Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:12]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:12][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]=1[NH2:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1cccc2ccccc12
Solvent: O
Solvent: CN(C)C=O
Product: Nc1c(Br)ccc2ccccc12

Procedure:
To a solution of naphthalen-1-amine (10 g, 69.8 mmol) in N,N-dimethylformamide (50 mL) at 0° C. was added N-bromosuccinimide (12.4 g, 69.8 mmol) in N,N-dimethylformamide (50 mL). The reaction mixture stirred for 1 hour before the addition of water (400 mL). The product was extracted with ethyl acetate (3×200 mL), and the combined ethyl acetate washes were extracted with brine (3×50 mL). The ethyl acetate was concentrated, and the crude material was purified by flash chromatography (0-20% ethyl acetate/hexanes) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.15-8.24 (m, 1 H) 7.73-7.82 (m, 1 H) 7.40-7.52 (m, 3 H) 7.07 (d, J=8.82 Hz, 1 H) 5.87 (s, 2 H); MS (APCI+) m/z 222.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](C(S)C(OCC)=O)=[S:10])=[CH:4][CH:3]=1.[NH:18]([C:20]([O:22][CH3:23])=[O:21])[NH2:19]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:19][NH:18][C:20]([O:22][CH3:23])=[O:21])=[S:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(S)C(=S)Cc1ccc(Cl)cc1
Reactant: COC(=O)NN
Solvent: ClCCl
Product: COC(=O)NNC(=S)Cc1ccc(Cl)cc1

Procedure:
A mixture of 130 g of 2-[2-(4-chlorophenyl)-1-thioxoethyl]thioglycolic acid, ethyl ester, 45 g of methyl hydrazinocarboxylate and 500 ml of dichloromethane was heated at reflux for 4 hours, then concentrated in vacuo. The residue was taken up in 1.2 liters of ether and extracted with three 500 ml portions of 0.5N sodium hydroxide. The alkaline extracts were combined, washed with ether and acidified with 6N hydrochloric acid to pH 4. The solution was extracted three times with a mixture of ether and dichloromethane. The organic phases were combined and concentrated. The residual oil was concentrated at 70°-75° C. for one hour at 0.1 mmHg. The residue was crystallized from acetone-methylcyclohexane and then from toluene, giving the desired product as ivory colored crystals, mp 147.5°-148° C. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90MHz: 3.80 (s, 3H, OCH3); 4.03 (s, 2H, CH2CS); 7.31 (bs, 4H, C6H4); 8.60 (bs, 1H, NH); 9.90 (bs, 1H, NH).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([OH:15])[C:7]=1[F:16])[CH3:2].[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41]O)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:27]([O:31][C:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41][O:15][C:8]2[CH:9]=[C:10]([O:12][CH2:13][CH3:14])[CH:11]=[C:6]([CH:5]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=3)[C:4]([O:3][CH2:1][CH3:2])=[O:26])[C:7]=2[F:16])[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(O)c1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(OCCC2CCN(C(=O)OC(C)(C)C)CC2)c1F

Procedure:
In analogy to example 1.5, (RS)-(4-cyano-phenylamino)-(5-ethoxy-2-fluoro-3-hydroxy-phenyl)-acetic acid ethyl ester described in example 1.4 was reacted with 4-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester, diethyl azodicarboxylate and triphenylphosphine to give (RS)-4-(2-{3-[(4-cyano-phenylamino)-ethoxycarbonyl-methyl]-5-ethoxy-2-fluoro-phenoxy}-ethyl)-piperidine-1-carboxylic acid tert-butyl ester as a colorless solid. MS: 570.2 ([M+H]+).
Reaction SMILES: CS(O[CH2:6][C@H:7]([N:29]1[C:37]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:36]2[C:31]([N:32]([CH3:47])[C:33](=[O:46])[N:34]([CH3:45])[C:35]2=[O:44])=[CH:30]1)[CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)=O.[CH3:48][NH:49][CH3:50]>CN(C=O)C.CCOC(C)=O>[CH3:48][N:49]([CH2:6][C@H:7]([N:29]1[C:37]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[C:36]2[C:31]([N:32]([CH3:47])[C:33](=[O:46])[N:34]([CH3:45])[C:35]2=[O:44])=[CH:30]1)[CH2:8][S:9][C:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:50]
Reactant: CNC
Reactant: Cn1c(=O)c2c(-c3ccccc3)n([C@@H](COS(C)(=O)=O)CSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)n1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Temperature: 120 °C

