-1-yl]-ethanone (66 mg, 0.148 mmole) was dissolved in ethyl methyl ketone (4 ml) and chlorotrimethylsilane (0.03 ml, 0.23 mmole) was added. After 1 hour the hydrochloride was isolated as a colourless solid in a yield of 65% (46 mg) (Example 53). A melting point could not be determined. The hydrochloride was obtained as a diastereoisomer mixture.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].S([O-])([O-])(=O)=O.[Mg+2].[CH2:15]([O:17][C:18](=[O:34])[C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][C:20]=1[CH:32]=O)[CH3:16]>ClCCl.C(N(CC)CC)C>[CH2:15]([O:17][C:18](=[O:34])[C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][C:20]=1[CH:32]=[N:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])[CH3:16]
Reactant: CCOC(=O)CN
Reactant: CCOC(=O)c1ccc(Oc2ccccc2)cc1C=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN=Cc1cc(Oc2ccccc2)ccc1C(=O)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 101.4 %

Procedure:
To a dried flask with glycine ethyl ester hydrochloride salt (62 mg) was added anhydrous dichloromethane (2 mL), followed by triethylamine (124 μL). Then magnesium sulfate (pre-dried on high vacuum by heat gun, 100 mg) was added, followed by addition of a dichloromethane (1 mL) solution of 2-formyl-4-phenoxy-benzoic acid ethyl ester (120 mg). The flask of 2-formyl-4-phenoxy-benzoic acid ethyl ester was further rinsed with 0.5 mL of dichloromethane. The resulting mixture was stirred at room temperature under nitrogen for 15 h. The mixture was filtered and rinsed with dichloromethane. After removal of solvent, the reaction was diluted with ether (15 mL) and washed with brine twice and dried. Filtration and removal of solvent gave the title compound 160 mg as an oil with good purity. 1H NMR (200 MHz, CDCl3) δ 9.02 (d, J=1.2, 1H), 7.94 (d, J=8.6 Hz, 1H), 7.63 (d, J=2.4, 1H), 7.40-7.32 (m, 2H), 7.20-7.11 (m, 1H), 7.06-6.97 (m, 3H), 4.41 (s, 2H), 4.35 (q, J=7.0 Hz, 2H), 4.21 (q, J=7.4 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H), 1.28 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C([N+]([O-])=O)=NC=CC=1.[F:28][C:29]1[CH:30]=[C:31]([C:36](=[O:38])[CH3:37])[CH:32]=[CH:33][C:34]=1F>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[CH:11][C:10]=1[O:17][C:34]1[CH:33]=[CH:32][C:31]([C:36](=[O:38])[CH3:37])=[CH:30][C:29]=1[F:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(F)c(F)c1
Reactant: CCc1ccc(O)c(OCc2ccccc2)c1
Agent: O=[N+]([O-])c1ncccc1F
Product: CCc1ccc(Oc2ccc(C(C)=O)cc2F)c(OCc2ccccc2)c1
Yield: 96 %

