Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[O:25][CH2:26][CH2:27][CH2:28]Cl>CS(C)=O.O>[CH2:7]([NH:14][CH2:28][CH2:27][CH2:26][O:25][C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCCCOc1ccc2ccccc2c1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(CNCCCOc2ccc3ccccc3c2)cc1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and benzyl amine (0.36 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2-naphthyloxy)-1-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 6 hrs. and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-benzyl-[3-(naphthalen-2-yloxy)-propyl]amine, solid, m.p. 109° C., (yield 0.62 gm, 93.6%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[C:30]([Cl:31])=[CH:29][C:14]([C:15]([NH:17][C@H:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][NH2:26])[CH2:20][C@H:19]2[O:27][CH3:28])=[O:16])=[C:13]([O:32][CH3:33])[CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>ClCCl>[NH2:10][C:11]1[C:30]([Cl:31])=[CH:29][C:14]([C:15]([NH:17][C@H:18]2[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][NH:26][C:2]3[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:20][C@H:19]2[O:27][CH3:28])=[O:16])=[C:13]([O:32][CH3:33])[CH:12]=1
Reactant: N#Cc1cccnc1Cl
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCN)C[C@H]1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCNc2ncccc2C#N)C[C@H]1OC
Temperature: 70 °C
Reaction time: 20 h
Yield: 21.6 %

Procedure:
A mixture of 1.66 parts of 2-chloro-3-pyridinecarbonitrile, 4.28 parts of cis-4-amino-N-[1-(2-aminoethyl)-3-methoxy-4-piperidinyl]-5-chloro-2-methoxybenzamide, 1.3 parts of sodium carbonate and 22.5 parts of N.N-dimethylacetamide was stirred for 20 hours at 70° C. The reaction mixture was taken up in dichloromethane. The organic layer was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.19 parts (21.6%) of cis-4-amino-5-chloro-N-[1-[2-[(3-cyano-2-pyridinyl)amino]ethyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide; mp. 134.0° C. (compound 32).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]>CO.[Pd]>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:2]2
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1Cl
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1cnc2ccc(OC)cc2c1
Reaction time: 20 h

Procedure:
Ethyl 4-chloro-6-methoxyquinoline-3-carboxylate (640 mg, 2.4 mmol) was dissolved in MeOH (30 mL). TEA (0.67 mL, 4.8 mmol) and 10% Pd on carbon (0.1 g) were added. The mixture was allowed to stir under an atmosphere of hydrogen (50 psi) for 20 h and was then filtered through Celite. Removal of solvents gave ethyl 6-methoxyquinoline-3-carboxylate, which was used without further purification. LCMS: (FA) ES+ 232.0.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[CH:9]=[C:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(N2CCCC2)cc1Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
A 100 mL round-bottom flask was charged with 2-chloro-4-fluorobenzaldehyde (2.50 g, 15.8 mmol, 1.00 equiv), pyrrolidine (2.20 g, 30.9 mmol, 2.00 equiv), potassium carbonate (4.40 g, 31.8 mmol, 2.00 equiv), DMSO (50 mL). The resulting solution was stirred overnight at 100° C., diluted with H2O (50 mL), extracted with ethyl acetate (3×30 mL). The organic layers were combined and washed with brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (20/80) to provide 2.40 g (73% yield) of 2-chloro-4-(pyrrolidin-1-yl)benzaldehyde as a yellow solid. LCMS: (ESI, m/z): 210 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][C:8](=[O:10])[N:7](C(=O)CCCCCCCC)[CH2:6][C:5]1=[O:21])(=[O:3])[CH3:2].[CH3:22][CH:23]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:24][C:25](Cl)=[O:26]>>[C:1]([N:4]1[CH2:9][C:8](=[O:10])[N:7]([C:25](=[O:26])[CH2:24][CH:23]([CH3:22])[CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:6][C:5]1=[O:21])(=[O:3])[CH3:2]
Reactant: CCCCCCCCC(=O)N1CC(=O)N(C(C)=O)CC1=O
Reactant: CC(CC(=O)Cl)CC(C)(C)C
Product: CC(=O)N1CC(=O)N(C(=O)CC(C)CC(C)(C)C)CC1=O

