Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[C:21]1([CH3:29])[CH:26]=[CH:25][C:24]([NH:27]N)=[CH:23][CH:22]=1.Cl>>[C:14]1([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:27]([C:24]4[CH:25]=[CH:26][C:21]([CH3:29])=[CH:22][CH:23]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Agent: Cl
Product: Cc1ccc(-n2nccc2-c2nn(-c3ccccc3)ccc2=O)cc1
Yield: 67 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and p-tolylhydrazine×HCl according to the method described for Example 1 in 67% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:16]=2)[C:11]([OH:13])=O)=[N:6][CH:7]=1.Cl.Cl.[CH3:25][C:26]1[N:31]=[CH:30][C:29]([C@H:32]([NH2:34])[CH3:33])=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)[CH:16]=2)[C:11]([NH:34][C@@H:32]([C:29]2[CH:30]=[N:31][C:26]([CH3:25])=[CH:27][CH:28]=2)[CH3:33])=[O:13])=[N:6][CH:7]=1
Reactant: Cc1ccc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)O)c2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(5-methylpyridin-2-yl)-5-(thiazol-2-yloxy)benzoic acid (40 mg, 0.13 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (60 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol), and N,N-diisopropylethylamine (400 μL, 2.3 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a light brown solid.
Reaction SMILES: [CH3:1][OH:2].[CH2:3]1[CH2:7]O[CH2:5][CH2:4]1>C1C=CC=CC=1>[CH2:3]([C:7]1[CH:5]=[CH:4][CH:3]=[CH:7][C:1]=1[OH:2])[CH:4]=[CH2:5]
Reactant: C1CCOC1
Reactant: CO
Solvent: c1ccccc1
Product: C=CCc1ccccc1O
Temperature: 148.88888888888889 °C

Procedure:
200 g of linear (NPCl2)n in benzene (total volume is about 2400 ml) is added (20 to 30 minutes) the alkyl or aryloxides prepared in a) in 1200 ml of THF and 2500 ml of benzene. The reaction mixture is then stirred at about 300° F. for twenty-four hours. Upon cooling, the polymer is coagulated by pouring into a ten gallon can containing two gallons of methanol with agitation. The solvents are then drawn off. Additional methanol may be added if the polymer does not separate cleanly from the solution. The solid, as free as possible of solvent, is then desalted by washing with water. The resulting chlorine-free polymer is dried at 50° to 60° C. under vacuum.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: C1CCNCC1
Product: Brc1cccc(CN2CCCCC2)n1
Yield: 82.7 %

Procedure:
The title compound was prepared in a manner similar to that described in Example 18, Step C, using 6-bromo-pyridine-2-carbaldehyde (0.406 g, 2.18 mmol) and piperidine (0.186 g, 2.18 mmol). The crude product was purified (SiO2: 0-4% 2 M NH3 in MeOH/DCM) to provide the title compound (0.46 g, 83%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[C:1]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
Methoxyaryl 1i can be coupled with benzoyl chloride 2i, either commercially available or prepared in situ from the corresponding benzoic acid, using a Lewis acid, typically AlCl3 or the like, to give benzophenone product 3i. Reduction of 3i can be accomplished by triethylsilane and an appropriate protic or Lewis acid, typically trifluoroacetic acid or borontrifluoroetherate, to give arylbenzyl 4i.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][NH2:32])[CH2:21]1.C(N(C(C)C)CC)(C)C>C(#N)C>[NH2:32][CH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH:22]1[CH2:23][CH2:24][N:20]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]3[CH:12]3[CH2:14][CH2:13]3)=[CH:4][C:3]=2[F:19])[CH2:21]1
Reactant: NCc1ccccc1C1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: NCc1ccccc1C1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Temperature: 25 °C
Yield: 43.2 %

Procedure:
A suspension of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1.13 g, 4.0 mmol), 2-(3-pyrrolidinyl) benzenemethanamine (1.25 g, 5.0 mmol), and a diisopropylethylamine (2.07 g, 16.0 mmol) in acetonitrile (50 mL) was heated at gentle reflux for 24 hours. The suspension was allowed to cool to room temperature; the precipitated solids were filtered, washed successively with cold acetonitrile and ether, and dried in vacuo to give the title compound (0.73 g, 43%) as a white solid, after recrystallization from methanol, mp 226°-228° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([I:13])=[C:6]2[CH:12]=[CH:11][NH:10][C:7]2=[N:8][CH:9]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>CN(C)C=O>[Cl:3][C:4]1[C:5]([I:13])=[C:6]2[CH:12]=[CH:11][N:10]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[C:7]2=[N:8][CH:9]=1
Reactant: Clc1cnc2[nH]ccc2c1I
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(I)c(Cl)cnc32)cc1
Reaction time: 0.5 h