Procedure:
(S)-2-(1,3-Dimethyl-2,4-dioxo-5-phenyl-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)-3-(tritylthio)propyl methanesulfonate (step 3)(1.7 g, 2.55 mmol) was dissolved in DMF (12 mL) and dimethylamine (40% wt. aqueous solution) (1.455 mL, 11.49 mmol) was added. The mixture was heated under microwave irradiation at 120° C. for 15 h. The reaction mixture was diluted with EtOAc and washed with brine (4×). The organic phase was dried over sodium sulphate and evaporated under vacuum. The residue was redissolved in DCM and evaporated onto silica. Purification by chromatography on silica, eluting with 20-100% EtOAc in iso-hexane gave the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]2([CH2:21][C:22]([O-:24])=O)[N:18]=[C:19]=[S:20].[CH3:25][NH2:26]>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]3([CH2:21][C:22](=[O:24])[N:26]([CH3:25])[C:19](=[S:20])[NH:18]3)[CH2:6][CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:8][C:9]2=[CH:10][CH:11]=1
Reactant: CN
Reactant: O=C([O-])CC1(N=C=S)CC(c2ccccc2)Oc2ccc(Br)cc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN1C(=O)CC2(CC(c3ccccc3)Oc3ccc(Br)cc32)NC1=S
Reaction time: 1 h

Procedure:
To a solution of 2-(6-bromo-4-isothiocyanato-2-phenylchroman-4-yl)acetate (192 mg, 0.46 mmol) in DCM (5 mL) is added a solution of 2 M MeNH2 in THF (1.3 mL), and stirred for 1 h. The solvent is removed under reduced pressure and the residue is dissolved in DCM (2 mL) and hexane (2 mL) and evaporated to afford 6-bromo-1′-methyl-2-phenyl-2′-thioxo-2′,3′-dihydro-1′H-spiro[chroman-4,4′-pyrimidin]-6′(5′H)-one as a white foam (209 mg), which is used for the next step without further purification. MS ESI +ve m/z 417 (M+H)+.
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.[OH-].[NH4+]>[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O>[CH2:1]1[O:9][C@H:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(C2CO2)cc1
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: c1ccc([C@H]2CO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
A 500-mL flask, equipped with a temperature probe, a mechanical stirrer, a vacuum adapter, and a dip tube, was charged with (S,S)—Co(salen) (5.51 g, 0.0083 mol, 0.500 mol %), styrene oxide (200.0 g, 1.66 mol, 100 mol %), and water (59.8 g, 3.32 mol, 200 mol %). A slight vacuum was applied to the flask to draw air into the reaction mixture through the dip tube (subsurface), and agitation was initiated. The flask was placed in a water bath and p-nitrobenzoic acid (2.83 g, 0.0166 mol, 1.00 mol %) was added in one portion. After stirring overnight at room temperature, the reaction was deemed complete by HPLC. The reaction mixture was a brown solution with suspended orange solids. Ammonium hydroxide (4.15 g, 4.63 mL, 28% NH3, 0.0332 mol, 2.00 mol %) was added and the reaction mixture was stirred at room temperature with continued air flow for 1 h. A dark brown solution was obtained. Air flow through the reaction mixture was stopped, and the reaction mixture was washed with water (2×200 mL). The organic layer was fractionally distilled to give (S)-styrene oxide (67.86 g, 67.9% yield, 99.6% e.e.). The aqueous layer was treated with activated carbon and warmed to a gentle boil. After cooling and filtration, the aqueous layer was concentrated to give (R)-styrene glycol (95.25 g, 95.3% yield, 93.9% e.e.).
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[O:22][CH2:23][C:24]([CH3:26])=[CH2:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34].C1COCC1>O>[CH2:1]([N:8]([C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34])[C@H:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][C@H:10]1[O:22][CH2:23][C:24]([CH3:26])=[CH2:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C=C(C)CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N(Cc1ccccc1)C(=O)OCc1ccccc1
Yield: 90.5 %