Procedure:
##STR26## Synthesized as for 1-Acetyl-4-nonanoyl-2,5-piperazinedione in EXAMPLE I using 3,5,5-trimethylhexanoyl chloride in place of nonanoyl chloride.
Reaction SMILES: [H][H].[CH2:3]([N:10]([CH2:21][CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([N+:32]([O-])=O)[CH:30]=2)[NH:25][C:24]=1[C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[C:37]([CH3:42])[CH:36]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>[Ni]>[CH2:3]([N:10]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)[CH2:21][CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([NH2:32])[CH:30]=2)[NH:25][C:24]=1[C:35]1[CH:36]=[C:37]([CH3:42])[CH:38]=[C:39]([CH3:41])[CH:40]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc([N+](=O)[O-])cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Agent: [Ni]
Product: Cc1cc(C)cc(-c2[nH]c3ccc(N)cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
To a stirred solution of benzyl-{2-[2-(3,5-dimethylphenyl)-5-nitro-1H-indol-3-yl]ethyl}-(4-pyridin-3-yl-butyl)amine (350 mg in 30 mL absolute ethanol) was added ca. 30 mg of Raney” nickel. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 3 hours the reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo. Purification by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 96:4:1) gave the title compound (246 mg).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[CH:6]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[CH:13]=O)([CH3:8])[CH3:7]>C(Cl)Cl.CCCCCC.[Zn]>[Br:2][C:1]([Br:5])=[CH:13][C:12]1[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:10]([O:9][CH:6]([CH3:8])[CH3:7])[CH:11]=1
Reactant: COc1ccc(C=O)cc1OC(C)C
Reactant: BrC(Br)(Br)Br
Agent: [Zn]
Solvent: ClCCl
Solvent: CCCCCC
Product: COc1ccc(C=C(Br)Br)cc1OC(C)C
Temperature: 0 °C
Reaction time: 22 h
Yield: 99.8 %

Procedure:
Carbon tetrabromide (51.3 g, 154.7 mmol) was added portion-wise to a magnetically stirred mixture of zinc dust (10.1 g, 154.5 mmol) and PP3 (40.5 g, 154.4 mmol) in CH2Cl2 (350 mL) maintained at 0° C. on an ice-salt bath. The resulting suspension was allowed to warm to room temperature and then stirred for a further 22 h. After this time the reaction mixture was re-cooled to 0° C. and isovanillin isopropyl ether (15.0 g, 77.3 mmol) was added dropwise over 2 min. The resulting mixture was allowed to stir at room temperature for 1 h then diluted with hexane (200 mL) and filtered through a No. 3 porosity sintered-glass funnel. The filtrate was concentrated on to silica gel (400-200 mesh, 30 g) and the resulting solid added to the top of a flash chromatography column (20 cm long×10 cm wide) which was subjected to gradient elution with 2:1, 1:1 then 1:2 hexane/CH2Cl2. Concentration of the appropriate fractions (Rf 0.5 in 1:1 hexane/CH2Cl2) afforded the title compound (27.0 g, 99%) as white crystalline masses, m.p. 67-69° C. νmax (KBr) 3009, 2975, 2929, 1597, 1572, 1508, 1463, 1441, 1429,1373, 1301, 1276, 1260, 1233, 1144, 1110 and 999 cm1. 1H n.m.r. δ7.38 (s, 1H), 7.24 (d, J=2.1 Hz, 1H), 7.08 (dd, J=8.4 and 2.1 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 4.53 (septet, J=6.0 Hz, 1H), 3.86 (s, 3H), 1.38 (d, J=6.0 Hz, 6H). 13C n.m.r. δ150.5 (C), 146.7(C), 136.4 (CH), 127.7(C), 122.1 (CH), 115.3 (CH), 111.3 (CH), 87.0(C), 71.4 (CH), 55.8 (CH3), 22.0 (2×CH3). Mass spectrum m/z 352 (20) 350 (40) 348 (22)(M+•), 310 (50) 308 (100) 306 (50) [(M−C3H6)+•], 295 (30), 293 (61) 291 (33) [(M−C3H6−CH3+•)+]. Anal. Calcd for C12H14Br2O2 C, 41.2; H, 4.0; Br, 45.7. Found: C, 41.1; H, 3.7: Br, 45.3%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[C:13](C)(C)[CH2:12]1.[CH2:20]([N:24]=[C:25]=[O:26])[CH2:21][CH2:22][CH3:23]>>[CH2:20]([NH:24][C:25]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1)=[O:26])[CH2:21][CH2:22][CH3:23]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1(C)C
Reactant: CCCCN=C=O
Product: CCCCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 95.8 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1methyl-dimethyl-piperidin-4-yl)-1H indole and 11.1 mg (0.131 mMol) n-butyl isocyanate, 20.6 mg (96%) of the title compound were recovered.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=4[O:30][CH3:31])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:32][NH2:33]>>[CH3:32][NH:33][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=3[O:30][CH3:31])[C:15]=2[O:14]1
Reactant: COc1cccc(-c2cccc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c1OC
Reactant: CN
Product: CNCC1Cc2cccc(-c3cccc(OC)c3OC)c2O1

