Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[C:4]([CH3:10])[N:3]=1.[C:11]1([CH2:17][C:18]#[CH:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:19]#[C:18][CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([CH3:10])[N:3]=1
Reactant: C#CCc1ccccc1
Reactant: Cc1nc(N)nc(N)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(N)c1C#CCc1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 39.3 %

Procedure:
A reaction vessel containing 0.8 gram (0.0032 mole) of 2,4-diamino-5-iodo-6-methylpyrimidine, 0.5 mL (0.0042 mole) of 3-phenyl-1-propyne, 0.2 gram (catalyst) of bis(triphenylphosphine)palladium(II) chloride, 0.05 gram (catalyst) of copper iodide, and 8 mL of triethylamine is evacuated and refilled with dry nitrogen gas three times. The reaction mixture is then stirred at ambient temperature for about 60 hours. After this time, the reaction mixture is diluted with 100 mL of water. The mixture is then extracted with three 75 mL portions of ethyl acetate. The combined extracts are washed with three 75 mL portions of an aqueous 5% lithium chloride solution. The organic layer is dried with sodium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel, using 5-15% methanol methylene chloride mixtures as eluants. The appropriate product-containing fractions are combined and concentrated under reduced pressure, yielding 0.3 gram of 2,4-diamino-6-methyl-5-(3-phenyl-1-propynyl)pyrimidine. The NMR spectrum is consistent with the proposed structure. Other fractions containing less pure product are combined and concentrated under reduced pressure to a residue. This residue is subjected to column chromatography on neutral alumina, using 2.5-10% methanol in methylene chloride mixtures as eluants. The product-containing fractions are combined and concentrated under reduced pressure, yielding an additional 0.2 gram of 2,4-diamino-6-methyl-5-(3-phenyl-1-propynyl)pyrimidine. The NMR spectrum is consistent with the proposed structure. The two solids are combined, yielding about 0.5 gram of 2,4-diamino-6-methyl-5-(3-phenyl-1-propynyl)pyrimidine, mp 145°-149° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][C:16]([C:18]3[NH:27][C:26](=[O:28])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[O:17])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:30]1([CH2:39][CH2:40][O:41][CH2:42][CH3:43])[C:35](=[O:36])[NH:34][C:33](=[O:37])[NH:32][C:31]1=[O:38].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:42]([O:41][CH2:40][CH2:39][C:30]1([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:15][C:16]([C:18]4[NH:27][C:26](=[O:28])[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[O:17])[CH:9]=3)=[CH:4][CH:3]=2)[C:31](=[O:38])[NH:32][C:33](=[O:37])[NH:34][C:35]1=[O:36])[CH3:43]
Reactant: O=C(NCc1cccc(-c2ccc(O)cc2)c1)c1nc2ccccc2c(=O)[nH]1
Reactant: CCOCCC1(Br)C(=O)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOCCC1(Oc2ccc(-c3cccc(CNC(=O)c4nc5ccccc5c(=O)[nH]4)c3)cc2)C(=O)NC(=O)NC1=O
Yield: 51 %