Procedure:
The same operation as in Example (103a) was performed using tert-butyl cis(±)-4-(benzylamino)-3-[(2-methyl-2-propen-1-yl)oxy]piperidine-1-carboxylate obtained in Example (117c) (4.4 g, 12.2 mmol), sodium bicarbonate, benzyl chloroformate (2.81 g, 16 mmol), THF (15 mL) and water (15 mL). The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 1/2, 1/1) to obtain 5.46 g of the title compound as a colorless oily substance (99%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]#[N:9])=[CH:6][CH:7]=1.[N-:10]=[N+:11]=[N-:12].[Na+].[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[N:4][CH:3]=1
Reactant: N#Cc1ccc(Br)cn1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccc(-c2nnn[nH]2)nc1
Temperature: 120 °C

Procedure:
A mixture of 3-bromo-6-cyano-pyridine (2 g, 10.9 mmol), sodium azide (0.85 g, 13 mmol), and ammonium chloride (0.59 g, 11 mmol) in N,N-dimethylformamide (20 mL) was heated for 1 h at 120° C. The reaction mixture was diluted with ethyl acetate (˜100 mL) and the product was isolated by filtration and then washed with ethyl acetate to give the title compound, an off-white amorphous solid which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:12](O)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(Cl)(=O)C([Cl:30])=O.Cl>C1COCC1.CN(C)C=O>[CH2:1]([CH:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:12]([Cl:30])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCCCC(CCCCCCCCCC)C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(CCCCCCCCCC)C(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 100 mL round bottom flask is charged with 1.15 g (3.13 mmol) of 2-decyltetradecanoic acid (available as ISOCARB 24 from Sasol America), which is dissolved in 20 mL of THF with stirring under inert atmosphere. The solution is cooled to 0° C. and 1.1 mL (12.6 mmol) oxalyl chloride is added dropwise. Upon addition of N,N-dimethylformamide (DMF, 2-3 drops as catalyst), gaseous HCl is observed to evolve from the reaction mixture, after which the mixture is allowed to slowly warm to room temperature. Gas evolution ceases after 30 min, and the reaction is allowed to stir for an additional 30 min before removing solvent by rotary evaporation. The crude acid chloride is redissolved in 10 mL of fresh dry THF and then added dropwise and slowly to the appropriate amine solution, as described below.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]2[C:3]1=[CH:4][C:5]1[N:9]=[C:8]([SH:10])[NH:7][C:6]=1[CH:11]=2.[OH-].[Na+].Cl.Cl[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>O>[CH3:1][C:2]1([CH3:18])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]2[C:3]1=[CH:4][C:5]1[N:9]=[C:8]([S:10][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[NH:7][C:6]=1[CH:11]=2
Reactant: CC1(C)CCC(C)(C)c2cc3[nH]c(S)nc3cc21
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc3[nH]c(SCc4ccccn4)nc3cc21
Yield: 57.6 %

