Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[CH2:9][CH2:8][C:7]1=[O:18].[C:19]([C:23]1[N:28]=[C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[C:25]([C:35]([F:38])([F:37])[F:36])[N:24]=1)([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.C(OCC)(=O)C>CN(C)C=O>[C:19]([C:23]1[N:28]=[C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[C:10](=[O:17])[CH2:9][CH2:8][C:7]3=[O:18])[CH2:33][CH2:34]2)[CH:26]=[C:25]([C:35]([F:36])([F:37])[F:38])[N:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: O=C1CCC(=O)N(CCCCCl)c2ccccc21
Reactant: CC(C)(C)c1nc(N2CCNCC2)cc(C(F)(F)F)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)c1nc(N2CCN(CCCCN3C(=O)CCC(=O)c4ccccc43)CC2)cc(C(F)(F)F)n1

Procedure:
1-(4-Chlorobutyl)-3,4-dihydro-1H-1-benzazepine-2,5-dione (3.29 mmol, 1.75 g, 70%), 2-tert-butyl-4-piperazin-1-yl-6-(trifluoromethyl)pyrimidine (3.56 mmol, 1.03 g; preparation according to WO 99/02503) and triethylamine (13.17 mmol, 1.33 g) in dimethylformamide (100 ml) were stirred at 100° C. for 12 h. Afterward, ethyl acetate was added and the mixture was washed twice with water. The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The oily residue was purified by chromatography on silica gel (eluent: 95:5 v/v dichloromethane:methanol); yield 0.42 g.
Reaction SMILES: C(OO)(C)(C)C.[OH:7][CH:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[N:11]([OH:16])[C:10]([CH3:18])([CH3:17])[CH2:9]1.[CH2:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20]>[Mo](=O)(=O)=O.O>[OH:7][CH:8]1[CH2:13][C:12]([CH3:14])([CH3:15])[N:11]([O:16][CH:19]([CH3:20])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]([CH3:18])([CH3:17])[CH2:9]1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: CCc1ccccc1
Agent: O=[Mo](=O)=O
Agent: CC(C)(C)OO
Solvent: O
Product: CC(ON1C(C)(C)CC(O)CC1(C)C)c1ccccc1
Temperature: 120 °C
Yield: 53 %

Procedure:
70% Aqueous tert-butyl hydroperoxide (74.8 grams, 609 mmol) is added over 30 minutes to a mixture of 35.0 grams (203 mmol) of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 2.0 grams of molybdenum trioxide and 200 ml of ethylbenzene which is heated to 120° C. The reaction mixture is maintained at reflux throughout the addition and water is collected in a Dean-Stark trap. The red mixture is heated at reflux for three hours after the addition is complete in order to discharge the red color of the N-oxyl compound. Solids are removed by filtration and the filtrate is concentrated at reduced pressure to obtain a yellow oil. Purification of the oil by flash chromatography (silica gel; 4:1 hexane:ethylacetate) affords 30.0 grams (53% yield) of the title compound as a white solid melting at 95-97° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[O:10][N:9]=2)[S:5][C:4]=1[CH2:26]O)[CH3:2].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:53]1[CH2:56][CH:55]([C:57]([O:59][CH3:60])=[O:58])[CH2:54]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:3]1[CH:7]=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[O:10][N:9]=2)[S:5][C:4]=1[CH2:26][N:53]1[CH2:56][CH:55]([C:57]([O:59][CH3:60])=[O:58])[CH2:54]1)[CH3:2]
Reactant: COC(=O)C1CNC1
Reactant: CCc1cc(-c2noc(-c3ccc(Oc4ccccc4)cc3)n2)sc1CO
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(-c2noc(-c3ccc(Oc4ccccc4)cc3)n2)sc1CN1CC(C(=O)OC)C1