Procedure:
A suspension of N-[(4′-hydroxybiphenyl-3-yl)methyl]-4-oxo-3,4-dihydroquinazoline-2-carboxamide obtained in Reference Example 119 (0.100 g, 0.269 mmol), 5-bromo-5-[2-(ethyloxy)ethyl]pyrimidine-2,4,6(1H,3H,5H)-trione obtained according to the methods described in WO02/34726 and the like (0.075 g, 0.269 mmol) and potassium carbonate (0.186 g, 1.34 mmol) in DMF (5 mL) was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate-IPE to give the title compound as a white powder (0.078 g, 51%).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:3]=1[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][C:3]=1[CH2:4][N:5]([CH2:6][C:7]1[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[C:9]([C:17]([F:18])([F:19])[F:20])[CH:8]=1)[C:29](=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of [2-amino-5-(trifluoromethyl)benzyl][3,5-bis(trifluoromethyl)benzyl]amine (Example 3) (270 mg, 0.65 mmol) in methylene chloride at 0° C., acetic anhydride (0.061 mL, 0.65 mmol) in methylene chloride and then triethylamine were added (0.018 mL, 0.13 mmol). The solution was stirred for 0.5 hours at 0° C. This solution was washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated. The title compound was purified by column chromatography using 40% EtOAC/hexane. 1H NMR (CDCl3, 500 MHz) δ 7.80 (s, 1H), 7.56 (s, 2H), 7.30 (d, J=8.5 Hz, 1H), 7.04 (s, 1H), 6.65 (d, J=8.5 Hz, 1H), 4.67 (s, 2H), 4.65 (s, 2H), 2.22 (s, 3H).
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1.[F:23][C:24]1[CH:29]=[C:28]([O:30]C)[C:27]([F:32])=[CH:26][C:25]=1[N:33]1[CH2:38][CH2:37][CH:36]([C:39]([N:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:40])[CH2:35][CH2:34]1>>[F:23][C:24]1[CH:29]=[C:28]([OH:30])[C:27]([F:32])=[CH:26][C:25]=1[N:33]1[CH2:38][CH2:37][CH:36]([C:39]([N:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:40])[CH2:35][CH2:34]1
Reactant: COc1cc(F)c(N2CCC(C(=O)N3CCCCC3)CC2)cc1F
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1
Product: O=C(C1CCN(c2cc(F)c(O)cc2F)CC1)N1CCCCC1
Yield: 45.7 %

Procedure:
Production Example 2 was repeated except that 1-(4-methoxyphenyl)-4-phenethylpiperazine was replaced with 1-[1-(2,5-difluoro-4-methoxyphenyl)-4-piperidylcarbonyl]piperidine (406 mg). The resulting crude product was purified on TLC (developer, chloroform: methanol=12:1) to provide 1-[1-(2,5-difluoro-4-hydroxyphenyl)-4-piperidylcarbonyl]piperidine (178 mg).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([F:18])[C:10]=1[F:19])C1C=CC=CC=1>CO.C1COCC1.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([F:19])[C:11]=1[F:18]
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1F
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(O)c(F)c1F
Temperature: 32 °C
Reaction time: 13 h
Yield: 840.2 %

Procedure:
To a suspension of 1-(benzyloxy)-2,3-difluoro-4-nitrobenzene (1.93 g, 0.73 mmol) in CH3OH (45 mL) and THF (9 mL) was added Pd/C (333 mg, 6% Pd content, 53%˜55% water content). The mixture was stirred at 32° C. for 13 hours under H2 atmosphere. The mixture was filtered through a CELITE® pad, which was washed with 50 mL of EtOAc. The filtrate was concentrated in vacuo and the residue was washed with 30 mL of CH2Cl2 to give the title compound as a dark brown solid (0.89 g, 84%).
Reaction SMILES: F.[C:2]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]([N:20]2[CH2:25][CH2:24][CH:23]([O:26][Si](C(C)(C)C)(C)C)[CH2:22][CH2:21]2)=[O:19])=[N:15][CH:16]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(#N)C>[C:2]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]([N:20]2[CH2:21][CH2:22][CH:23]([OH:26])[CH2:24][CH2:25]2)=[O:19])=[N:15][CH:16]=1)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(C(=O)Oc2ccc(NC(=O)c3ccccc3)cn2)CC1
Agent: F
Solvent: CC#N
Product: O=C(Nc1ccc(OC(=O)N2CCC(O)CC2)nc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
Hydrofluoric acid (min. 40% in water, 0.50 mL) was added to a stirred solution of 4-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carboxylic acid 5-benzoylamino-pyridin-2-yl ester (364 mg, 0.77 mmol) in acetonitrile. After stirring overnight at room temperature the solvent was evaporated in vacuo. The residue was redissolved in dichloromethane. After addition of triethylamine (1 mL) the solution was filtered over a short pad of silicagel and washed with ethyl acetate:acetone 50:50. Evaporation of the solvent yielded the title compound (180 mg, 68% yield) as a white solid.
Reaction SMILES: FS([O-])(=O)=O.Cl[C:7]1[C:11]([Cl:12])=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:9][N+:8]=1[CH3:18].[C:19](#[N:23])[CH2:20][C:21]#[N:22]>C(O)(C)C>[Cl:12][C:11]1[C:7](=[C:20]([C:19]#[N:23])[C:21]#[N:22])[N:8]([CH3:18])[S:9][C:10]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: N#CCC#N
Reactant: CCOC(=O)c1s[n+](C)c(Cl)c1Cl
Agent: O=S(=O)([O-])F
Solvent: CC(C)O
Product: CCOC(=O)C1=C(Cl)C(=C(C#N)C#N)N(C)S1
Reaction time: 0.5 h
Yield: 43.8 %