Procedure:
The title compound was prepared (0.137 g, 63%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(2,3-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.283 g, 0.64 mmol) and methylamine (0.199 g, 6.42 mmol). mp 163-166° C.
Reaction SMILES: [CH3:1][C:2](=[O:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[CH:8]1[C:13]([CH:14]=O)=[CH:12][C:11]2[O:16][CH2:17][O:18][C:10]=2[CH:9]=1.[OH-].[Na+]>C(O)C.O>[O:18]1[C:10]2[CH:9]=[CH:8][C:13]([CH:14]=[CH:1][C:2](=[O:7])[C:3]([CH3:6])([CH3:5])[CH3:4])=[CH:12][C:11]=2[O:16][CH2:17]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(=O)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)C(=O)C=Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.1 %

Procedure:
To a mixture of pinacolone (55 g) and piperonal (75 g) in ethanol (200 ml) was added a sodium hydroxide (5.0 g) in water (115 ml) solution. The mixture solidified after stirring at room temperature for 2 days. Filtration collected 137 g of solid which was then dissolved in ethyl acetate (500 ml), washed with water (500 ml), and dried over anhydrous magnesium sulfate. Concentration and trituration in hexane yielded 104.5 g of colorless solid product, mp 94°-96° C. Using essentially the same procedures, additional alpha, beta-unsaturated ketones were prepared as intermediates and are listed in Table 5. [see Pace, E, Atti Acad Lincei, [6], 9, 778 (1929); Chemical Abstracts, 23, 4942, 1929].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](O)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:17].CCN(C1C=CC=CC=1)CC>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:17])=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc(SC)nc1O
Solvent: CCN(CC)c1ccccc1
Product: CCOC(=O)c1cnc(SC)nc1Cl
Yield: 77136.7 %

Procedure:
A mixture of 4-hydroxy-2-(methylsulfanyl)pyrimidine-5-carboxylic acid ethyl ester (50 g, 0.234 mmol), POCl3 (110 mL, 1.17 mmol) and diethylaniline (70 mL, 0.28 mmol) was refluxed for 5 h. The solvent was removed under vacuum and the residue was dissolved in ice H2O and cautiously neutralized with aqueous NaHCO3. After extraction with EtOAc (3×400 mL), the organic extracts were combined, dried and concentrated to give 4-chloro-2-(methylsulfanyl)pyrimidine-5-carboxylic acid ethyl ester as a yellow solid (42 g, 77% yield). 1H NMR (300 MHz, CDCl3): δ 8.92 (s, 1H), 4.41 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[NH2:16])=[CH:4][CH2:3]1.Cl.Cl[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]Cl>ClC1C=CC=CC=1Cl>[CH3:1][C:2]1([CH3:17])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=2[N:16]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:4][CH2:3]1
Reactant: COc1ccc(C2=CCC(C)(C)CC2)c(N)c1
Reactant: ClCCNCCCl
Agent: Cl
Solvent: Clc1ccccc1Cl
Product: COc1ccc(C2=CCC(C)(C)CC2)c(N2CCNCC2)c1
Temperature: 25 °C
Yield: 48.2 %

Procedure:
A solution of 2-(4,4-dimethylcyclohex-1-enyl)-5-methoxyphenylamine (3.35 g, 14.5 mmol) prepared in Example (1d) and bis(2-chloroethyl)amine hydrochloride (3.1 g, 17.4 mmol) in 1,2-dichlorobenzene (10 mL) was stirred at 210° C. for 30 minutes. Nitrogen gas was blown into the reactor several times during the reaction to remove the excess hydrogen chloride gas in the reactor. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 2.1 g of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[Br:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([F:17])[CH:11]=1.N1C=CC=CC=1>ClCCl>[Br:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][S:5]([CH2:4][CH2:3][CH2:2][Cl:1])(=[O:7])=[O:6])=[C:12]([F:17])[CH:11]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: O=S(=O)(Cl)CCCCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(CCCCl)Nc1ccc(Br)cc1F
Reaction time: 1 h