Procedure:
The crude product of the title compound was synthesized by conducting the reaction similar to that mentioned in Example 1 (1f) using {3-ethyl-5-[5-(4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methanol (0.19 g, 0.50 mmol) that was obtained in Example 22 (22f), carbon tetrabromide (0.33 g, 0.99 mmol), triphenylphosphine (0.26 g, 0.99 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.11 g, 0.75 mmol), N,N-diisopropylethylamine (0.22 mL, 1.2 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2:8 to 4:6) as the eluent to afford the title compound (0.17 g) in a yield of 72% as a pale yellow crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([CH3:13])([CH3:12])[C:10]#[CH:11]>O1CCOCC1.CCCCCC.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[C:6]2[C:7]=1[NH:8][C:9]([CH3:12])([CH3:13])[CH:10]=[CH:11]2
Reactant: C#CC(C)(C)Nc1ccc(C(C)C(=O)OCC)cc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCCCCC
Solvent: C1COCCO1
Product: CCOC(=O)C(C)c1cc(Cl)c2c(c1)C=CC(C)(C)N2
Yield: 93.8 %

Procedure:
6.5 g of Ethyl 2-[3-chloro-4-(1,1-dimethyl-2-propynylamino)phenyl]propionate (Compound 1) was dissolved in 70 ml of dioxane, and 10.0 g of zinc chloride were added thereto. The mixture was reacted at 95° C. for 15 hours under nitrogen atmosphere. After the reaction, the mixture was diluted with 100 ml of hexane, and subjected to column chromatography on silica gel. The solvent was distilled off to give 6.1 g of Ethyl 2-(8-chloro-1,2-dihydro-2,2-dimethylquinolin-6-yl)propionate (Compound 6).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)([O-:16])=[O:15].CCN(C(C)C)C(C)C.CN1CCCC1=O>O>[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([O:23][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Clc1ccncc1-c1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccncc2-c2ccccc2)cc1
Yield: 48.7 %

Procedure:
4-Chloro-3-phenylpyridine (200 mg, 1.06 mM), paranitrophenol (440 mg, 3.18 mM), Hunig's base (isoPr2EtN, diisopropylethylamine, 1 ml) and 1-methylpyrrolidone (2 ml) were stirred at 160° C. for 2 hours. Water was added, extraction was performed with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=4:1, and then 2:1) to obtain 4-(4-nitrophenoxy)-3-phenylpyridine (150 mg) as a light yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][C:15]3[CH:16]=[CH:17][C:18]([F:36])=[C:19]([NH:21][C:22](=[O:35])[C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[C:24]=4[Cl:34])[CH:20]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.N1C=CC=CC=1.[CH:43]1([C:46](Cl)=[O:47])[CH2:45][CH2:44]1>O1CCCC1.C(OCC)(=O)C>[Cl:34][C:24]1[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([NH:21][C:19]1[CH:20]=[C:15]([O:14][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:46]([CH:43]4[CH2:45][CH2:44]4)=[O:47])[S:3][C:4]=3[C:10]=2[N+:11]([O-:13])=[O:12])[CH:16]=[CH:17][C:18]=1[F:36])=[O:35]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4c3[N+](=O)[O-])ccc2F)c1Cl
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3[N+](=O)[O-])ccc2F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
To a solution of N-{5-[(2-amino-7-nitro-1,3-benzothiazol-6-yl)oxy]-2-fluorophenyl}-2-chloro-3-(1-cyano-1-methylethyl)benzamide (150 mg, 0.285 mmol) produced in Example 41(iii) in tetrahydrofuran (8 mL) were added pyridine (160 μL, 2.0 mmol) and cyclopropanecarbonyl chloride (39 μL, 0.428 mmol), and the mixture was stirred at room temperature for 1 hr. Pyridine (160 μL, 2.0 mmol) and cyclopropanecarbonyl chloride (10 μL, 0.11 mmol) were added, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was diluted with ethyl acetate (50 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=60/40→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/diethyl ether to give the title compound (54 mg, 32%) as a yellow powder.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:8]([CH3:11])([O-:10])=[O:9].CCCCC=CCCC>C(O)(C)C>[N+:8]([CH2:11][CH:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]1)([O-:10])=[O:9]
Reactant: O=C1CCCCC1
Reactant: C[N+](=O)[O-]
Agent: CCCC=CCCCC
Solvent: CC(C)O
Product: O=C1CCCC(C[N+](=O)[O-])C1
Yield: 100 %