Procedure:
3,4-Dichloro-5-ethoxycarbonyl-2-methylisothiazolium fluorosulfonate (7.5 g, 0.022 mole) was dissolved in 75 ml of isopropanol. Malononitrile (1.5 g, 0.023 mol) was added the mixture stirred for 30 min. The yellow solid was collected and washed with isopropanol to yield 2.6 g (44%) of product, mp 134-136. Analysis calculated for C10H8ClN3O2S2 : C 44.51; H, 3.00; Cl, 13.16; N, 15.57; S, 11.90. Found: C, 44.34; H, 2.82; Cl, 12.60; N, 14.82; S, 11.42.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:14]=1.CC(C)([O-])C.[K+].Br[CH2:25][CH2:26][N:27]1[CH:31]=[CH:30][CH:29]=[CH:28]1.[I-].[K+]>CN(C=O)C>[NH2:1][C:2]1[C:3]([C:15]([NH2:17])=[O:16])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:25][CH2:26][N:27]3[CH:31]=[CH:30][CH:29]=[CH:28]3)[C:6]=2[N:14]=1
Reactant: NC(=O)c1cc2c(nc1N)[nH]c1ccccc12
Reactant: BrCCn1cccc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc2c3ccccc3n(CCn3cccc3)c2nc1N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 70 mg, 0.310 mmol) in DMF (2 mL) was added potassium tert-butoxide (84 mg, 0.749 mmol). The reaction mixture was stirred at room temperature for 10 min, then 1-(2-bromoethyl)-1H-pyrrole (162 mg, 0.930 mmol) and potassium iodide (164 mg, 0.930 mmol) were added and the mixture was stirred at room temperature overnight. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (150 mL). The layers were separated and the organic layer washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (0-3% methanol in methylene chloride gradient) to yield material which was subsequently triturated with ether to give pure 2-amino-9-[2-(1H-pyrrol-1-yl)ethyl]-9H-pyrido[2,3-b]indole-3-carboxamide as a white powder (20, 25 mg, 25%). NH4OAc standard conditions. DAD Retention time =6.79 min. M+H=320. 1H NMR (300 MHz, DMSO-d6): Δ 8.71 (s, 1H), 7.97-7.89 (m, 1H), 7.79-7.69 (m, 1H), 7.67-7.50 (m, 2H), 7.24-7.04 (m, 4H), 6.62-6.59 (m, 2H), 5.88-5.82 (m, 2H), 4.57-4.47 (m, 2H), 4.34-4.24 (m, 2H).
Reaction SMILES: [CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([C:7]2[CH2:11][CH2:10][CH2:9][N:8]=2)[CH:2]=1>CO.[Pd]>[CH:1]1[CH:6]=[N:5][CH:4]=[C:3]([CH:7]2[NH:8][CH2:9][CH2:10][CH2:11]2)[CH:2]=1
Reactant: c1cncc(C2=NCCC2)c1
Agent: [Pd]
Solvent: CO
Product: c1cncc(C2CCCN2)c1
Yield: 84.6 %