Procedure:
9.0 g of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-1H-naphth(2,3-d)imidazole-2-thiol were suspended in 60 ml of alcohol in a 250 ml sulfonation flask equipped with stirrer, thermometer, dropping funnel and reflux condenser. A solution of 3.24 g of sodium hydroxide in 20 ml of water was added dropwise thereto while stirring well and the mixture was stirred at room temperature for an additional 30 minutes. After adding 6.0 g of 2-chloromethyl-pyridine hydrochloride, the mixture was boiled at reflux overnight and subsequently evaporated. The residue was taken up in 1 l of ethyl acetate, washed neutral three times with 250 ml of water, dried over sodium sulfate and, after evaporation in vacuo, recystallized from acetonitrile. There were obtained 7.0 g (57.3% of theory) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-[(2-pyridylmethyl)thio]-1H-naphth(2,3-d)-imidazole of melting point 199°-200° C.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[C:21](=[O:22])[C:10]2[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[N:12][O:13][C:9]=2[CH2:8][CH2:7]1)[CH3:4].Cl.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37]CNC[CH2:33]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)C>O>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[C:10]2[C:21](=[O:22])[CH:6]([CH2:5][N:3]3[CH2:2][CH2:33][N:32]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[O:25][CH3:24])[CH2:37][CH2:4]3)[CH2:7][CH2:8][C:9]=2[O:13][N:12]=1
Reactant: CN(C)CC1CCc2onc(-c3ccccc3F)c2C1=O
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: COc1ccccc1N1CCN(CC2CCc3onc(-c4ccccc4F)c3C2=O)CC1
Temperature: 25 °C
Yield: 76.1 %

Procedure:
To a solution consisting of 6,7-dihydro-5-dimethylaminomethyl-3-(2-fluorophenyl)-1,2-benzisoxazol-4(5H)-one hydrochloride (2.40 g) in distilled water (24 ml) was added 1-(2-methoxyphenyl)piperazine hydrochloride (3.38 g) and potassium carbonate (1.02 g) at room temperature with stirring. The resulting reaction mixture was heated to reflux for 25 min. and allowed to cool to room temperature. Diethyl ether was then added and the layers separated. The aqueous phase was extracted twice with ether. The combined organics were washed with brine and dried (Na2SO4). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, ether) afforded 2.45 g of 6,7-dihydro-3-(2-fluorophenyl)-5-(4-(2-methoxyphenyl)-1-piperazinyl)methyl-1,2-benzisoxazol-4(5H)-one as a foam. The compound was flushed thru alumina with dichloromethane to give an oil. The maleate was prepared in ethanol and the resulting salt was washed with ether, m.p. 153°-155° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[NH:16][C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1.[CH2:21](Br)[C:22]#[CH:23]>>[CH3:1][C:2]1([CH3:20])[C:7]2[CH:8]=[C:9]([C:12]3[N:16]([CH2:23][C:22]#[CH:21])[C:15]([C:17]#[N:18])=[CH:14][CH:13]=3)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:19])[O:3]1
Reactant: C#CCBr
Reactant: CC1(C)OC(=O)Nc2ccc(-c3ccc(C#N)[nH]3)cc21
Product: C#CCn1c(C#N)ccc1-c1ccc2c(c1)C(C)(C)OC(=O)N2