Procedure:
According to the procedure of example 21(a3) except substituting 4-Ethyl-2-methoxy phenol by 2-(benzyloxy)-4-ethylphenol (1.3 g, 5.7 mmol) and 3-Fluoro-2-nitropyridine by 1-(3,4-difluorophenyl)ethanone (0.98 g, 6.27 mmol), the title compound was prepared as a clear oil in 96% yield (2 g) and used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].[H-].[Na+].CS(C)=O.Cl[CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[C:23]([O-])=[O:24]>O>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([C:23](=[O:24])[C:22]([CH3:27])([CH3:26])[CH2:21][CH3:20])[C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12]
Reactant: CC(C)(CCCl)C(=O)[O-]
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCC(C)(C)C(=O)n1cnc2c1c(=O)[nH]c(=O)n2C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
This example illustrates a synthesis of 3-Methyl-7-methylpivaloyl-1-(8,9-oxidononyl)xanthine (inventive compound no. 1409). A mixture of 3-methylxanthine (Aldrich, 1.00 g, 6.0 mmol), sodium hydride (145 mg, 6.0 mmol) and dimethyl sulfoxide (20 mL) was stirred until homogeneous (0.5 hours). Chloromethylpivalate (865mL, 904 mg, 6.0 mmol) was added and the reaction stirred for 18 hours. The reaction mixture was poured into water (70 mL) and then extracted with 25% ethanol/dichloromethane (4×60 mL). The combined organic extracts were dried over sodium sulfate and evaporated under vacuum to a volume of 40 mL. This solution was cooled in icewater, whereupon a thick white precipitate was formed. The solid was filtered off under suction and dried under vacuum to yield 1.43 g (90% yield) 3-methyl-7-(methylpivaloyl)xanthine (inventive compound no. 1404).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].OC1C=CC=C2C=1N=CC=C2.[F:18][C:19]1[CH:20]=[C:21]([C:26]2[CH:27]=[CH:28][C:29](=[O:40])[N:30]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35](I)[CH:34]=3)[N:31]=2)[CH:22]=[C:23]([F:25])[CH:24]=1.[CH3:41][C:42]1[CH:43]=[CH:44][C:45](=[O:48])[NH:46][N:47]=1.N>CN(C=O)C.[Cu]I.C(OCC)(=O)C>[F:18][C:19]1[CH:20]=[C:21]([C:26]2[CH:27]=[CH:28][C:29](=[O:40])[N:30]([CH2:32][C:33]3[CH:34]=[C:35]([N:46]4[C:45](=[O:48])[CH:44]=[CH:43][C:42]([CH3:41])=[N:47]4)[CH:36]=[CH:37][CH:38]=3)[N:31]=2)[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: Cc1ccc(=O)[nH]n1
Reactant: O=c1ccc(-c2cc(F)cc(F)c2)nn1Cc1cccc(I)c1
Agent: [Cu]I
Agent: N
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(=O)n(-c2cccc(Cn3nc(-c4cc(F)cc(F)c4)ccc3=O)c2)n1
Temperature: 120 °C

Procedure:
3.2 14.3 mg (0.08 mmol) of copper(I) iodide, 76 mg (0.55 mmol) of potassium carbonate and 11 mg (0.08 mmol) of 8-hydroxyquinoline are added to a solution of 212 mg (0.50 mmol) of 6-(3,5-difluorophenyl)-2-(3-iodobenzyl)-2H-pyridazin-3-one and 55.1 mg (0.5 mmol) of 6-methylpyridazin-3(2H)-one in 2 ml of DMF, and the mixture is heated at 120° C. for 24 hours. The reaction mixture is allowed to cool, and 10% aqueous ammonia solution and ethyl acetate are added. The resultant precipitate is filtered off with suction, washed with water and dried. The residue is boiled in ethyl acetate, filtered off with suction and washed with ethyl acetate. The residue is dried in vacuo: 1-{3-[3-(3,5-difluorophenyl)-6-oxo-6H-pyridazin-1-ylmethyl]phenyl}-3-methyl-6H-pyridazin-6-one (“A8”) as brownish crystals; ESI 407.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]=2[N:4]=[C:3]1[NH:15][NH:16][C:17](OCC)=[O:18]>CN(C=O)C>[CH3:1][C:2]1([CH3:22])[O:7][C:6]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]=2[N:4]2[C:17](=[O:18])[NH:16][N:15]=[C:3]12
Reactant: CCOC(=O)NNC1=Nc2cc([N+](=O)[O-])ccc2OC1(C)C
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc([N+](=O)[O-])cc2-n2c1n[nH]c2=O

Procedure:
Ethyl 2-(2,2-dimethyl-6-nitro-2H-benzo[b][1,4]oxazin-3-yl)hydrazine-1-carboxylate (300 mg) was dissolved in DMF (3 ml). The reaction mixture was microwaved at 200° C. for 10 min. The reaction solution was evaporated to give 4,4-dimethyl-8-nitro-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]oxazin-1-one.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:4]([CH2:5][C:6](=[O:8])[CH3:7])[CH:3]1[CH2:9][CH:10]=O.C[Si]([N:17]([CH3:19])[CH3:18])(C)C>>[CH3:18][N:17]([CH3:19])[CH:10]=[CH:9][CH:3]1[CH:4]([CH2:5][C:6](=[O:8])[CH3:7])[C:2]1([CH3:12])[CH3:1]
Reactant: CC(=O)CC1C(CC=O)C1(C)C
Reactant: CN(C)[Si](C)(C)C
Product: CC(=O)CC1C(C=CN(C)C)C1(C)C
Yield: 86.1 %