Procedure:
Myosmine (32 g, 0.219 mol) was dissolved in 150 ml of methanol and hydrogenated at atmospheric pressure with 1.3 g of 10% palladium on carbon as catalyst. After 5 hours the mixture was filtered and the filtrate was concentrated to get a brown solid (32 g, 94.9% purity by GC). It was further purified by vacuum distillation at 0.1 mm Hg to get pure nornicotine (27.46 g, 84.7% yield, 97.5% purity by GC). 1H NMR (CDCl3): δ 1.66-2.72 (2H, m), 3.0 (2H, m), 4.13 (1H, t), 7.24 (1H, m), 7.69 (1H, dt), 8.46 (1H, dd), and 8.59 (1H, d). 13C-NMR (CDCl3): δ 148.4, 148.1, 140.16, 134.1, 123.3, 60.0, 46.8, 34.2, and 25.4. IR: 3291, 2960, 1641, 1578 Cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[O:10]2)=[CH:5][CH:4]=1.[CH2:16]=[O:17].O>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13](=[O:14])[N:12]([CH2:16][OH:17])[C:11](=[O:15])[O:10]2)=[CH:7][CH:8]=1
Reactant: C=O
Reactant: COc1ccc(-n2oc(=O)[nH]c2=O)cc1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-n2oc(=O)n(CO)c2=O)cc1
Reaction time: 2 h

Procedure:
2-(4-Methoxyphenyl)-1,2,4-oxadiazolidin-3,5-dione (0.05 mole) dissolved in methanol (100 ml) and aqueous formaldehyde (37% conc.; 0.06 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux, with stirring for a period of about 2 hours. After this time the reaction mixture is stripped of methanol and water, leaving a residue. This residue is dissolved in methylene chloride, and the resulting solution is washed with water. The washed solution is dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product 2-(4-methoxyphenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12](=[O:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[CH2:11]([C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[O:4][CH2:3][CH:2]([OH:1])[CH2:15][N:27]1[CH2:26][CH2:25][N:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH3:16])[CH2:29][CH2:28]1)[C:12](=[O:14])[CH3:13]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CC(=O)Cc1cccc(OCC2CO2)c1
Product: COc1ccccc1N1CCN(CC(O)COc2cccc(CC(C)=O)c2)CC1

Procedure:
3-(2,3-Epoxypropoxy)-phenylacetone is reacted with 2-methoxyphenylpiperazine analogously to Example 2(a). 1-[3-(Propan-2-on-yl)-phenoxy]-3-[4-(2-methoxyphenyl)-piperazin-1-yl]-propan-2-ol is obtained as a syrupy product.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]1[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=1.O>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:24][C:25]3[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=3)[C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Reactant: Cn1ccc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc(CN2C(=O)C3COCCN3c3nc(Cl)ncc32)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To a mixture of 2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (100 mg, 0.416 mmol), K2CO3 (115 mg, 0.831 mmol) in DMF (2 mL) at 0° C., was added 3-(chloromethyl)-1-methyl-1H-pyrazole (54.3 mg, 0.416 mmol). The mixture was stirred at 0° C. for 30 minutes and then at room temperature for overnight. Water was added and the mixture was extracted with EtOAc (2×). The aqueous layer was basified and then extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and evaporated in vacuo to give 2-chloro-5-((1-methyl-1H-pyrazol-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (104 mg) which was used in the next step without further purification. MS [M+H] Found 335.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:21]=1.[CH3:22]N(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].IC>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:22])[C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:21]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCCC2)CC1(F)F
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Product: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Reaction time: 3 h

Procedure:
To a mixture of 10.5 g (0.0332 mole) of 2-chloro-9-cyclohexyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-246), 25 mL of dimethylformamide and 16.2 g (0.0498 mole) of cesium carbonate was added 28.3 g (0.1992 mole) of iodomethane. The mixture was stirred for 3 hours, then 80 mL of water was added and the solid collected by suction filtration to give 10.0 g of 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[CH:5]#[N:6]>>[C:5](#[N:6])[CH2:1][CH:2]=[CH:3][CH3:4].[CH3:1][CH:2]([CH:3]=[CH2:4])[C:5]#[N:6]
Reactant: C#N
Reactant: C=CC=C
Product: C=CC(C)C#N
Product: CC=CCC#N