Procedure:
3-chloropropane-1-sulfonyl chloride (3.16 ml, 0.026M) was added to a solution of 4-bromo-2-fluoroaniline (5.00 g, 0.026M) and pyridine (2.12 ml, 0.026M) in dichloromethane (100 ml) at 0° C. The reaction mixture was stirred for 1 hr, after which time it was partitioned between dichloromethane (100 ml) and 1N hydrochloric acid (100 ml). The organics were separated and dried over magnesium sulfate, filtered and concentrated in vacuuo to afford the title compound as a yellow oil (8.3 g). 1H NMR (CDCl3): δ 2.54 (m, 2H), 2.90 (m, 2H), 3.64 (d, J=2.56 Hz, 2H), 6.91 (d, J=3.56 Hz, 1H), 7.07 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([CH3:12])[CH2:5]2.C(Cl)(Cl)Cl.[N:17]1C2C(=CC=CC=2)C=C[CH:18]=1>>[C:18]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([CH3:12])[CH2:5]2)#[N:17]
Reactant: CC1Cc2cc(Br)ccc2C1=O
Reactant: c1ccc2ncccc2c1
Solvent: ClC(Cl)Cl
Product: CC1Cc2cc(C#N)ccc2C1=O

Procedure:
5-Bromo-2-methyl-1-indanone (2.0 g) and cuprous cyanide (4.0 g) in quinoline (50 ml ) were stirred at 200° for 2 hours. The mixture was cooled, treated with chloroform (100 ml ) and filtered to remove copper salts. The filtrate was then washed with 6N hydrochloric acid (3×100 ml ) and evaporated to give the crude product as a brown gum. Crystallisation from ethanol-water gave 5-cyano-2-methyl-1-indanone (1.46 g, m.p. 90°-1°).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][N:19]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH:33]=[N:32][N:31]=[CH:30]4)=[CH:25][CH:24]=3)C(=O)C)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[OH-].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:9][CH2:10][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][NH:19][C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH:30]=[N:31][N:32]=[CH:33]4)=[CH:27][CH:28]=3)[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CC(=O)N(CC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1)c1ccc(-n2cnnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Clc1cnc(N2CCC([C@H]3C[C@H]3CCNc3ccc(-n4cnnc4)cc3)CC2)nc1
Temperature: 80 °C

Procedure:
N-(2-{(1S,2S)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl)-N-[4-(4H-1,2,4-triazol-4-yl)phenyl]acetamide from step 1 of this example was dissolved in ethanol (0.5 mL), added sodium hydroxide (60% w/w, 0.3 mL) and heated to 80° C. for 5.5 hours. The reaction was cooled to room temperature, water (10 mL) was added and extracted with ethyl acetate (20 mL). The organic phase was dried by magnesium sulfate, filtered, concentrated and purified by column chromatography through a 25 gram Biotage SNAP KP-Sil™ silica gel cartridge eluting with 50% acetone/hexanes to give the title compound as a white-solid.
Reaction SMILES: [C:1]12([C:8]3[C:13](Cl)=[N:12][N:11]4[C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:16][N:17]=[C:10]4[CH:9]=3)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][OH:31].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O>CN(C)C=O>[C:1]12([C:8]3[C:13]([O:31][CH2:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)=[N:12][N:11]4[C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:16][N:17]=[C:10]4[CH:9]=3)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2
Reactant: Clc1nn2c(-c3ccccc3)nnc2cc1C12CCC(CC1)C2
Reactant: OCc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2nnc3cc(C45CCC(CC4)C5)c(OCc4ccccn4)nn23)cc1
Reaction time: 3 h

Procedure:
To a solution of 7-(bicyclo[2.2.1]hept-1-yl)-6-chloro-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (0.08 g, 0.25 mM, Example 1, step b) and 2-pyridylcarbinol (0.06 ml, 0.5 mM) in N,N-dimethylformamide (2 ml) under nitrogen was added lithium bis(trimethylsilyl)amide as a 1 mol solution in hexanes (0.375 ml). The reaction was stirred for 3 hours. Water was added until the solution became cloudy and after stirring for a further 15 minutes a solid was collected by filtration. This solid was recrystallised from ethyl acetate-hexane to give the required product (0.050 g, m.p.=166-168° C.). 1H NMR (360 MHz, DMSO) δ1.55 (2H, m), 1.91 (4H, m), 1.97 (2H, m), 2.13 (2H, m), 2.49 (1H, m), 5.77 (2H, s), 7.54 (1H, m), 7.69 (4H, s), 8.00 (1H, t, J=7.6 Hz), 8.28 (1H, s), 8.34 (2H, dd, J=7.6 and 1.5 Hz), 8.80 (1H, m); MS (ES+) m/e 398 [MH]+. Anal. Found C, 72.16; H, 5.59; N, 17.41. C24H23N5O. 0.1H2O requires C, 72.20; H, 5.86; N, 17.54%.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:37][CH2:38][O:39][CH3:40]>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[N:13]([CH2:37][CH2:38][O:39][CH3:40])[C:12]2=[O:24])[CH2:25][CH2:26]1)=[O:7]
Reactant: COCCCl
Reactant: Cc1ccccc1N1C(C)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: COCCN1C(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N(c2ccccc2C)C1C