Procedure:
21.9 g of cyclohexanone are left to stand together with 175 ml of nitromethane and 2.1 g of 5-diazabicyclo-[4.3.0.]non-5-ene (DBN) in 250 ml of isopropanol at room temperature for 2 days The working up is carried out in analogy to the procedure for Example 1 and provides 37.2 g (100% of theory) of 3-(nitromethyl)cyclohexanone which is pure enough for the next reaction.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[C:27]([O:29][CH3:30])=[O:28].N1C=CC=CC=1.C(OC)(C)(C)C>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]=1[C:27]([O:29][CH3:30])=[O:28])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1c(O)ccc2ccccc12
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trifluoromethanesulfonic anhydride (492 g, 1.74 mol, 1.1 eq) in dichloromethane (0.5 L) was added over 1.5 hours to a suspension of methyl 2-hydroxy-1-naphthoate (319 g, 1.58 mol) and pyridine (330 ml, 4.08 mol, 2.6 eq) in dichloromethane (1.7 L) maintained at an internal temperature between −70 and −50° C., under nitrogen. Once the addition was complete, the mixture was allowed to warm to ambient temperature and stirred for 16 hours, after which time all solids had dissolved. Methyl tert-butyl ether (MTBE, 2.5 L) was added, causing precipitation. The solids were removed by filtration and washed with MTBE (0.5 L). The MTBE solutions were combined and washed with 2 N HCl(aq) (0.3 L then 0.2 L), water (2×2.5 L) and brine (2 L). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was dissolved in toluene (2.5 L) and washed with 1 N NaOH (aq) (0.5 L), water (2.5 L) and brine (1 L). The toluene solution was dried (MgSO4), filtered and concentrated under reduced pressure. Initially a slightly brown oil, the product crystallised on standing. Yield 438.5 g, 83%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](SC)=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[C:11]#[N:12])=[CH:4][CH:3]=1.[CH3:19][CH:20]([NH2:25])[C:21]([CH3:24])([CH3:23])[CH3:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:25][CH:20]([CH3:19])[C:21]([CH3:24])([CH3:23])[CH3:22])=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[C:11]#[N:12])=[CH:4][CH:3]=1
Reactant: CSC(Nc1ccc(Cl)cc1)=C(C#N)S(C)(=O)=O
Reactant: CC(N)C(C)(C)C
Product: CC(NC(Nc1ccc(Cl)cc1)=C(C#N)S(C)(=O)=O)C(C)(C)C
Yield: 85 %

Procedure:
3-(4-Chlorophenylamino)-2-methylsulfonyl-3-methylsulfanyl-propenenitrile (0.242 g, 0.8 mmol) was stirred in 1,2,2-trimethylpropylamine (1 ml) for 17 h at 75° C. under nitrogen. Work-up as described in EXAMPLE 17, 2) without chromatography gave 0.240 g (85%) of the title compound. Mp 160.5-161.5° C. 1H NMR (200 MHz, CDCl3): δ=0.87 (s, 9H), 0.97 (d, 3H), 3.1 (m, 4H), 7.07 (d, 1H), 7.49 (d, 2H); Analysis: calc. for C16H22ClN3O2S: C, 54.00%; H, 6.23%; N, 11.81%; Found: C, 54.26%; H, 6.33%; N, 11.76%.
Reaction SMILES: [OH-].[K+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.F[C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]#[N:12]>CS(C)=O>[N:3]1([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: N#Cc1ccccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#Cc1ccccc1-n1ccnc1
Reaction time: 1 h