Procedure:
A nickel complex from a reaction mixture of a reactor of Examples 3, 4, 6, 9, 10, 12, 13, 14, 15, or 16 contacts 1,3-butadiene and hydrogen cyanide in a reaction zone. A catalyst forms to produce 3-pentenenitrile, 2-methyl-3-butenenitrile, or a combination thereof.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:10]([C:13]1[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[CH:15][C:14]=1[OH:21])(=[O:12])[CH3:11].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[C:10]([C:13]1[CH:18]=[C:17]([CH2:19][N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]2)[CH:16]=[CH:15][C:14]=1[OH:21])(=[O:12])[CH3:11]
Reactant: CC(=O)c1cc(CCl)ccc1O
Reactant: OCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cc(CN2CCN(CCO)CC2)ccc1O
Reaction time: 8 h

Procedure:
2-Piperazin-1-yl-ethanol (260 mg, 2 mmol) and 2-acetyl-4-chloromethyl phenol (368 mg, 2 mmol) were stirred in chloroform at room temperature. Sodium carbonate (106 mg, 1 mmol) was added and the reaction mixture was stirred overnight. The solid was filtered off and the organic layer washed with water followed by brine, dried over sodium sulfate, filtered and evaporated to obtain the crude product, which was crystallized from ethyl acetate-hexane to receive the title product as yellowish-white crystals (400 mg 72%), mp=72-75° C. C15H22N2O3 requires: N 10.06 found: N 9.70.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:4](=[O:18])[CH:3]=1.[CH3:19][C:20](=[N:22][NH2:23])[CH3:21].CNN>>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:9]=[C:8]([N:5]2[C:4](=[O:18])[CH:3]=[C:2]([NH:23][N:22]=[C:20]([CH3:21])[CH3:19])[CH:7]=[N:6]2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=c1cc(Cl)cnn1-c1cccc(C(F)(F)F)c1
Reactant: CC(C)=NN
Agent: CNN
Product: CC(C)=NNc1cnn(-c2cccc(C(F)(F)F)c2)c(=O)c1

Procedure:
Following essentially the same procedure as in example 2, but using an equivalent amount of 5-chloro-2-(3-trifluoromethylphenyl)-pyridazin-3(2H)-one and acetone hydrazone in place of the 4,5-dichloro-2-(3-trifluoromethylphenyl)-pyridazin-3(2H)-one and methylhydrazine used therein, there is obtained 2-(3-trifluoromethylphenyl)-5-(2-isopropylidenehydrazino)-pyridazin-3(2H)-one, (m.p. 255° to 257° C).
Reaction SMILES: [OH-:1].[K+].O[N:4]=[C:5]([O:7][CH2:8][CH3:9])[CH3:6].Cl[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.O>CN(C)C=O>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([O:1][CH2:6][C:5](=[NH:4])[O:7][CH2:8][CH3:9])=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CCOC(C)=NO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=N)COc1ccc([N+](=O)[O-])cc1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
To a suspension of 23.8 g (0.42 mol) of potassium hydroxide in 220 ml of N,N-dimethylformamide at 10° C. are added 40.0 g of ethyl N-hydroxyethaneimidoate (0.39 mol) (compound VI: R3═C2H5; R4═CH3). A solution of 55.6 g of 4-chloronitrobenzene (0.35 mol) (compound V: Hal=Cl) (55.6 g) in N,N-dimethylformamide is then added slowly, at 10° C. The mixture is stirred for 24 hours at 20° C. and 1 L of water is then added. The precipitate is filtered off and the solid is washed with water and oven-dried at 30° C. under vacuum to constant weight.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH2:8]Br)([CH3:4])([CH3:3])[CH3:2].[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[CH2:8][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CN2CCNCC2)cc(C(C)(C)C)c1