Procedure:
To an ambient suspension of sodium hydride (0.560 g, 23.34 mmol) in N,N-dimethylformamide (40 mL) was added a solution of 5-chloro-4-iodo-1H-pyrrolo[2,3-b]pyridine (5.0 g, 17.95 mmol) (Example 1E) in N,N-dimethylformamide (10 mL) slowly. The reaction was stirred for 0.5 hours, and a solution of para-toluenesulfonyl chloride (3.59 g, 18.85 mmol) in N,N-dimethylformamide (8 mL) was added. The reaction was stirred for 1 hour and was then quenched by pipetting the reaction portionwise into water (50 mL) with vigorous stirring. The solid was filtered and air-dried to give the title compound as a solid. MS ESI(+) m/z 433 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:10][CH3:11])=[CH:7][C:8]#[N:9])=[CH:4][CH:3]=1.[Br:14]Br.O1CCCC1>C(Cl)(Cl)(Cl)Cl>[Br:14][C:7](=[C:6]([NH:10][CH3:11])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=1)[C:8]#[N:9]
Reactant: BrBr
Reactant: CNC(=CC#N)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CNC(=C(Br)C#N)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A solution of p-chloro-β-(methylamino)cinnamonitrile (19.3 g, 0.1 mol) in carbon tetrachloride at 70° C. is treated dropwise with a solution of bromine (16.8 g, 0.105 mol) in carbon tetrachloride over a 30-40 minute period (tetrahydrofuran is added as needed during the bromine addition to aid dissolution of the reaction mixture). The reaction mixture is stirred for 30 minutes at 70° C., cooled to room temperature and concentrated to give a yellow crystalline precipitate. The mixture is filtered, the filter cake is washed with carbon tetrachloride and dried to give the title product as a yellow solid, 18.8 g (69% yield), mp 178.0°-178.5° C., identified by IR, NMR and mass spectral analyses.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[C:10]2[C:5](=[CH:6][C:7]([O:28][CH3:29])=[C:8]([O:26][CH3:27])[CH:9]=2)[N:4]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(O)C>[CH3:27][O:26][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:28][CH3:29])[N:4]=[C:3]([CH2:2][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccccc1OC
Solvent: CCO
Product: CCOC(=O)c1c(CN2CCOCC2)nc2cc(OC)c(OC)cc2c1-c1ccccc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.7 %

Procedure:
A mixture of ethyl 2-chloromethyl-6,7-dimethoxy-4-(2-methoxyphenyl)quinoline-3-carboxylate (1.0 g), morpholine (1.25 g) and ethanol (13 ml) was stirred at room temperature for 3 days. The precipitated crystals were separated by filtration and recrystallized from ethyl acetate-hexane to give ethyl 6,7-dimethoxy-4-(2-methoxyphenyl)-2-morpholinomethylquinoline-3-carboxylate (0.76 g, 68%). Colorless prisms, mp. 153°-154° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH:23]([NH:26][CH3:27])([CH3:25])[CH3:24]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:26]([CH:23]([CH3:25])[CH3:24])[CH3:27])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Reactant: CNC(C)C
Product: CC(C)N(C)CCCCOc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and N-Isopropylmethylamine were converted to yield {4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-isopropyl-methyl-amine, MS: 389 (MH+, 1Cl).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH:24]([NH:26][CH2:27][C@@H:28]([C:30]2[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=2)[OH:29])[CH3:25])=[CH:17][CH:16]=1.I.[NH2:38][C:39]1[C:40]([C:47]([NH:49][C:50](=[NH:53])SC)=[O:48])=[N:41][C:42]([Cl:46])=[C:43]([NH2:45])[N:44]=1>C(O)C>[NH2:38][C:39]1[C:40]([C:47]([NH:49][C:50](=[NH:53])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH:24]([NH:26][CH2:27][C@H:28]([OH:29])[C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=3)[CH3:25])=[CH:19][CH:20]=2)=[O:48])=[N:41][C:42]([Cl:46])=[C:43]([NH2:45])[N:44]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(CCCc1ccc(CCCCN)cc1)NC[C@H](O)c1cccc(O)c1
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(CCCc1ccc(CCCCNC(=N)NC(=O)c2nc(Cl)c(N)nc2N)cc1)NC[C@H](O)c1cccc(O)c1
Temperature: 75 °C
Reaction time: 4.5 h
Yield: 30.4 %