Procedure:
To 6.7 g of 2,2-dimethyl-3-(2-oxopropyl)cyclopropylacetaldehyde at 0° C. was added 5.2 g of trimethylsilyldimethylamine over a 5 min period. The resulting product was distilled through a spiral bantamware column to yield 6.7 g of the desired product having a boiling point of 85°-90° at 1 mm Hg.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[CH2:21]([C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1)[CH2:22][CH3:23]>>[CH3:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]2[N:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=[C:2]([S:30][C:27]3[CH:28]=[CH:29][C:24]([CH2:21][CH2:22][CH3:23])=[CH:25][CH:26]=3)[CH:7]=2)[CH2:9][CH2:10]1
Reactant: CCCc1ccc(S)cc1
Reactant: CN1CCN(c2cc(Cl)nc(-c3ccccc3)n2)CC1
Product: CCCc1ccc(Sc2cc(N3CCN(C)CC3)nc(-c3ccccc3)n2)cc1

Procedure:
Similarly, 4-chloro-6-(4-methyl-1-piperazinyl)-2-phenylpyrimidine is reacted with p-propylthiophenol to afford 6-(4-methyl-1-piperazinyl)-2-phenyl-4-(4-propylphenylthio)pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[CH:11](O)=O>>[NH:10]1[C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=[CH:11]1
Reactant: O=CO
Reactant: N#Cc1ccc(N)c(N)c1
Product: N#Cc1ccc2[nH]cnc2c1
Yield: 98 %

Procedure:
A solution of 3,4-diaminobenzonitrile (1 g; 7.51 mmol) in formic acid (40 mL) was heated at reflux for 3 hours then concentrated in vacuo to give a brown oily residue. It was extracted with EtOAc from a saturated aqueous solution of NaHCO3, dried over MgSO4 and evaporated under vacuum to give the title compound as a light pink solid (1.05 g, 98%). 1H NMR (DMSO-d6): δ 12.97 (br s, 1H), 8.48 (s, 1H), 8.16 (d, J=0.8 Hz, 1H), 7.76 (d, J=8.3 Hz, 1H), 7.59 (dd, J=8.3, 1.5 Hz, 1H). LC/MS (Method B): 144.1 (M+H)+.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5]>C(O)C>[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].[CH2:4]([OH:5])[CH3:3]
Reactant: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: O=C([O-])/C=C/C(=O)[O-]

Procedure:
Fumarate is prepared from 6.3 g (0.0158 mol) of base in 100 ml of ethanol and 1.83 g (0.0158 mol) of fumaric acid in 180 ml of ethanol. The clear solution obtained is concentrated almost completely, ethyl acetate is added and the mixture is triturated. A white solid is obtained, which product is recrystallised in ethanol (68.3% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][CH:12]=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[C:14]2[NH:20][C:21]1[C:26]([Cl:27])=[CH:25][N:24]=[CH:23][C:22]=1[Cl:28].[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:27][C:26]1[CH:25]=[N:24][CH:23]=[C:22]([Cl:28])[C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:10]([O:29][CH3:30])=[CH:11][CH:12]=2)[NH:17][C:16](=[O:19])[CH:15]=1
Reactant: C1CNCCN1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCN1CCNCC1

Procedure:
The title compound was prepared from 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (Intermediate 4) and piperazine following the procedure outlined in Example 15 (modifications: 40° C., 8 h, purified by reverse-phase HPLC). 1H NMR (400 MHz, DMSO-d6, bis HCl salt): δ 11.79 (br, 1H), 10.51 (s, 1H), 9.81 (br, 1H), 9.73 (br, 1H), 9.25 (s, 1H), 8.82 (s, 2H), 8.02 (d, 1H), 7.17 (d, 1H), 4.97 (s, 1H), 4.01 (t, 2H), 3.95 (s, 3H), 3.68 (br d, 2H), 3.58-3.35 (br m, 4H), 3.26 (br, 2H), 3.13 (m, 2H), 1.84-1.70 (m, 4H), 1.50-1.32 (m, 4H); MS (ESI): 520.4.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([NH:38][NH2:39])=[CH:30][CH:29]=1>>[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([N:38]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:24])([F:25])[F:26])(=[O:21])=[O:22])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:39]2)=[CH:30][CH:29]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)ccc1=O
Reactant: NNc1ccnc2ccccc12
Product: O=c1ccn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)nc1-c1ccnn1-c1ccnc2ccccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-27) and quinolin-4-yl-hydrazine according to the method described for example 43. MS: M=498.1 (M+H)+