Procedure:
Synthesized according to General Procedure A: 3,5-di-tert-butylbenzyl bromide (4{22}, 5 g, 17.7 mmol, 1 equiv.), piperazine (9.1 g, 105.9 mmol, 6 equiv.), THF (38.7 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{22} (4.15 g, 82%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 7.31 (t, 1H, J=2.0 Hz), 7.15 (d, 2H, J=2.0 Hz), 3.51 (s, 2H), 2.89 (t, 4H, J=5.0 Hz), 2.42 (br s, 4H), 1.73 (br s, 1H), 1.33 (s, 18H). 13C-NMR (125 MHz, CDCl3): δ 150.3, 136.8, 123.3, 120.7, 64.1, 54.3, 46.1, 34.7, 31.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:5]2=1.[N:22]([O-:24])=[O:23].[Na+]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([N+:22]([O-:24])=[O:23])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[C:6]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:5]2=1
Reactant: O=N[O-]
Reactant: O=C(Nc1cncc2[nH]c3ccc(Cl)cc3c12)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cncc2[nH]c3c([N+](=O)[O-])cc(Cl)cc3c12)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 92 %

Procedure:
N-(6-chloro-9H-β-carbolin-4-yl)-2,2,2-trifluoro-acetamide (125 mg, 0.4 mmol, 1 equiv.) was dissolved in 2 ml TFA and NaNO2 (541 mg, 7.84 mmol, 2 equiv.) was added in one portion. The solution was stirred at room temperature for 4 hr. Volatiles were removed by rotovap, and the resulting oily orange solids were suspended in water, neutralized with a saturated aqueous sodium bicarbonate solution and filtered to give 132 mg (92%) of N-(6-chloro-8-nitro-9H-β-carbolin-4-yl)-2,2,2-trifluoro-acetamide. 1H-NMR (300 MHz, DMSO-d6): δ 12.87 (s, 1H), 12.03 (s, 1H), 9.11 (s, 1H), 8.56 (s, 1H), 8.53 (s, 1H), 8.26 (s, 1H). Formic acid standard conditions. DAD RT=2.27 min. M+H=359.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH3:21])[CH2:18][CH2:19][NH2:20])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25].[NH:36]([C:40]1[S:41][CH:42]=[C:43]([CH2:45][S:46][CH2:47][CH2:48][NH2:49])[N:44]=1)[C:37]([NH2:39])=[NH:38]>>[NH:36]([C:40]1[S:41][CH:42]=[C:43]([CH2:45][S:46][CH2:47][CH2:48][NH:49][C:24]([NH:20][CH2:19][CH2:18][N:17]([CH2:16][CH2:15][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH3:21])=[O:25])[N:44]=1)[C:37]([NH2:39])=[NH:38]
Reactant: COc1ccc(CN(CCN(C)CCN)c2ccccn2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Product: COc1ccc(CN(CCN(C)CCNC(=O)NCCSCc2csc(NC(=N)N)n2)c2ccccn2)cc1

Procedure:
Preparation is effected analogously to Example 63, using 0.53 g (1.7 mmol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,2-ethanediamine and the equimolar amounts of 1,1'-carbonyldiimidazole and 2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethaneamine as starting materials. Working up by chromatography analogously to Example 63 yields the purified title compound in the form of a viscous oil; MS (+FAB method): m/z (rel. int. [%])=572 ([M+H]+, 1), 121 (100); IR (KBr): 1644 cm-1 (C≡O). For further analysis, a portion of the compound is converted into the picric acid salt and recrystallised from ethanol; m.p.: 84° C. (ethanol).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=1[F:1]
Reactant: Cc1ccc(C(=O)O)c(F)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)cc1F
Reaction time: 8 h

Procedure:
To a solution of 2-fluoro-4-methyl-benzoic acid (1.1 g, 7.13 mmol) in methanol (20 mL) add thionyl chloride (1.02 g, 8.56 mmol). Stir the resulting mixture overnight then concentrate under vacuum to give the title compound (1.2 g) as a white solid.