Procedure:
To a stirred solution of KOH (5.81 g) in DMSO (15 mL) was added imidazole (5.0 g, 73.4 mmol). The mixture was stirred for 1 hour, then 2-fluorobenzonitrile (8.76 mL) in DMSO (10 mL) was added dropwise over 20 minutes. The reaction mixture was stirred at room temperature overnight and the product was collected by filtration and washed with water to afford 10.91 g of 2-(1-imidazolyl)benzonitrile as a white solid.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[CH3:17][C:18]([O:21][C:22]([N:24]1[CH2:31][C:30]2[O:29][C:28]([CH2:32][OH:33])=[N:27][C:26]=2[CH2:25]1)=[O:23])([CH3:20])[CH3:19].[C:34]1(O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CO>[CH3:20][C:18]([O:21][C:22]([N:24]1[CH2:31][C:30]2[O:29][C:28]([CH2:32][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[N:27][C:26]=2[CH2:25]1)=[O:23])([CH3:17])[CH3:19]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1Cc2nc(CO)oc2C1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1Cc2nc(COc3ccccc3)oc2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.3 %

Procedure:
Di-tert-butyl azodicarboxylate (0.079 g, 0.34 mmol) was added portionwise to a stirred solution of 4,6-dihydro-2-(hydroxymethyl)-5H-pyrrolo[3,4-d]oxazole-5-carboxylic acid 1,1-dimethylethyl ester (0.055 g, 0.23 mmol), phenol (0.032 g, 0.34 mmol) and triphenylphosphine (0.090 g, 034 mmol) in THF (1 mL) at 0° C. The mixture was stirred at room temperature for 10 minutes, diluted with MeOH and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 10/90). The desired fractions were collected and evaporated in vacuo to yield 4,6-dihydro-2-(phenoxymethyl)-5H-pyrrolo[3,4-d]oxazole-5-carboxylic acid 1,1-dimethylethyl ester (0.073 g, quantitative yield) as a clear oil that was used in the next step without further purification. C17H20N2O4 LCMS: Rt 3.06, m/z 317 [M+H]+ (using method, LC-MS Method 6).
Reaction SMILES: [NH:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:2]([C:4]([OH:6])=O)[CH3:3].ClC(OCC(C)C)=O.CN1CCOCC1.[F:29][C:30]1[CH:31]=[C:32]([N:37]2[CH:42]=[CH:41][CH:40]=[C:39]([NH2:43])[CH:38]2[NH2:44])[CH:33]=[C:34]([F:36])[CH:35]=1>C(Cl)Cl.O>[C:10]([O:9][C:7](=[O:8])[NH:1][C@@H:2]([CH3:3])[C:4]([NH:43][C:39]1[C:38]([NH:37][C:32]2[CH:33]=[C:34]([F:36])[CH:35]=[C:30]([F:29])[CH:31]=2)=[N:44][CH:42]=[CH:41][CH:40]=1)=[O:6])([CH3:13])([CH3:12])[CH3:11]
Reactant: NC1=CC=CN(c2cc(F)cc(F)c2)C1N
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccnc1Nc1cc(F)cc(F)c1
Reaction time: 0.5 h

Procedure:
Boc-L-Ala-OH (2.05 g, 10.8 mmol) and isobutyl chloroformate (1.4 g, 10.8 mmol) were dissolved in DCM (20 mL) and N-methyl morpholine (1.14 g, 11.3 mmol) was added to at −10° C. and stirred for 30 min. To the mixture was added N1-(3,5-difluorophenyl)-pyridine-2,3-diamine (1.2 g, 5.42 mmol) dissolved in DCM (10 mL). The reaction mixture was stirred at −10° C. for 30 min and then at rt overnight. After completion of the reaction, water (100 mL) was added and the organic layer was extracted with DCM (200 mL), dried over sodium sulfate and concentrated to provide a crude product, which was purified by column chromatography using 100-200 mesh silica gel and 35% EtOAc in hexane to provide (S)-tert-butyl-1-(2-(3,5-difluorophenylamino)pyridine-3-ylamino)-1-oxopropan-2-ylcarbamate: LC-MS (ESI) m/z 393.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=O)=[CH:4][CH:3]=1.[C:14]([C:16]([C:25]#[N:26])=[C:17]1[CH:22]=[C:21]([CH3:23])[O:20][C:19]([CH3:24])=[CH:18]1)#[N:15].N1CCCCC1>C(O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](/[CH:12]=[CH:23]/[C:21]2[O:20][C:19]([CH3:24])=[CH:18][C:17](=[C:16]([C:25]#[N:26])[C:14]#[N:15])[CH:22]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)c2ccccc12
Reactant: CC1=CC(=C(C#N)C#N)C=C(C)O1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC1=CC(=C(C#N)C#N)C=C(/C=C/c2ccc(O)c3ccccc23)O1
Yield: 48.2 %