Procedure:
Diisopropylethylamine (0.45 mL, 2.58 mmol) was added to a mixture of amino alcohol 142 (0.63 g, 1.69 mmol) and 1-(3,5-diamino-6-chloropyrazine-2-carbonyl)-2-methylisothiourea hydriodide (0.66 g, 2.58 mmol) in absolute ethanol (10 mL). The mixture was stirred at 75° C. (oil bath) for 4.5 h. After this time the mixture was cooled to rt and the solvent was removed by rotary evaporation. Purification by column chromatography (silica gel, a gradient of 5:95 to 10:90 methanol/dichloromethane, followed by a gradient of 5:95 to 10:90 (10% concentrated aqueous ammonium hydroxide/methanol)/dichloromethane) and subsequent drying in a 40° C. vacuum oven for 88 h afforded the phenol derivative 143 (0.30 g, 30% yield) as a yellow solid: mp 82-86° C.; 1H NMR (500 MHz, DMSO-d6) δ 0.93 (dd, 3H, J=6.0, 3.5 Hz), 1.21-1.28 (m, 1H), 1.32-1.40 (m, 1H), 1.49-1.60 (m, 6H), 1.75 (s, 1H), 2.49-2.66 (m, 5H), 3.11-3.19 (m, 2H), 4.44-4.48 (m, 1H), 5.17 (br s, 1H), 6.59-6.72 (m, 6H), 7.06-7.11 (m, 5H), 9.09 (br s, 1H); m/z (ESI) 583 [C29H39ClN8O3+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14](O)[CH2:15][CH2:16][CH:17]([C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[OH:18])[CH:6]=[C:7]([I:13])[C:8]=1[O:9][CH2:10][CH2:11][OH:12].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:14]2[CH2:15][CH2:16][C@H:17]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)[O:18]2)[CH:6]=[C:7]([I:13])[C:8]=1[O:9][CH2:10][CH2:11][OH:12]
Reactant: COc1cc(C(O)CCC(O)c2cc(OC)c(OC)c(OC)c2)cc(I)c1OCCO
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(I)c1OCCO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 1-(3-methoxy-4-hydroxyethoxy-5-iodophenyl)-4-(3,4,5-trimethoxyphenyl)-1,4-butanediol (11.8 g, 21.5 mmol) in chloroform (100 mL) at 0° C. was added dropwise trifluoroacetic acid (9.82 g, 86.1 mmol) in chloroform (100 mL) over 30 minutes. The solution was stirred at 0° C. for 2 hours and then at room temperature for 1 hour. The reaction mixture was quenched with 1N NaOH and chloroform (100 mL) was added. The organic layer was washed with 1N NaOH solution, water and saturated NaCl solution, and then dried over MgSO4, filtered and evaporated in vacuo to an oil which was a cis and trans mixture. The trans isomer was isolated by column chromatography (silica, 1:1 hexane/ethyl acetate) (4.7 g, 41.4%) as the faster eluting isomer. 1H NMR (CDCl3): 1.99 (m, 2H); 2.47 (m, 2H); 3.83 (t, 2H); 3.84 (s, 3H); 3.87 (s, 3H); 3.89 (s, 6H); 4.16 (t, 2H); 5.18 (m, 2H), 6.62 (s, 2H); 6.96 (d, 1H); 7.39 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[CH3:1][C:2]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][N:4]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH2:3]1
Reactant: CCOC(=O)C1(C)CCCNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(C)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 65 °C
Reaction time: 6 h
Yield: 83.1 %