Procedure:
5-(4,4-Dimethyl-2-oxo-1,4,dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrol-2-carbonitrile (0.74 g, 2.8 mmol) and propargylbromide (0.5 g, 4.2 mmol) were reacted, according to General Method A, to afford the title compound, m.p. 222-224° C. (0.13 g, 15%). 1H-NMR (DMSO-d6) δ 1.65 (s, 6H), 3.64 (t, J=2.3 Hz, 1H), 4.85 (d, J=2.3 Hz, 2H), 6.37 (d, J=4 Hz, 1H), 7.01 (d, J=8.2 Hz, 1H), 7.11 (d, J=4 Hz, 1H), 7.43 (m, 2H), 10.45 (s, 1H), MS (APCI (−)) m/z 304 (M−H)−
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:12][CH:13]=[CH2:14])[CH2:9][NH:10][CH3:11])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:24]([C:26]1[CH:27]=[C:28]([C:36](Cl)=[O:37])[C:29]2[CH2:30][CH2:31][CH2:32][CH2:33][C:34]=2[CH:35]=1)#[N:25]>C(Cl)Cl>[C:24]([C:26]1[CH:27]=[C:28]([C:36]([N:10]([CH2:9][C@H:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:12][CH:13]=[CH2:14])[CH3:11])=[O:37])[C:29]2[CH2:30][CH2:31][CH2:32][CH2:33][C:34]=2[CH:35]=1)#[N:25]
Reactant: C=CC[C@H](CNC)c1ccc(F)cc1
Reactant: N#Cc1cc2c(c(C(=O)Cl)c1)CCCC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC[C@H](CN(C)C(=O)c1cc(C#N)cc2c1CCCC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
[(2S)-2-(4-Fluorophenyl)pent-4-en-1-yl]methylamine (see Bioorg. Med. Chem. Lett; 2001; 265-270; 300 mg, 1.55 mmol) was dissolved in CH2Cl2 (30 m]L) and to the resultant solution were added DIPEA (440 mg, 3.40 mmol) together with 3-cyano-5,6,7,8-tetrahydronaphthalene-1-carbonyl chloride (see WO 00/34243; 341 mg, 1.55 mmol). The mixture was stirred for 2 h at room temperature, diluted with CH2Cl2 (20 mL) and then washed with water, aqueous KHSO4 solution and finally with brine. The solution was dried over Na2SO4 and then the solvent was evaporated. The residue was chromatographed on silica gel using a mixture of heptane and ethyl acetate as eluent (7:3) and there was obtained 460 mg (78%) of 3-cyano-N-[(2S)-2-(4-fluorophenyl)pent-4-en-1-yl]-N-methyl-5,6,7,8-tetrahydronaphthalene-1-carboxamide as an oil. 1H NMR (400 MHz, CDCl3): 0.8-4.2 (cm, 16H), 4.8-5.1 (m, 2H), 5.6-5.8 (m, 1H), 6.7-7.4 (cm, 6H); LCMS: m/z 377 (M+1)+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>N1C=CC=CC=1>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][C:8]3[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=3)[CH2:2][CH2:3]2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(CN2CCNCC2)cc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(CN2CCN(C(=O)c3ccc(Cl)cc3)CC2)cc1
Temperature: 0 °C

Procedure:
To a solution of 15.3 g. (50 mmole) methyl 4-(piperazin-1-ylmethyl)-benzoate and 175 ml. anhydrous pyridine, there is added dropwise, at 0°-5° C., 8.7 g. (50 mmole) 4-chlorobenzoyl chloride and the reaction mixture kept for a further hour at 0° to 5° C., then overnight at 20° C. The reaction mixture is stirred into ice water and the precipitated product is filtered off with suction, washed with water and dried to give 18.5 g. (quantitative) of the desired product; m.p. 134°-135° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:34][C:35]1[CH:63]=[CH:62][C:38]([CH2:39][N:40]2[C:45](=[O:46])[C:44]([CH2:47]OS(C)(=O)=O)=[CH:43][C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:41]2)=[CH:37][CH:36]=1.CN1CCNCC1>>[F:34][C:35]1[CH:63]=[CH:62][C:38]([CH2:39][N:40]2[C:45](=[O:46])[C:44]([CH2:47][N:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)=[CH:43][C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:41]2)=[CH:37][CH:36]=1
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Agent: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Yield: 45.8 %

Procedure:
Following the procedure of Example 1 (10), 2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiprazine were reacted to yield the title compound as a slightly-brown crystalline powder (yield: 45.8%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[N:18]1([C:23]2[CH2:27][CH2:26][CH2:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([C:4]([C:24]2[CH2:25][CH2:26][CH2:27][C:23]=2[N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: C1=C(N2CCCC2)CCC1
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(C1=C(N2CCCC2)CCC1)c1cccnc1Cl
Reaction time: 21 h