Procedure:
4-hydroxy-1-naphtaldehyde (0.70 g (5.81 mmol)), 4-(dicyanomethylene)-2,6-dimethyl-4H-pyrane (1.0 g (5.81 mmol)), piperidine (0.50 g (5.81 mmol)), and ethanol (50 mL) were added to a 50-mL three-neck flask. The resultant was heated and refluxed under an argon atmosphere for 6 hours and then the solvent was removed under reduced pressure, followed by purification by column chromatography (SiO2, CHCl3:MeOH=10:1 (v/v)). Thus a desired compound was obtained (yield: 48.2%).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][C:6]1[N:16]2[C:17]3[C:12]([CH2:13][CH2:14][CH2:15]2)=[CH:11][CH:10]=[CH:9][C:8]=3[C:7]=1[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26]>C(Cl)(Cl)Cl>[CH3:26][CH:25]([CH3:27])[C:24]([C:10]1[CH:11]=[C:12]2[C:17]3=[C:8]([C:7]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:6]([CH3:5])[N:16]3[CH2:15][CH2:14][CH2:13]2)[CH:9]=1)=[O:28]
Reactant: CC(C)C(=O)Cl
Reactant: CCOC(=O)Cc1c(C)n2c3c(cccc13)CCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Cc1c(C)n2c3c(cc(C(=O)C(C)C)cc13)CCC2
Temperature: 10 °C
Reaction time: 12 h

Procedure:
63 g of aluminum trichloride were suspended in 150 ml of chloroform at a temperature of 10° C. A mixture of ethyl 5,6-dihydro-2-methyl-4H-pyrrolo[3,2,1-ij]quinoline-1-acetate and 26.3 g of isobutyryl chloride in 150 ml of chloroform was added to the suspension while the temperature was maintained at 10° C. The reaction mixture was stirred at room temperature for hour, then heated under reflux for 4 hours and kept at room temperature for a further 12 hours. A further 10 g of aluminum chloride were then added, and the mixture was heated under reflux for a further hour. The reaction mixture was worked up by pouring it onto ice and then extracting with dichloromethane. The organic phase was washed with dilute aqueous sodium hydroxide solution, then washed with water until neutral, dried and concentrated. 80 g of crude product were obtained, which was purified by chromatography on a silica gel column using dichloromethane as the eluent. 42.5 g of ethyl 5,6-dihydro-8-(2-methyl-1-oxopropyl)-2-methyl-4H-pyrrolo[3,2,1-ij]quinoline-1-acetate were obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:23][NH2:24])([N:14]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:26][C:27]1[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=1[C:29](OC)=[O:30].C(N(CC)CC)C>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:23][N:24]2[CH2:26][C:27]3[C:28](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:29]2=[O:30])([N:14]2[CH2:19][CH2:18][N:17]([CH:20]3[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1(N2CCN(C3CC3)CC2)CCN(Cc2ccccc2)CC1
Reactant: COC(=O)c1ccccc1CBr
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C1c2ccccc2CN1CC1(N2CCN(C3CC3)CC2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 51 %