Procedure:
To a round bottom flask was added ethyl 3-methylpiperidine-3-carboxylate (2.040 g, 11.91 mmol), 1-fluoro-4-nitrobenzene (1.765 g, 12.51 mmol), DMF (20 ml) and K2CO3 (2.140 g, 15.49 mmol). The reaction was stirred at 65° C. for 6 hrs. After this time, the reaction was diluted with EtOAc. The resulting solution was washed with water (2×) and saturated aqueous NaCl. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The resulting residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-30% EtOAc/Hex to give product, ethyl 3-methyl-1-(4-nitrophenyl)piperidine-3-carboxylate (2.922 g, 9.90 mmol, 83% yield) as a yellow oily residue. Anal. Calcd. for C15H20N2O4 m/z 292.3, found: 293.2 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.10 (d, J=9.34 Hz, 2 H), 6.87 (d, J=9.34 Hz, 2 H,) 4.18 (d, J=13.19 Hz, 1 H), 4.11 (q, J=7.15 Hz, 2 H), 3.80-3.58 (m, 1 H), 3.00 (s, 1 H), 2.90 (d, J=13.19 Hz, 1 H), 2.40-2.23 (m, 1 H), 1.75 (dd, J=8.52, 4.12 Hz, 2 H), 1.42 (s, 1 H), 1.26-1.14 (m, 6 H).
Reaction SMILES: [CH:1]([N:4]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)([CH3:3])[CH3:2].[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24]([OH:29])=[CH:23][C:22]=2[O:21]1>N1C(C)=CC(C)=CC=1C.C(OCC)(=O)C>[CH:14]1([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:13])[C:6]2[CH:11]=[CH:10][C:9]([O:29][C:24]3[CH:25]=[CH:26][C:27]4[O:28][CH2:20][O:21][C:22]=4[CH:23]=3)=[CH:8][CH:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC(C)N(C(=O)c1ccc(Br)cc1)C1CCCCC1
Reactant: Oc1ccc2c(c1)OCO2
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCOC(C)=O
Product: CC(C)N(C(=O)c1ccc(Oc2ccc3c(c2)OCO3)cc1)C1CCCCC1

Procedure:
The reaction was carried out in the same manner as described in Example 1 using p-bromobenzoic acid N-isopropyl-N-cyclohexyl amide (2.904 g, 8.96 mmol), 3,4-methylenedioxyphenol (1.354 g, 9.80 mmol) and cuprous oxide (641 mg, 4.48 mmol) in 2,4,6-collidine (15 ml). After 24 hr of refluxing, the reaction was cooled, diluted with ethyl acetate, and extracted with 0.5N HCl. A precipitate that formed on extraction was filtered and the aqueous filtrate was re-extracted with ethyl acetate. The organic layers were combined and washed three times with 6N HCl, twice with H2O, three times with 5% NaOH, twice with H2O and dried (Na2SO4) The drying agent was removed by filtration, and the filtrate concentrated in vacuo to give the crude product as a black oil. This was chromatographed on silica gel using mixtures of ethyl acetate and hexane as eluents to give the title compound as an oil.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:11]([C:27](O)=[O:28])[C:10]=2[C:30](O)=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:33]([O:35][C:36](=[O:45])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=1)[CH3:34].O>C(O)(=O)C>[CH2:33]([O:35][C:36](=[O:45])[CH2:37][C:38]1[CH:39]=[CH:40][C:41]([N:44]2[C:27](=[O:28])[C:11]3[C:12]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]4=[C:9]([O:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:10]=3[C:30]2=[O:31])=[CH:42][CH:43]=1)[CH3:34]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: O=C(O)c1c(C(=O)O)c(OCc2ccccc2)c2ccccc2c1OCc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCc4ccccc4)c4ccccc4c3OCc3ccccc3)C2=O)cc1
Reaction time: 8 h
Yield: 99.4 %

Procedure:
A mixture of 1,4-bis[(phenylmethyl)oxy]-2,3-naphthalenedicarboxylic acid (2.0 g, 4.67 mmol) and ethyl(4-aminophenyl)acetate (1.67 g, 9.35 mmol) were heated to 120° C. in acetic acid (30 ml) for 2 hours. The mixture solidified on standing at room temperature overnight. Water was added and the solid collected by filtration and washed with water. This was dried under vacuum to give the title compound (2.65 g, 4.64 mmol). LC/MS: Rt=4.24, [MH]+ 572.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9](/[CH:12]=[CH:13]/[CH2:14][CH2:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:24]([CH:29](CO)[CH2:30][OH:31])CCCC.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9](/[CH:12]=[CH:13]/[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH:20]3[O:31][CH2:30][CH2:29][CH2:24][O:21]3)=[CH:22][CH:23]=2)[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCC(CO)CO
Reactant: CCCCC[C@H]1CC[C@H](/C=C/CCc2ccc(C=O)cc2)CC1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCCC[C@H]1CC[C@H](/C=C/CCc2ccc(C3OCCCO3)cc2)CC1
Reaction time: 2 h