Procedure:
Dissolve 2-chloronicotinoyl chloride (0.10 mole) in CHCl3 (90ml). Add the resulting solution to a 5° C solution of triethylamine (0.10 mole) and an enamine, 1-(1-pyrrolidinyl)-1-cyclopentene (0.10 mole), dissolved in CHCl3 (90ml). Allow C-acylation to proceed for 21 hrs., while the temperature of the reaction mixture rises to 25° after the second hour. Monitor the course of the reaction by thin-layer chromatography as needed. Wash the resulting solution with water, aqueous NaHCO3 solution, and with water. After drying, carefully evaporate solvent to obtain the enaminoketone, (2-chloro-3-pyridinyl)[2-(1-pyrrolidinyl)-1-cyclopenten-1-yl]methanone, m.p. 102.5°-104.0° C., after recrystallization from ethyl acetate. This compound is referred to in Examples 1 and 3 below as Compound 1.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C1([Mg]Cl)C=CC=CC=1.[CH3:20][C:21]([CH3:25])([CH3:24])[CH:22]=[O:23]>C1COCC1>[I:8][C:5]1[CH:6]=[CH:7][C:2]([CH:22]([OH:23])[C:21]([CH3:25])([CH3:24])[CH3:20])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(I)ccc1I
Reactant: CC(C)(C)C=O
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)C(O)c1ccc(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 80.9 %

Procedure:
Under a nitrogen atmosphere a solution of 1,4-diiodo-2-nitrobenzene (3.0 g, 8.0 mmol) in anhydrous THF (20 mL) was cooled to minus 40° C., and then a solution of phenylmagnesium chloride (2 M in THF, 4.8 mL, 9.6 mmol) was added dropwise at a rate that the temperature would not exceed minus 35° C. Upon completion of the addition the mixture was stirred for ten minutes, followed by addition of trimethylacetaldehyde (1.2 mL, 11.2 mmol), and the mixture was stirred for 30 minutes at minus 40° C. The mixture was gradually warmed up to room temperature, quenched with saturated ammonium chloride (60 mL), poured into water (120 mL), and extracted with ethyl acetate twice (60 mL each). The combined organic phase was washed with water (60 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography to yield racemic (RS)-1-(4-iodo-2-nitrophenyl)-2,2-dimethyl-1-propanol (2.17 g, 81%) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 8.04 (d, 1H, J=1.6 Hz, Ph-H), 7.88 (dd, 1H, J=1.6 and 8.4 Hz, Ph-H), 7.51 (d, 1H, J=8.4 Hz, Ph-H), 5.28 (d, 1H, J=3.6 Hz, Ph-CH), 2.29 (d, 1H, J=3.6 Hz, OH), 0.85 (s, 9H, C(CH3)3). 13C NMR (100 MHz, CDCl3): δ 149.87 (C), 141.0 (CH), 136.2 (C), 132.3 (CH), 131.63 (CH), 91.85 (C), 74.33 (CH), 36.81 (C), 25.6 (CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[Cl:12][C:13]([Cl:18])([Cl:17])[C:14](Cl)=[O:15]>ClCCl.CCN(CC)CC>[Cl:12][C:13]([Cl:18])([Cl:17])[C:14]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2)=[O:15]
Reactant: Nc1cccc2cnccc12
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc2cnccc12)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 65.1 %

Procedure:
A solution of 5-aminoisoquinoline (1.0 g, 6.9 mmol) in dichloromethane (40 mL) and Et3N (1 mL) at 5° C. was treated with trichloroacetyl chloride (1.38 g, 7.6 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 14 hours, concentrated, diluted with ethyl acetate and washed with 1N HCl. The aqueous layer was treated with aqueous NaHCO3 and extracted with ethyl acetate. The organic layer the was washed with water and concentrated. The solid residue was suspended in ethyl acetate (5 mL) and filtered to obtain 1.3 g (65%) of the title compound as a tan solid. 1H NMR (300 MHz, d6-DMSO) δ 11.20 (broad s, 1H), 9.41, (s, 1H), 8.60 (d, 1H), 8.18 (m, 1H), 7.77 (m, 2H), 7.77 (d, 1H); MS (DCI/NH3) m/z 289 (M+H)+.