Procedure:
The title compound, MS: m/e=542.2 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and 2-chloroethyl-methyl ether.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[Li]CCCC.[C:14]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20])#[N:15]>C1COCC1>[Br:8][C:4]1[N:3]=[C:2]([CH:19]([OH:20])[C:18]2[CH:17]=[C:16]([CH:23]=[CH:22][CH:21]=2)[C:14]#[N:15])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: N#Cc1cccc(C=O)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1cccc(C(O)c2cccc(Br)n2)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 2,6-dibromopyridine (6 g, 25.33 mmol) in anhydrous THF (150 mL) under N2 @−78° C. was added n-BuLi (10.13 mL, 2.5M) dropwise. The mixture was stirred @ −78° C. for 15 min and 3-cyanobenzaldehyde (3.32 g, 25.33 mmol) in anhydrous THF (10 mL, rinsed with 5 mL) was added. The mixture was stirred for 20 min @ −78° C. then warmed to 0° C. and stirred for 1 hr. The mixture was quenched with saturated aqueous NH4Cl, and the resulting mixture was extracted 3× with EtOAc. The combined organics were dried (anhd. Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (15-30% EtOAc in Hexanes) to give 3-[(6-bromopyridin-2-yl)(hydroxy)methyl]benzonitrile. LRMS m/z (M+H) Calcd.: 289.0, found 289.1.
Reaction SMILES: [OH:1][C:2]1([CH2:9][N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([CH:20]=O)=[C:18]([CH3:19])[C:12]=3[C:11]2=[O:22])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Br:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2>>[Br:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[C:27]2=[CH:20][C:17]1[NH:16][C:13]2[CH2:14][CH2:15][N:10]([CH2:9][C:2]3([OH:1])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]3)[C:11](=[O:22])[C:12]=2[C:18]=1[CH3:19]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CC1(O)CCN(C)CC1)CC2
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: Cc1c(C=C2C(=O)Nc3ccc(Br)cc32)[nH]c2c1C(=O)N(CC1(O)CCN(C)CC1)CC2
Yield: 48.05 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(4-hydroxy-1-methyl-piperidin-4-ylmethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-bromo-1,3-dihydro-indol-2-one as starting materials to give 2-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(4-hydroxy-1-methyl-piperidin-4-ylmethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (39 mg, 48.05%) as a yellow solid.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([NH:5][C:6](=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][N:15]=1)SC)#[N:4]>C(O)C>[C:3]([NH:5][C:6]([NH:2][CH3:1])=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][N:15]=1)#[N:4]
Reactant: COc1ccnc(CSCCN=C(NC#N)SC)c1
Reactant: CN
Solvent: CCO
Product: CNC(=NCCSCc1cc(OC)ccn1)NC#N
Reaction time: 8 h

Procedure:
Methylamine in ethanol (33%, 20 cc) was added to a stirred solution of N-cyano-N'-[2-((4-methoxy-2-pyridyl)methylthio)ethyl]-S-methylisothiourea (3.56 g) in ethanol (25 cc) at 35°, and the mixture was left to stand overnight. Nitrogen was bubbled through the solution and the crystals were filtered off to give the title product, (2.75 g) m.p. 121°-122°.
Reaction SMILES: [C:1]([CH2:3][C:4](OCC)=O)#N.[C:9]([CH2:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])#[N:10]>>[C:9]([C:11](=[CH:4][CH:3]=[CH2:1])[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])#[N:10]
Reactant: C=CCOC(=O)CC#N
Reactant: CCOC(=O)CC#N
Product: C=CC=C(C#N)C(=O)OCC=C

Procedure:
Allyl 2-cyanopenta-2,4-dienoate was prepared by the method described in Example 1 by replacing ethyl cyanoacetate by an equivalent quantity of allyl cyanoacetate. The yield of product from this reaction was 80%. The structure of the product was confirmed by an infra-red spectrum.