Procedure:
a solution of 3 g of 4-[4E-(trans-4-pentylcyclohexyl)-3-butenyl]benzaldehyde and 1.7 g of 2-pentyl-1,3-propanediol in 50 ml of toluene was treated with 2 drops of 10% (vol.) sulphuric acid. The mixture was heated to boiling for 2 hours, whereby the resulting water was simultaneously distilled off. Then, 4 drops of triethylamine were added to the reaction mixture. After cooling the mixture was washed with 50 ml of 1N sodium hydrogen carbonate solution and twice with 50 ml of water each time, dried over magnesium sulphate, filtered and subsequently concentrated. Chromatography of the residue on silica gel with toluene and recrystallization from acetone gave 1.2 g of trans-5-pentyl-2-(4-[4E-(trans-4-pentylcyclohexyl)-3-butenyl]phenyl-1,3-dioxane.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][C:25](=[O:30])[CH2:24]4)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(Cl)cc2)CC1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Product: O=C1Cc2cc(NC(=O)C(=O)N3CCC(Cc4ccc(Cl)cc4)CC3)ccc2N1

Procedure:
The title compound is prepared from [4-(4-chloro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 33b) and 5-amino-1,3-dihydro-indol-2-one according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 195° C. (isopropanol-diethyl ether)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH2:12]([O:14][C:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)=[O:16])[CH3:13].C([O-])([O-])=O.[Na+].[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>O1CCOCC1.C(OCC)(=O)C>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:21]2[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=2)[C:15]([O:14][CH2:12][CH3:13])=[O:16])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc(-c2cnc(N)c([N+](=O)[O-])c2)c1
Temperature: 90 °C
Reaction time: 10 h
Yield: 75.5 %

Procedure:
To a solution of 5-bromo-3-nitropyridin-2-amine (5.00 g, 23.97 mmol) in dioxane (115 mL) was added 3-(ethoxycarbonyl)phenylboronic acid (4.65 g, 23.97 mmol) and 1N Na2CO3 aqueous solution (92.2 mL, 92.2 mmol). The reaction mixture was degassed using Argon gas for 20 min followed by the addition of dichlorobis(triphenylphospine) palladium(II) (971 mg, 1.38 mmol) and 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (881 mg, 2.07 mmol). The reaction flask was put into the preheated oil-bath at 90° C. The reaction mixture was further stirred at 90° C. for a period of 10 h after which it was filtered and partitioned between ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography using a 90:10 v/v hexane:ethyl acetate as solvent to afford ethyl 3-(6-amino-5-nitropyridin-3-yl)benzoate (5.2 g, 78% yield) as a tan solid.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:8]=1)=O.[CH3:27][C:28]([CH3:33])([CH3:32])[CH2:29][NH:30][NH2:31]>CO>[CH3:27][C:28]([CH3:33])([CH3:32])[CH2:29][N:30]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[CH:16][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=[N:31]1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(N3CCOCC3)cc2)ccc1=O
Reactant: CC(C)(C)CNN
Solvent: CO
Product: CC(C)(C)Cn1nccc1-c1nn(-c2ccc(N3CCOCC3)cc2)ccc1=O
Yield: 22.4 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-morpholin-4-ylphenyl)pyridazin-4(1H)-one (300 mg, 0.85 mmol) in 20 mL of methanol, 2,2-dimethylpropylhydrazine (346 mg, 3.39 mmol) was added, the resulting mixture was refluxed for 4 hours, and then concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1 M acetic acid aqueous solution and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give the title compound (75 mg, 22% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3): δ 0.83 (9H, s), 3.22-3.25 (4H, m), 3.88-3.90 (4H, m), 4.41 (2H, s), 6.70 (1H, d, J=7.6 Hz), 7.00 (2H, d, J=9.2 Hz), 7.08 (1H, d, J=2.0 Hz), 7.45 (2H, d, J=9.2 Hz), 7.58 (1H, d, J=2.0 Hz), 8.14 (1H, d, J=8.0 Hz); LCMS (mobile phase: from 70% water and 30% CH3CN to 5% water and 95% CH3CN in 6 min, finally under these conditions for 0.5 min.) purity is >95%, Rt=2.656 min; MS Calcd.: 393, MS Found: 394 (M++H).