Procedure:
To a solution of (1-benzyl-4-(4-cyclopropylpiperazin-1-yl)piperidin-4-yl)methanamine (see above: synthesis of amine AM12) (1.22 mmol, 1.0 equiv.) and methyl 2-(bromomethyl)benzoate (1.22 mmol, 1.0 equiv.) in benzene (3 ml/mmol) was added triethylamine (2.44 mmol, 2.0 equiv.) and the resulting reaction mixture was refluxed for 25 h. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and the organic layer was successively washed with water and brine. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure to give the crude product which was purified by silica gel column chromatography. Yield: 51%.
Reaction SMILES: [NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:2]([C:7]([CH:9]=[N+]=[N-])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[ClH:19]>CCOCC>[NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:2]([C:7]([CH2:9][Cl:19])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: Cl
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)C=[N+]=[N-]
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)CCl
Reaction time: 0.08 h

Procedure:
Boc-LeuCHN2 (4.40 g, 17.2 mmoles) was dissolved in 50 mL of ether and cooled to 0°; anhydrous 3.45N ethanolic:HCl (5.22 mL, 18.0 mmoles) was added. After about 5 minutes, the resulting solution was washed with cold water, saturated aqueous sodium chloride, and was dried over anhydrous sodium sulfate. Solvent was evaporated to yield crystalline Boc-LeuCH2Cl. Product was isolated and washed with petroleum ether to yield 0.84 g (mp 65°-66°) in a first crop and 1.94 g (mp 64°-65.5°) in a second crop isolated from cold petroleum ether.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]([O:18][C:19]([N:21]1[CH2:25][C@H:24]([OH:26])[CH2:23][C@H:22]1[C:27](=[O:31])[N:28]([CH3:30])[CH3:29])=[O:20])([CH3:17])([CH3:16])[CH3:15].N1C=CC=CC=1>C(Cl)Cl>[C:14]([O:18][C:19]([N:21]1[CH2:25][C@H:24]([O:26][S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])[CH2:23][C@H:22]1[C:27](=[O:31])[N:28]([CH3:29])[CH3:30])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)OC(C)(C)C
Temperature: 4 °C
Reaction time: 16 h
Yield: 40.2 %

Procedure:
4-Nitrobenzenesulfonyl chloride (0.895 g) was added to a stirred solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxy-2-(N,N-dimethylcarbamoyl)pyrrolidine (0.993 g) and pyridine (0.6 g) in methylene chloride (10 ml) and stirred at 4° C. for 16 hours under an atmosphere of nitrogen. The reaction mixture was washed with aqueous citric acid (1.0 M), saturated sodium bicarbonate and dried over magnesium sulfate. The product was then purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 95/5). The fractions containing the required product were combined and evaporated under vacuum to give (2S,4R)-1-(tert-butoxycarbonyl)-2-(N,N-dimethylcarbamoyl)-4-[(4-nitrophenyl)sulfonyloxy]pyrrolidine as a yellow gum (0.685 g); 1H NMR Spectrum: (DMSO d6) 1.30-1.36 (s, 9H), 1.98-2.07 (m, 1H); 2.37-2.48 (m, 1H); 2.83 (s, 3H), 3.00 (s, 3H), 3.45-3.55 (m, 2H), 4.70 (m, 1H), 5.23 (m, 1H), 8.21 (d, 2H), 8.47 (d, 2H).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[CH:19][C:20]([O:22]C)=[O:21])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+].O.Cl>O1CCCC1.C(OCC)(=O)C>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2ccc(C=CC(=O)OC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2ccc(C=CC(=O)O)cc2)cc1
Yield: 104.8 %

Procedure:
To a mixture of Methyl 3-[4-(4-pentylphenyl)phenyl]acrylate (0.41 g) in tetrahydrofuran (5ml) was added 3N NaOH aqueous solution (1.3 ml), and the resultant mixture was heated to 85° C. for 10 hours. The reaction mixture was poured into a mixture of cold water and ethyl acetate, and adjusted to about pH 2 with 6N hydrochloric acid. The separated organic layer was washed in turn with water and brine, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 3-[4-(4-Pentylphenyl)phenyl]acrylic acid (0.41 g).